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One microorganism can cause 1, 2, 3 or many more clinical symptoms. The bacteria vibrio cholerae is a curved gram-negative bacteria that causes cholera. Cholera is an epidemic in many countries, mainly where hygiene is a problem. The bacterium has several characteristics:Is a vibrio → is curvedHas a flagellum → makes rapid movements possibleThe bacterium is spread by drinking contaminated water or direct contact between people. Not everyone who is a carrier becomes sick, but people with acid-inhibitors, elderly and children are more susceptible.It is a non-invasive micro-organism → it doesn't cause inflammation or fever. There is no host response involved, but it does produce a cholera toxin. It is a toxin-mediated disease, which causes hyperactivity of the cell → pumps which pump water and elektrolytes out of the cell are activated:The cholera toxin can bind to the membrane of the villi via a G-proteincAMP is activated irreversibly in the cellcAMP leads to an active secretion of kalium, natrium, chloride, bicarbonate and water → results in a watery diarrheaThis is called rice water stoolThe pumps can pump up to 15 L a day. This can cause dehydration and a low blood pressure, especially among children. The taenia species is a species of tapeworms in the bowel. Humans are the definitive host. The worms make eggs, which can be eaten by cows, causing the taenia to reproduce. Cows are the intermediary host → when a person eats raw cow meat, they can become infected. Another taenia species is taenia solium. The legionella bacterium is a gram-negative bacterium that is very small. Legionella pneumophila can lead to 2 diseases:PneumoniaIf someone is T-cell immunocompromisedPontiac feverLegionella survives in the cell → it needs help from T-cells to be destroyedThe legionella...
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Mechanisms of Disease 1 2020/2021 UL
Mechanisms of Disease 1 HC1: Introduction to G2MD1
HC1: Introduction to G2MD1
There are 7 basic mechanisms of disease:
- Acute and chronic inflammation
- Disordered immunity
- Immunodeficiency
- Immunopathology
- Cell tissue injury and repair
- Haemodynamic disorders
- Growth disorders
- Neoplastic
- Non-neoplastic
- Metabolic and degenerative disorders
- Congenital abnormalities
- Genetic
- Non-genetic
Mechanisms of Disease 1 HC2: Introduction to the immune system
HC2: Introduction to the immune system
Narcolepsy
Narcolepsy is a neurological disorder linked to HLA and autoimmunity. When a narcolepsy-patient is excited, his muscles relax and he passes out.
Defense mechanisms
The human body is challenged by many different types of pathogens, which trigger different immune responses. The body is made of a very firm physical and chemical barrier, which prevents pathogens from invading and taking over. The basic defense mechanisms of the body are organized in 3 layers:
- Physical barriers
- Innate immune system
- Adaptive immune system
Physical barrier
The physical barrier prevents bacteria from entering the body. This is mostly done by commensal flora, specific bacteria which protect the body. Epithelia form a tough impenetrable barrier which lines the outer surface and inner cavities of the body, for example:
- Respiratory tract: various airway epithelial functions collectively form a major host defense
- Cilia ensure that pathogens are moved upwards
- Skin: contains a stratum corneum which makes it even harder for pathogens to enter
- Gastro-intestinal tracts: contain goblet cells → mucus production
- Goblet cells are large white cells
- Mucus contains antibacterial enzymes
- Urine tracts
The human body itself also possesses many bacteria, which aren't damaging but protect the body from intruders. They ensure that other bacteria don't colonize.
Innate immune system
The innate immune system delays pathogenic replication and spreading until the adaptive immune system can take over. Without the innate immune system, spreading of the pathogen can't slow down. Without the adaptive immune system, the pathogen can't die completely.
In case of an injury, the physical barrier is damaged → intruders can easily enter the body. As a result, the innate immune system is switched on. The innate immune system is pre-programmed → it is activated quickly, a few hours after the pathogen has entered. The innate immune system blocks about 95% of the pathogen-attacks. It isn't a changeable system → it can only process certain pathogens with a limited amount of receptors and proteins.
Leukocytes
Leukocytes are white blood cells. Blood usually contains 4,5-109leukocytes/L. The morphology and normal distribution of leukocytes in blood has certain properties:
- Eosinophils (5)
- Color depends on liquid used
- 1-6% of leukocytes
- Monocytes (2)
- Relatively large
- 2-10% of leukocytes
- Coffee-bean shaped big nuclei
- Produced daily
- Can stay in tissue for months-years
- Neutrophils (3,4)
- Produced continuously by the bone marrow
- 40-75% of leukocytes
- Only survive for 1-2 days in tissue once they have left the bloodstream
- Segmented nuclei
- Lymphocytes (1)
- Can stay in tissue for months
- 20-50% of leukocytes
- Relatively small volume of cytoplasm
- Relatively large nucleus
- Basophils (6)
- Play an important role in allergic responses
- <1% of leukocytes
Origin of immune cells:
White blood cells can be created in 3 different ways. All leukocytes originate from hematopoietic stem cells, which reside in the bone marrow:
- Lymphoid line: hematopoietic stem cell → common lymphoid
Mechanisms of Disease 1 HC3: Innate and adaptive immune responses & key cytokines
HC3: Innate and adaptive immune responses & key cytokines
Barriers
There are 3 barriers that form the body's defense mechanism:
- Mechanical barriers
- Chemical barriers
- Microbiological barriers
If the barrier is breached, the innate immune response kicks in. It recognizes that a pathogen has invaded the body and tries to innate it. If the innate immune system cannot destroy the pathogen immediately, it will continue with the induced response. It attracts more lymphocytes to the area of infection → inflammation. When this still isn't enough to destroy the pathogen, the adaptive immune system is activated. B- and T-cells are activated to combat the pathogens. If this doesn't work, the infection becomes chronic or can lead to death.
Innate versus adaptive immune response
Different aspects of the immune system are deployed depending on the type of infection and the location:
| Innate | Adaptive |
Phylogeny | All multicellular organisms | Only vertebrates |
Location | Mainly body surfaces | Mainly lymph nodes and spleen |
Specificity | Broad (shared structures) | Specific (single antigens and epitopes) |
Speed | Immediate/early response | Delayed/later response |
Memory | None | Stronger and quicker repeated response |
Components
Innate immunity has different components divided into 3 categories:
- Barriers
- Soluble proteins
- Cytokines
- Complement system
- Defensins (antimicrobial peptides)
- Inter-related soluble protein systems
- Lipid inflammatory mediators
- Cells
- NK-cell
- Monocyte, macrophage, dendritic cell
- Neutrophil
- Eosinophil
- Basophil
- Mast cell
5 stages
An innate immune response has 5 stages:
- Recognition of infection or damage
- The immune system distinguishes "self" from "non-self": macrophage receptors recognize the cell-surface carbohydrates of bacterial cells but not those of human cells
- The macrophage expresses several receptors specific for bacterial constituents: pattern recognition receptors (PRR) are activated by pathogen-associated molecular patterns (PAMPs)
- For example Toll-like receptors
- Recruitment of cells and soluble proteins
- Elimination of the microbe
- Binding of the pathogen to phagocytic receptors on macrophages induces its engulfment and degradation
- Binding of pathogen components to pathogen recognition receptors on macrophages induces the synthesis of inflammatory cytokines
- Resolution of inflammation, repair and return to homeostasis
- Induction of adaptive immunity if necessary
Acute inflammatory response:
Cytokines cause the acute inflammatory response. There are many types of cytokines with many different functions, but they all result in inflammation at the infected place:
- IL-1band TNF-a: induce blood vessels to become more permeable, enabling effector cells and fluid containing soluble effector molecules to enter the infected tissue
- IL-6: induces fat and muscle cells to metabolize, make heat and raise the temperature in the infected tissue
- CKCL8: recruits neutrophils from the blood and guides the to the infected tissue
- IL-12: recruits and activates NK-cells that in turn secrete
Mechanisms of Disease 1 HC4: Pathology of normal immune response
HC4: Pathology of normal immune response
Techniques to visualize diseased tissue
Pathology always starts with tissue:
- Biopsies
- Resections
- Autopsies
3 techniques can be combined to make a final diagnosis:
- Immunohistochemical techniques
- Possible to make a diagnosis in an hour
- Tissue is frozen
- Light microscopy
- Most important
- A tissue specimen goes into a paraffine block to make very thin slices → the slices are stained
- Glomeruli of a healthy kidney have silver staining
- In case of chronic inflammation, blue dots are present → lymfocytes
- Electron microscopy
- Used to look for details
- For example podocytes
- Used to look for details
Myocardial infarction:
Normal light microscopy of the heart shows that all cells have a nucleus (the heart is a muscle). Many blood vessels and few lymphocytes are present. A myocardial infarction is an ischemic injury, usually caused by a thrombus in a coronary artery:
- Cell death: necrosis of myocytes
- Hours after the incident
- Cardiomyocytes lose their nucleus
- Neutrophils are the first leukocytes to arrive to clean up the necrotic tissue
- Inflammatory reaction with neutrophilic granulocytes
- Days after the incident
- Ischemic tissue is infiltrated massively by cells with lobulated nuclei → neutrophilic granulocytes
- Fibroblast proliferation: remodeling of connective tissue through collagen disposition
- Weeks after the incident
- Fibrotic tissue is starting to replace the dead cells
- Scar formation
- Months after the incident
This is a general mechanism that can be applied in all tissues → the same process can happen in inflamed skin or lung tissue.
Histomorphology of inflammatory cells and their markers
Inflammatory cells have a distinct histomorphology:
- Granulocytes
- Indicate an acute infection or inflammatory process
- Polymorphonuclear cells
- Neutrophils
- Most frequent
- Eosinophils
- Less frequent
- Basophils
- Very rare
- Neutrophils
- Marker: MPO
- Lymphocytes
- Are associated with chronic processes
- Dark nuclei
- Small cytoplasm
- Mononuclear cells
- Markers
- CD3: entire population
- CD8: cytotoxic T-cells
- CD4: T-helper cells
- Plasma cells
- Produce antibodies
- Pericentric nucleus
- B-cells
- Marker: CD20
- Macrophages
- Large cells
- Present to clean up the mess → digest all sorts of things
- May turn into multinucleated cells
- Marker: CD68
- Other cells
- Dendritic cells
- Fibroblasts
- Histiocytes
Visualizing what one cannot directly see
Some questions cannot be answered by "just" looking at light microscopy:
- How can B-cells be distinguished from T-cells?
- Is the complement system involved?
- Are these large cells indeed macrophages or are they tumor-cells?
- Is there a SARS-CoV2 related protein in this cell?
- Are immune complexes involved?
Immunohistochemistry:
Immunohistochemistry is a technique which makes it possible to visualize proteins in tissue. Proteins are stained with a color. This is done by picking an antibody that fits nicely into the protein and then adding color to it.
This technique can be used to visualize B- and T-cells in
.....read more
Mechanisms of Disease 1 HC5: B- and T-cell generation and diversity
HC5: B- and T-cell generation and diversity
Diverse repertoire
A diverse repertoire is necessary because humans are exposed to many different pathogens:
- Innate immunity can react to some constant properties of pathogens
- Adaptive immunity should respond to all possible pathogens, previously encountered and new
- Adaptive immunity shows a high degree of antigen specificity
- Adaptive immunity shows memory and is able to improve upon re-exposure
Antigen specificity:
B- and T-cells play a very important part in adaptive immunity. The difference between B-cells and T-cells is obvious:
- B-cells: host defense against extracellular pathogens
- T-cells: host defense against intracellular pathogens
Both cells are characterized by receptors on the surface which have specificity for one antigen → one cell has one specificity. This makes it possible for cells to respond do different pathogens.
B-cell receptors and secreted antibodies
Immunoglobulin:
Antibodies are also known as immunoglobulin (Ig). They are large, Y-shaped proteins produced by B-cells to neutralize pathogens. Antibodies recognize unique molecules of the pathogen → antigens. Antibodies can occur in 2 physical forms:
- Soluble form: has been secreted from the cell to be free in the blood plasma
- Membrane-bound form: the B-cell receptor
Every B-cell has a B-cell receptor → a surface immunoglobulin protein which is attached to the membrane of the B-cell. The B-cell receptor has a transmembrane region with which it signals to B-cells. When an antigen binds to the immunoglobulin, it will start producing soluble antibodies → the final antibodies present in circulation.
Clonal selection:
Clonal selection has 2 main functions:
- Generate a large variety of lymphocytes
- Select and expand the cell with wanted specificity
Clonal selection makes it possible for the immune system to respond to things it hasn't dealt with before.
During clonal selection, a large variety of B-cells is generated out of which the correct cell is selected:
- A precursor cell makes many different cells which prepare the body for every threat that may be present
- There are lymphocytes with receptors for many different antigens
- During infection, lymphocytes with receptors that recognize the antigen give an activation signal
- The receptors form crosslinks with the antigen
- The lymphocytes with the correct receptor proliferate and differentiate
- The lymphocytes give effector cells that terminate the infection
This is peculiar, because one cell has one specificity, and one gene is one protein. This would mean that an unlimited amount of genes is necessary to be able to have receptors for every antigen.
Antibody properties:
B-cells secrete antibodies of the same specificity as the membrane-bound immunoglobulin. The immunoglobulin/antibody is a central molecule of the B-cell. It consists of:
- 2 heavy chains and 2 light chains
- N-termini and C-termini
- The C-termini attach the antibody to the plasma membrane
- Disulfide bonds → the heavy and light chains are covalently bound to each other
- A constant region and variable region
- The constant region is the same for every immunoglobulin
- The variable region is specific
Mechanisms of Disease 1 HC6: Mechanisms of adaptive immunity
HC6: Mechanisms of adaptive immunity
T-cell activation
There are several types of lymphocytes:
- CD8 T-cell
- Mass destructors → kill cells
- B-cell
- Production of antibodies
- Regulatory T-cell
- Dampen everything
- CD4 T-cell
- Mostly helper-cells → aid other cells in fighting pathogens
There are 2 types of MHC molecules, which are distinguished by their peptides being produced in 2 different cellular compartments:
- MHC class I: peptides derived from protein synthesis by the presenting cell → the antigen is produced by the cell itself
- An exception is cross-presentation of endocytosed proteins on MHC class I molecules
- Can be expressed by all nucleated cells
- CD8 T-cells bind to the a3domain of MHC class I
- The cell is infected and needs to be cleared
- MHC class II: peptides derived from endocytosed proteins → the antigen is taken up from the surroundings
- These proteins are extracellular
- Can be expressed by all antigen-presenting cells
- Dendritic cells always present MHC class II
- CD4 T-cells bind to the b2domain of MHC class II
- The cell itself isn't infected and doesn't need to be cleared
How do T-cells get activated?
Activation of the adaptive immune system starts when T-cells are activated. T-cells get activated by antigen presenting cells. Antigen presenting cells are part of the innate immune system:
- Dendritic cells, macrophages or neutrophils engulf pathogens such as bacteria and viruses and digest these to obtain antigens
- The bacteria is engulfed by a phagosome, which fuses with a lysosome that degrades the bacteria into smaller particles
- Lysosomes have enzymes and a very low pH
- The bacteria is engulfed by a phagosome, which fuses with a lysosome that degrades the bacteria into smaller particles
- The cells present the foreign antigens with MHC molecules on their surface
- A naive T-cell binds transiently to the antigen presenting cell it meets
- The TCR screens the peptide through the MHC-complex
- The TCR delivers an antigen-specific signal
- T-cell-antigen presenting cell interaction is stabilized for days
- A second signal is required to trigger activation of the naive T-cell → co-stimulation
- Co-stimulation plays an important role → the combination of an antigen-specific signal and a co-stimulatory signal is required to activate a naive T-cell
- The co-signal is derived from an alarm signal from the dendritic cell
- A B7 unit is expressed → IL-2 production
- If there isn't any B7 expression, the T-cell won't be activated
- A B7 unit has a CD80 or CD86 receptor, which will connect to CD28 on the naive T-cell
- A B7 unit is expressed → IL-2 production
- Activated T-cells switch on the expression of various genes, including interleukin-2 (IL-2)
- IL-2 drives proliferation and differentiation of activated naive T-cells
- Naive T-cells express the low affinity IL-2 receptor, activated cells express the high-affinity receptor
- Immunosuppressive drugs act by suppressing IL-2 production or action → T-cell responses are dampened
- For example cyclosporin, tacrolimus and rapamycin
- IL-2 drives proliferation and differentiation of activated naive T-cells
Mechanisms of Disease 1 HC7: Effector mechanisms of antibodies
HC7: Effector mechanisms of antibodies
B-cells
B-cells form the basis of humoral immunity by producing antibodies. They are part of the adaptive immune system. They possess antigen specificity and capacity to form memory upon clonal selection. During their final developmental stage, they form plasma cells.
Adaptive immunity is divided into 2 categories:
- Humoral immune response: antibody-mediated, B-cells
- Cell-mediated immune response: T-cells
An antigen is engulfed by an antigen-presenting cell and simultaneously presented to a helper T-cell and B-cell. To be presented to a T-cell, it's chopped into little pieces and attached to an MHC molecule. To be presented to a B-cell, it remains in its 3D-structure. Only when there's B-cell activation and sufficient T-cell help, there'll be formation of memory B-cells and plasma cells. Plasma cells produce the secreted antibody. Memory B-cells will remain in the body to protect the body from future attacks from the same antigen.
B-cell receptors:
On the surface of B-cells, there are antibodies → membrane bound immunoglobulins which serve as B-cell receptors:
- B-cells are characterized by the presence of surface immunoglobulins: the B-cell receptor (BCR)
- Each B-cell has multiple copies of the B-cell receptor
- Each B-cell generates BCR's with a single specificity
- The repertoire of BCR's is capable of recognizing millions of antigens
B-cell activation:
Globally, B-cell activation goes as follows:
- A resting B-cell has a membrane bound Ig → the B-cell receptor
- The membrane bound Ig encounters an antigen
- T-helper cells stimulate the B-cell to give rise to antibody-secreting plasma cells
B-cell stages:
Plasma cells may derive from B-cells, but they have different properties:
- Resting B-cell
- Surface Ig → only resting B-cells have receptors
- Surface MHC class II → present peptides to T-cells
- Growth
- Somatic hypermutation
- Isotype switch
- Plasma cell
- High-rate Ig secretion → produce and secrete antibodies
Antibody structures
An antibody comprises 2 light chains and 2 heavy chains. These chains come from different genes, meet together in the B-cell and are connected via disulfide bonds. The left-hand side of the antibody is exactly the same as the right-hand side.
Antibodies have 2 regions:
- Constant region: genetically the same in every antibody in every human
- Variable region: forms the antigen binding sites → explains why one antibody binds to a specific antigen
Antibodies have different domains and nomenclature:
- Fab domain: mediate the binding to the antigen → mediate antigen neutralization
- Fc domain: complement activation and triggering of Fc receptors
- Fc receptors are cellular receptors
Antibody isotypes:
Different isotypes have different immunological properties. The beginning of an antibody response starts with an IgM molecule that can be T-cell independent or T-cell dependent. Later on, it will switch to different isotypes. However, the basic structure of the antibodies remains the same. The differences are in the number of domains. When an antibody is switching isotypes, it's switching the constant domain → it's not necessarily switching the variable domain. Processes like affinity maturation and
.....read more
Mechanisms of Disease 1 HC8: B-cell development and antibodies
HC8: B-cell development and antibodies
SARS-CoV2
The SARS-CoV2 (COVID-19) virus can bind to the ACE2 receptor molecule. SARS-CoV2 has a spike protein, the S1 domain of this protein can bind to the ACE2 receptor in the respiratory tract and intestines. When the virus arrives, the following happens:
- Multiple spike proteins bind to different types of ACE2 molecules
- The virus has a small genome of only 30.000 base pairs → it needs human cells to proliferate
- Depending on the antibodies available, the virus is blocked a little
- If the epitopes on the spike proteins aren't blocked, the virus invades the human cells
- If everything goes well, antibodies that are fully blocking destroy the virus after a few days
Diversity
Every lymphocyte is different, because during development T-cells and B-cells preform rearrangements of immunoglobulin genes. Different parts of V-, J- and D-regions are coupled. This process can reach a diversity of 2 x 106. The diversity can grow even more at the junction site where V, D and J are coupled → junctional diversity. Here, there is an enormous deletion and inversion of nucleotides which increases the diversion up to 1012-1014.
There are several molecular processes in precursor B-cells and peripheral B-cells:
- The process of rearrangement takes place in the bone marrow
- Immature B-cells go into the periphery
- Immature B-cells arrive in the lymph node via arteries and exit the blood stream
- The immature B-cells arrive in the germinal center
- The immature B-cells come into contact with an antigen
- Under support of T-cells, proliferation, somatic hypermutation and class switch recombination of the B-cells takes place → plasma cells and memory B-cells are created
- This process takes a few days
- Antibodies are created
Somatic hypermutation:
Somatic hypermutation takes place in the gene segments that coat particles for the variable domains:
- The heavy chain's VDJ-exon
- The light chain's VJ-exon
There are 3 contact spots per antibody chain → complementary determining regions (CDRs). These are the spots where the mutation takes place during the germinal center response. Different rounds of mutation ensure that the antibody can fit into the epitope:
- There is an increased diversity
- The affinity for the antigen is increased
Class switch recombination:
Class switch recombination is critical to change the effective function of an antibody. These functions take place in the constant domains of antibodies, for instance whether an antibody is brought easily onto the epithelial layer. IgA plays a very important role in this process.
CSR exclusively takes place in immunoglobulin genes. A portion of the heavy chain locus is removed from the chromosome, and the gene segments surrounding the deleted portion are rejoined to retain a functional antibody gene that produces antibodies of a different isotype. This can occur multiple times and does not happen randomly → antibody genes are produced to create antibodies according to the B-cells that are most busy at the moment.
Immune monitoring
In total, there are more than
.....read more
Mechanisms of Disease 1 HC9: Tissue injury and repair
HC9: Tissue injury and repair
Cell adaptations
All diseases are results of visible cell abnormalities. There are 4 kinds of cell adaptations:
- Hypertrophy
- Atrophy
- Hyperplasia
- Metaplasia
Hypertrophy:
Hypertrophy is an increase in size of cells, resulting in increase in the size of an organ. This typically occurs in non-dividing cells and can be:
- Physiologic: hormonal → for example uterus growth
- During pregnancy, cells in the uterus increase in size → the amount of cytoplasm increases
- Pathologic: increased workload → for example cardiac hypertrophy due to hypertension or faulty valves
Hypertrophy has a specific mechanism:
- Sensors on the outside of the cell sense mechanical stress
- In the nucleus of the cell, transcription factors are activated
- Signaling pathways to make more contracting proteins are activated
- Because there are more elements, the cytoplasm becomes bigger
- The efficiency of the cell increases
Atrophy:
Atrophy is a reduction in cell size, resulting in a decrease in the size of the organ. This also can be physiologic of pathologic:
- Physiologic: embryonic development or a postmenopausal uterus
- Pathologic: many causes
The main causes of atrophy are:
- Decreased workload
- Mainly in muscles
- Denervation
- For example 2nd motor neuron disorders
- Decreased blood supply
- Decreased nutrition
- Aging
- For example involution → loss of hormonal stimulation
- Pressure
- For example tumors
Hyperplasia:
Hyperplasia is an increase in the number of cells, resulting in an increase in the size of an organ. This typically occurs in dividing cells and can be:
- Physiologic: hormonal or compensatory
- Compensatory hyperplasia: after liver resection, the liver can create new cells to grow back
- Pathologic: excess of growth factors
- This can occur as an adaptation to stress
Pathologic hyperplasia is distinct from cancer, but it will constitute a fertile soil in which cancerous proliferation may eventually rise.
Metaplasia:
Metaplasia is a reversible change in which one differentiated cell is replaced by another type, for example:
- Columnar → squamous
- In the cervix and anus
- Squamous → columnar
- In the esophagus
The body is divided in an inside and an outside world. Between these "worlds", there are junctions, for example:
- Gastro-esophageal
- Recto-anal
- Ecto-endocervical
When cells in the inside world get exposed to particles from the outside world, they adapt using metaplasia. They transform into layered squamous epithelia with lots of cytoplasm. An example of where this occurs is in the lung of a smoker.
Cell death
Death is defined by an irreversible injury:
- Reversible injuries → lead to recovery
- There isn't much visibility
- Irreversible injuries → result in death
- Biochemical alterations → cell death
- Ultrastructural changes
- Light microscopic changes
- Gross morphologic changes
Some injuries can lead to death if they're prolonged and/or severe enough:
- Adaptation → reversible injury → irreversible injury → death
Many things can cause cell
.....read more
Mechanisms of Disease 1 HC10: Repair mechanism
HC10: Repair mechanism
Apoptosis
Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program. This can be:
- Physiologic: pre-programmed
- Pathologic: associated with necrosis
Morphology:
Apoptosis has the following characteristics:
- Decrease in cell size
- Shrinkage
- Increase in chromatin concentration
- Hyperchromasia: the nucleus becomes small and dark
- Pyknosis → karyohexis → karyolysis
- Pyknosis = shrinkage
- Karyohexis/karyolysis = nuclear fragmentation
- Increase in membrane blebs
This is a very organized process → parts are recycled for the body to reuse. Apoptosis always results in phagocytosis, which is done by macrophages.
Biochemistry:
During apoptosis, the following processes take place:
- Protein digestion
- This is done by a family of caspases that ensure that the pre-programmed suicide happens in an organized way
- A family of enzymes
- This is done by a family of caspases that ensure that the pre-programmed suicide happens in an organized way
- DNA-breakdown
- Phagocytic recognition
There are several subcellular responses to caspase activation:
- Lysosomal response → auto-digestion
- Smooth endoplasmic reticulum (SER) activation
- Mitochondrial swelling
- Cytoskeleton breakdown
- Thin filaments
- Actin, myosin
- Microtubules
- Intermediate filaments
- Keratin, desmin, vimentin, neurofilaments, glial filaments
- Thin filaments
Necrosis
Necrosis isn't programmed and is much faster than apoptosis. It occurs when there is an immediate irreversible, progressive injury. There isn't any time for a nicely orchestrated process:
- A lot of fluid leaves the cell
- Neutrophils are attracted to the cell → inflammatory response
- Macrophages travel to the cell after a while
Necrosis versus apoptosis:
It is important to differentiate between necrosis and apoptosis:
- Apoptosis: normal death/replacements
- Shrinkage → reduced cell size
- Fragmented nucleus
- Intact plasma membrane
- Cellular content may be intact
- No adjacent inflammation
- Often physiologic
- Necrosis: premature death due to causes
- Swelling → enlarged cell size
- Karyolysed nucleus
- Disrupted plasma membrane
- Enzymatic digestion of cellular content
- Frequent adjacent inflammation
- Invariably pathologic
Clinical perspectives
Graft versus Host disease:
The pathway of apoptosis is activated in graft versus host disease. This is cytotoxic T-lymphocyte-mediated apoptosis
Dysregulated apoptosis:
Apoptosis is also activated in cancer. P53 can signal that there is too much injury in DNA and apoptosis is triggered. If P53 is mutated, the apoptosis-process is disregulated and damaged DNA will not result in apoptosis → cancer will progress.
Endometrial cancer:
In a case of endometrial cancer, grade 1 and stage I, the following is visible:
- Complex hyperplasia → atypical proliferation of epithelial cells with partly solid growth
- Squamous metaplasia → the tumor should be classified as endometrioid
- Large areas with necrosis in the center of the atypical proliferation
- Hypertrophic myometrial smooth muscle cells in the surrounding myometrium
- Atrophic ovaries
- Focal tubal metaplasia in the cervix
Ischemia and hypoxia:
Ischemia and hypoxia both cause cell injury. In both cases, there is a reduced oxygen availability. Ischemia is more damaging because there isn't any blood supply at all, which also will lead to nutrients deficiency.
Intracellular accumulations
Due to metabolic scenarios of cellular stress
.....read more
Mechanisms of Disease 1 HC11: Pathology of inflammatory reactions
HC11: Pathology of inflammatory reactions
Inflammation
Definition:
Inflammation is a reaction of a vascularized tissue to a pathogenic insult. It is characterized by the generation of inflammatory mediators and movement of fluid and leukocytes from the blood into extravascular tissues. It is a combination of:
- Calor (heat)
- Rubor (redness)
- Tumor (swelling)
- Dolor (pain)
- Functio laesa (disfunction)
Inflammation can be divided into 3 categories:
- Acute inflammation
- Chronic inflammation
- Granulomatous inflammation
Inflammation is necessary to fight pathogens. However, too much inflammation has negative consequences. This is the case in autoimmune diseases.
Players:
In the process of inflammation, 4 particles play an important part:
- Segmented neutrophils
- Neutral staining granules
- Pink cytoplasm
- Nucleus with condensed clumped chromatin and 3-5 lobes connected by thin chromatin filaments
- Monocytes → macrophage
- Kidney shaped nucleus with mature chromatin
- Vacuoles are commonly noted
- Low nuclear-to-cytoplasm ratio
- Lymphocytes
- Slightly larger than mature red blood cells
- High nucleus to cytoplasm ratio
- Round mature nucleus with clumped chromatin
- Scant, light blue cytoplasm with no granules
- Endothelium
- A layer of flat cells on the inside of blood vessels
Causes:
Inflammation isn't the same as infection → not all inflammation is caused by infection, and not all infections cause inflammation. There are 4 things that can cause inflammation:
- Infections
- Bacterial
- Viral
- Fungal
- Parasitic
- Immune reactions
- Allergy
- Autoimmune disease
- Tissue necrosis
- Ischemia
- Thermal injury
- Chemical injury
- Trauma
- Foreign bodies
- Dirt
- Sutures
- Et cetera
Process:
Inflammation starts with vascular changes:
- Increased blood flow needs to be slowed down → vasodilatation
- Vasodilatation leads to an increased permeability → fluid leaves the vessels
- The blood flow decreases → stasis
- Stasis causes thick blood vessels and edema
- Thick blood vessels cause redness and swelling at the place of infection
- Endothelial cells make openings with histamine and NO
- This is a very fast process that occurs within minutes-hours
- In case of a bacterial infection, endothelial cells are damaged due to microbiological toxines → endothelium can't close anymore → the blood pressure decreases more
- This can take hours to days
- This can happen in case of mengingococcal septicaemia
- The goal of these vascular changes is to attract neutrophils, monocytes and lymphocytes to the place of infection or tissue damage:
- Leukocytes "land" on the epithelia because of their slow speed
- The leukocytes start to roll → make contact with the epithelia
- The leukocytes migrate through the epithelia
- Neutrophils: are the first to arrive at the site of infection → endothelial cells already have binding spots for neutrophils in their cytoplasm
- These binding points are called P-selectin/E-selectin, which are called Weibel-Palade bodies when they're still inside the endothelial cells
- Monocytes: are the last to arrive at the site of infection → their binding spots have to be created, which takes a while
- Neutrophils: are the first to arrive at the site of infection → endothelial cells already have binding spots for neutrophils in their cytoplasm
Leukocyte
.....read more
Mechanisms of Disease 1 HC12: Introduction to infectious diseases
HC12: Introduction to infectious diseases
The earth's history
Bacteria form an essential part in the development of higher organisms:
- 4 billion years ago: the first bacteria (prokaryotes)
- 2,5 billion years ago: the first 1-cellular organisms (eukaryotes)
- 1,5 billion years ago: the first multicellular eukaryotes
- 0,5 billion years ago: the first fish
If the age of the earth was 1 year, bacteria would've come in February and humans only would have existed in the last minute of December 31st.
Determination of bacteria
Bacteria can be classified based on the structure of the cell wall
- No cell wall → mycoplasma
- Gram-negative → escherichia coli
- Gram-positive → streptococcus pyogenes
- Acid-fast → mycobacterium tuberculosis
Gram negative and positive bacteria can be distinguished with gram stains:
- Gram-negative
- Curved → vibrio campylobacter
- Rods → escherichia and salmonella
- Cocci → neisseria
- Spherical
- Gram-positive
- Rods
- Spore forming → clostridium
- Non spore forming
- Cocci
- Groups → staphylococci
- Chains → streptococci
- Rods
Interaction
Virulence factors describe what the bacterium does with the host (the human). Defense mechanisms describe how the host reacts to the bacterium.
S. pyogenes:
Streptococcus pyogenes is a gram-positive bacteria. They are called extracellular bacteria → cannot survive in a cell. Virulence factors of S. pyogenes are:
- Structural → leads to acute inflammation
- Peptidoglycan
- Lipoteichoic acid
- Products
- Characteristics → acute inflammation
S. pyogenes can enter the body when the barrier function is impaired, for example when the granulocyte function doesn't work due to alcoholism. Defense mechanisms of S. pyogenes are made up of the innate immune system.
Laboratory tests
There are 2 blood tests which can be used to test for inflammation:
- C-reactive protein (CRP)
- Acute phase protein
- There are lots of cytokines → liver responds by exciting lots of proteins (also CRP) → acute phase response
- Rises within hours
- Disappears in days
- Acute phase protein
- Erythrocyte sedimentation rate (ESR)
- Measure of the amount of proteins in the blood
- When there are a lot of proteins, they glue together as "stacks"
- Many proteins can do this
- When there are a lot of proteins, they glue together as "stacks"
- Dependent on the concentration of plasma proteins versus red blood cells
- Fibrinogen
- Immunoglobulins
- Nonspecific
- Rises and disappears more slowly
- Measure of the amount of proteins in the blood
Both are blood tests that aren't specific for a specific bacterium. CRP is an acute marker, ESR is a chronic marker.
Entamoeba histolytica
Entamoeba histolytica is a human pathogen. It lives in the bowel, where it may make a person ill. It is excreted with the feces in 2 forms:
- Cyst form: survives in the environment → bacteria in this form can be transmitted to other humans
Trophozoites: doesn't survive in the environment → dies within seconds/minutes
Mechanisms of Disease 1 HC13: Bacteria
HC13: Bacteria
Complexity
The complexity of an organism is based on its amount of base pairs:
- Prion: 103base pairs
- A single protein
- Virus: 104-5base pairs
- A set of proteins and nucleic acid
- Uses living cells
- 0,03-0,3 mm
- Made visible with an electron microscope
- Bacterium: 106base pairs
- A single cell prokaryote
- 0,1-10 mm
- Made visible with a light microscope
- Protozoa: 107base pairs
- A single cell eukaryote
- 4-10 mm
- Made visible with a light microscope
- Fungi: 108base pairs
- A multi-cellular eukaryote
- 4-10 mm
- Made visible with a light microscope
- Helminths: 109base pairs
- A multi-cellular eukaryote
- Approximately 40 mm
- Visible with the unaided human eye
Bacteria are the oldest form of life on earth. Bacteria are called prokaryotes because they don't have a nucleus. Millions can fit into the eye of a needle. Most live by themselves, but some in symbiosis. A bacterium doesn't have a nucleus or cell organelles. Bacteria can adapt to their surroundings very well.
Composition
Eukaryotes:
A eukaryotic cell has a:
- Membrane
- Cytoplasm with organelles
- Nucleus with DNA
Eukaryotic pathogens are protozoa, fungi and helminths.
Prokaryotes:
A prokaryotic cell, like a bacterium lacks a nucleus and cells organelles, but does consist of:
- DNA and RNA in the form of a ring
- Plasma membrane
- Mainly ribosomes are present in the cytoplasm
- Most (but not all) contain a cell wall
- Plays a part in the immune response → the target of antibiotics
- Protects the bacterium from its environment
- Contains:
- Capsule
- Flagella → for movement
- Pili → for attachment
- Plays a part in the immune response → the target of antibiotics
The cell wall is very important for bacteria:
- Protects against the environment
- Has antigenic properties → targeted by the immune response
- Has a role in pathogenesis
- Is relevant in diagnostics
Classification of bacteria
Classification based on cell wall composition:
Gram stains can be used to look at the cell walls of bacteria. A bacterium can be gram positive or gram negative:
- No cell wall → mycoplasma
- Gram staining cannot be used
- Gram positive → streptococcus pyogenes
- Keep their purple staining
- Gram negative → escherichia coli
- Lose the purple staining, are counterstained and become pink
- Acid-fast → mycobacterium tuberculosis
- The cell wall is so tight it cannot be colored with gram stains
Most bacteria are either gram-positive or negative. Whether a bacterium is gram-positive or negative is based on fundamental differences in their cell wall:
- Gram-positive bacteria
- Peptidoglycan on the outside
- This forms the actual cell wall
- Plasma membrane on the inside
- A lipid bilayer
- Lipoteichoic and teichoic acids sticking out of the cell wall
- More resistant to environmental conditions
- More difficult to kill with detergents
- Peptidoglycan on the outside
- Gram-negative bacteria
- Cell wall
- An outer membrane
- Many proteins can do this
- An outer membrane
- Cell wall
Mechanisms of Disease 1 HC14: Viruses
HC14: Viruses
Viral diseases
Viral infections are much more common than bacterial infections. Viruses are a major cause of human disease:
- Common cold: rhinoviruses, coronaviruses
- The flu: influenza
- Stomach flu: norovirus
- Fever blister: herpes simplex virus
- Meningitis or poliomyelitis: enterovirus
- HIV-AIDS
- Congenital CMV, rubella
- Et cetera
A virus is a small infectious agent that replicates only inside the host cell. It is a package containing either DNA or RNA (not both), but it is not a cell → it doesn't have organelles and fission. Surface components determine attachment to cell types.
Two important facts about viruses:
- Al viruses are obligate parasites that can only replicate in a cell
- All viruses are parasites of the host protein synthesis machinery → they must make mRNA that can be translated by host ribosomes
- Viruses use the host cell to make proteins from their mRNA
Viruses are classified by comparing morphology and replication cycles. This provides common basis for naming and allows common clinical approach.
Viral structure
There are very large and very small viruses. Viruses with a larger genome are more complex.
A virus can be naked or enveloped:
- Naked virus
- Capsid
- Nucleic acid
- Enveloped virus
- Envelope
- A lipid bilayer containing spikes
- Surrounds the capsid
- Capsid
- Nucleic acid
- Envelope
Terminology:
A few important terms that are used to determine the structure of a virus:
- Nucleic acid: DNA or RNA genome
- Capsid: protein structure surrounding the nucleic acid
- Nucleocapsid: capsid + nucleic acid
- Capsomere: subunit of the capsid
Capsid:
Capsid viruses have a symmetrical arrangement:
- Helical
- Icosahedral: 20 triangular seats
Capsid functions are:
- Packaging of viral parts
- Protection of nucleic acids
- Transport of nucleic acids from cell to cell
- Provision of specificity for attachment to the cell
- Spike proteins
Envelope:
The basic structure of an enveloped virus is as follows:
- Center with DNA or RNA
- A protein coat (capsid)
- A lipid membrane envelope
Capsid versus enveloped viruses:
Capsid and enveloped viruses differ from each other in multiple ways:
- Naked capsid virus
- More resistant to environmental conditions
- Drying
- More difficult to kill with detergent
- Sensitive to:
- Chlorine and iodine
- Enters the host cell by virus-induced endocytosis
- Exits the host cell by cell lysis
- More resistant to environmental conditions
- Enveloped virus
- More susceptible to environmental conditions
- Easier to kill with lipophilic detergentia than non-enveloped viruses
- Sensitive to:
- Chlorine and iodine
- Ethanol or propanol 70-95%
- Chlorhexidine 0,05-0,5%
- Ammonium, phenol
- Enters the host cell by membrane fusion or endocytosis
- Exits the host cell by budding
DNA and RNA
A virus is either a DNA or an RNA virus. It never can have DNA and RNA simultaneously.
DNA viruses:
General properties of DNA viruses are:
- Resemble host cell DNA
- Processing occurs within the host cell nucleus
- Relatively stable within the cell → can persist easily
- Usually have
Mechanisms of Disease 1 HC15: Fungi and parasites
HC15: Fungi and parasites
Definition
Parasites and fungi are eukaryotes. They are a mixture of single-cell and multi-cellular species and are more complex than viruses and bacteria.
Fungi:
A fungus is a eukaryotic organism that normally lives in the environment. It is an opportunistic pathogen. It has a more plant-like structure than a parasite.
Fungi are very common in the community. They are an important cause of disease and mortality in patients with an impaired immune system.
Parasites:
A parasite is a eukaryotic organism that lives in or on, and takes its nourishment from, another organism (for example a human host). It cannot complete its life cycle independently. It has a more animal-like structure than a fungus.
Parasites are globally still an important cause of disease and mortality. Travel-related infections are often parasitic → some parasites have a geographically limited occurrence. Parasitic infections are often related to socio-economic circumstances → there are many opportunities for prevention and control.
There are 2 types of parasites:
- Protozoa
- Helminths
Fungi
Structure:
A fungal (yeast) cell is a eukaryotic cell, which consists of:
- Cell membrane
- Nucleus
- Cytoplasm
- Cell organelles
- Special components
- In the rigid cell wall: mannan, flucan and chitin
- Both bacteria and fungi can have a cell wall
- In the cell membrane: ergosterol
- An important target for anti-fungal drugs
- In the rigid cell wall: mannan, flucan and chitin
Reproduction:
Fungi have different ways of reproducing:
- Yeast: budding → one cell separates from the other
- Molds
- Sexual: in the form of spores
- Conidia: asexual
Pathogenesis:
The cellular immune system is very important to combat fungi:
- Yeasts
- Granulocytes and macrophages
- T-cells
- Normal commensal bacterial population
- Molds
- Granulocytes and macrophages
- T-cell immunity
Species:
There are many important types of fungi, of which 2 are relevant for this course:
- Candida albicans → stomatitis, vaginitis
- Aspergillus fumigatus → pneumonia in patients with granulocytes
Parasites
Parasites have a very complex structure. Their life cycle depends on hosts:
- Parasites that depend on 1 host
- The parasite can either stay in the host for the whole cycle or exit and enter the host repeatedly
- Parasites that alternate between 2 different host species
- Malaria alternates between human hosts and mosquito hosts
- Parasites that alternate between many hosts
Parasites can be divided into 2 groups:
- Ecto-parasite: scabies mite (headlice)
- Endo-parasite
- Protozoa: entamoeba histolytica
- 1 cell
- Lives in the intestines
- Multiplies within the host
- Helminths: strongyloides stercoralis
- Multicellular
- Only transmitted in the tropics
- Stable population
- Strongyloids form an exception
- Inoculation dose determines the outcome
- Protozoa: entamoeba histolytica
Diagnosis:
The diagnosis of a parasitic infection can be made directly or indirectly:
- Direct: stage of the parasite
- Feces
- Blood
- Urine
- Other
- Indirect: via serology
- Entamoeba
- Toxoplasma
- Strongyloides
- Schistosoma
Protozoa
Structure:
A protozoa is a eukaryotic cell containing the following
.....read more
Mechanisms of Disease 1 HC16: Invaders
HC16: Invaders
Pathogenesis
All invaders can make people ill. They are micro-organisms which interact with a host. Humans are full of micro-organisms, which usually don't do anything.
There are 1014bacteria in the body. Some of these take place and colonize the bowel and mouth, forming protection from other bacteria. Others are only carried and don't cause any harm, or reside in the body in latent form.
Disease symptoms are mainly caused by the human immune host response → it takes 2 to tango. There are only a few micro-organisms which actually cause disease without there being an immune response.
Virulence factors
A virulence factor is any component, product or characteristic that contributes to the ability of a micro-organism to cause disease:
- Structural components
- Survival of the adverse environment
- Attachment to human structure
- Entry into the human body
- Induction of an inflammatory response
- Products
- Toxins
- Enzymes
- Tricks
- Kill a cell
- Decreasing the normal immune response
- Evading the normal immune response
- Latency
These factors help the virus to:
- Get inside
- Adhesion proteins or glycoproteins
- Endocytosis induced by micro-organisms
- Fimbriae
- Hyphae
- (Lipo)techoic acid
- Do harm
- Enzymes destructing tissue
- Hyphae
- Lipopolysaccharide (LPS)
- Lipoteichoic acid
- Peptidoglycan
- Toxin that activated adenylate cyclase
- Toxin acting as a superantigen
- Toxin inhibiting the release of neurotransmitters
- Toxin with cytotoxic activity
- Turn off/hide from the defender
- Antigenic shifts
- Antigenic variation
- Biofilm
- Protein inhibiting opsonization
- Intracellular survival
- Capsule
- Molecular mimicry
- Ability to remain latently in the host
It isn't necessary to memorize these factors.
Streptococcus pyogenes
Streptococcus pyogenes is a primary pathogen. It acts via a transient carrier in the throat.
Diagnostics show that it is a:
- Catalase test → gram positive cocci
- Culture plate → Group A b-hemolytic cocci
Symptoms:
Symptoms of an infection with streptococcus pyogenes are:
- Local or disseminated infections
- Tonsillitis, otitis media
- Impetigo, erysipelas
- Erysipelas are skin infections
- Childbed fever, sepsis
- Exotoxin-mediated syndromes
- Scarlet fever
- Streptococcal toxic shock syndrome
- Immunological effects
- Acute rheumatic fever
- Acute glomerulo-nephritis
Adhesion:
S. pyogenes has little hairs on its cell wall that touch the epithelial cell. The cell wall of s. pyogenes contains:
- Peptidoglycan
- S. pyogenes is a gram positive bacteria
- Lipoteichoid acid
- Potrusions connecting to components on the human cell
- Without these, adhesion wouldn't be possible → the bacteria would be gone after swallowing
Virulence factors:
Several other virulence factors pay an important role:
- Streptolysin → a toxin which makes pores in the cell
- Belongs to a class of pore-forming, membrane-active, exotoxins
- After formation of the pore, the epithelial cell dies
- Causes the lysis of red blood cells that is visible on a culture plate → b-hemolysis
- Belongs to a class of pore-forming, membrane-active, exotoxins
- Streptokinase → lysis of clot
- In case blood clotting is involved → the bacteria can go anywhere
- Blood
- In case blood clotting is involved → the bacteria can go anywhere
Mechanisms of Disease 1 HC17: Host versus invader
HC17: Host versus invader
Commensals, colonization and normal host defense
Sterile versus non-sterile areas:
A host has both sterile and non-sterile areas:
- Nonsterile areas
- Skin
- Elementary tract
- Alimentary tract
- Sterile areas → no bacteria are present
- The "inside"
- Stomach
- Deep respiratory tract
- Urinary tract
The human body has 1014-15 bacteria and 1013 body cells. Most bacteria reside in the intestines.
Commensals:
Commensals are normally present in every person. The skin only contains gram-positive bacteria because they have a thick peptidoglycan layer, which makes them resistant against a dry environment. This doesn't necessarily cause symptoms → commensals are harmless unless the immune system is impaired.
Colonization:
Humans have colonization resistance → bacteria are present on skin and mucosae to protect against adherence by other microorganisms.
Normal host defense:
The human body has different measures to achieve sterility:
- Physical
- Barriers: skin and mucosae
- Airways: ciliar activity, mucus, coughing
- Urinary tract: voiding, antimicrobial factors
- Chemical
- Gastric acid → kills bacteria
- Enzymes
- Lysozyme in tears
- Immunological
Exposure versus infection
Infection:
An infection is a structural or functional change caused by a micro-organism or its components or products. This includes the host response such as inflammation.
The microorganism staphylococcus aureus is carried by 1/3 of all humans in the nose. This, however, isn't an infection → nothing has changed. It only is a carrier. Something only becomes an infection once something has changed, for example:
- Pain
- Redness
- Puss
- Fever
Fever can have many causes, but more often than not it is caused by infection. The body temperature is regulated in the hypothalamus:
- Signals come from bacteria
- Lipopolic saccharides interact with Toll-like receptors on the macrophages → triggers the production of cytokines
- The interleukins attach to the epithelial cell and give signals → prostaglandins go to specialized cells which sets certain mechanisms in action:
- Vasoconstriction → containing body warmth
- Shivering → making body warmth
- Brown adipose tissue → ATP → making body warmth
Exposure:
There are many forms of exposure:
- Oral
- Trauma/operation
- Needle injury, blood, catheters
- Artrhopod
- Penetration of skin by the micro-organism itself
- Ascending infection
- Contact
- Inhalation, aspiration
Exposure to micro-organisms leads to:
- Colonization
- No symptoms
- Commensal or primary pathogens on skin or mucosae
- Transiently or permanently
- Competition for food and adhesion sites
- Infection
- Often, but not always
- Symptoms and/or signs
Natural course of infection
There are 2 groups of pathogens which can cause infections:
- Primary pathogens: no host defense disorder needed to become ill
- Opportunistic pathogens: host defense disorder needed to become ill
- The weaker microorganisms
Infection can be acquired endogenously or exogenously:
- Endogenous
- Commensals: "friendly" microorganisms every human has
- Skin
- Staphylococcus epidermidis
- Gram-positive
- Staphylococcus epidermidis
- Throat
- Streptococci
- Gram-positive
- Neisseria species
- Gram-negative
- Candida albicans
- Streptococci
- Skin
- Commensals: "friendly" microorganisms every human has
Mechanisms of Disease 1 HC18: Immune deficiencies and infection risk
HC18: Immune deficiencies and infection risk
Components of host defense
There are 6 components of host defense:
- Immunoglobulins
- T-cells
- Complement system
- Granulocytes
- Macrophages
- NK-cells
Impaired barrier function
There are many causes of an impaired barrier function:
- Literally
- Wounds
- Insect bites
- Penetration of the skin by catheters
- Skin/mucosal toxicity by cytostatic drugs
- Functionally
- Urinary catheter, incomplete emptying of the bladder
- Lack of gastric acid
- Lack of tears
- M. Sjörgen, an auto-immune disease
- Disturbance of normal airway cleaning
- Intubation, abnormal mucus, ciliary function, coughing, COPD
- Impaired colonization resistance
- All protecting bacteria are removed
- Can be caused by antibiotics
- All protecting bacteria are removed
Microorganisms:
Various microorganisms can cause an impaired barrier function:
- Literal: the microorganisms that already are on the skin or mucosal membranes
- Primary pathogens
- Staphylococcus aureus → skin or nose
- The most common cause of wound and catheter infection
- Streptococcus pyogenes → skin or throat
- Staphylococcus aureus → skin or nose
- Commensal opportunistic pathogens
- Staphylococcus epidermidis → bowel
- Cannot cause wound infections, but can cause catheter infections
- Escherichia coli → bowel
- Bacteroides fragilis → bowel
- Clostridium sp. → bowel
- Streptococcal sp. → throat or vagina
- Candida albicans → throat or vagina
- Staphylococcus epidermidis → bowel
- Primary pathogens
- Functional
- Urinary catheter, incomplete emptying of the bladder → escherichia coli
- Lack of gastric acid → salmonella species, vibrio cholera
- Lack of tears → haemophilus influenzae, streptococcus pneumoniae
- Disturbance of normal airway cleaning → streptococcus pneumoniae
Candida infection:
If all protecting bacteria are removed due to impaired colonization resistance, the candida will remain, multiply and cause local diseases, for example thrush ("spruw"). This can be caused by using antibiotics. It also is very common among HIV-patients.
Clostridium difficile:
Clostridium difficile is a gram-positive, anaerobic, rod-shaped bacteria that also survives in cases of impaired colonial resistance. It cannot be wiped out by antibiotics and isn't carried by everyone. When it starts to multiply, it causes pseudomembranous enterocolitis. A pseudomembrane consists of mucus and numerous granulocytes. This can cause the whole bowel to become necrotic.
A solution for such an infection is fecal microbiotica transplantation:
- A healthy person donates their feces
- The feces are washed and made into a fluid
- The feces are transmitted to the bowel via a catheter
- New and healthy microbiota are infused
This works in 80-90% of the cases.
Complement deficiency
Causes of complement deficiency are mainly genetic:
- Classical pathway
- Alternative pathway
- MB lectin pathway
- Terminal pathway (MAC)
One pathway can comprise for the falling out of the other. However, one is very essential to function correctly:
- Terminal pathway → forms the membrane attack complex (MAC)
- This can cause MAC Neisseria meningitis and Neisseria gonorrhoea infections
Hypogammaglobulinemia
In case of hypogammaglobulinemia, there is an immunoglobulin deficiency. Causes are:
- Congenital
- X-linked a-gammaglobulinemia
- The B-cells are lacking
- As part of SCID
- X-linked a-gammaglobulinemia
Mechanisms of Disease 1 HC19: Pathology of infectious diseases
HC19: Pathology of infectious diseases
Infectious diseases
In 80% of cases, the pathologist finds infectious disease patterns while trying to exclude malignancy. In 20% of cases, they get a biopsy intended to prove infectious origin. Pathologists try to think in patterns.
Spectrum of inflammatory responses
There is a spectrum of inflammatory responses to infection, which consists of 5 forms of inflammation:
- Suppurative/(purulent) acute inflammation → gram-positive or gram-negative bacteria
- Most common
- Acute inflammation
- Many neutrophils are present
- Pus is visible
- Mononuclear/granulomatous inflammation → mycobacteria, spirochetes, parasites, viruses
- Chronic inflammation
- Cytopathic-cytoproliferative inflammation → HSV, adenovirus, herpes virus, HPV
- Infected cells start proliferating under influence of viruses → necrotic responses
- Can lead to death very quickly
- Infected cells start proliferating under influence of viruses → necrotic responses
- Chronic inflammation and scarring → hepatitis B
- Mainly lymphocytes and specific antibody-producing cells are present
- Tissue necrosis → clostridium, hepatitis B
- No reaction → immune deficient host
Lung infections
If, on a CT scan, there are spots visible in the lung, its either malignancy or an infection. If there is a mononuclear or granulomatous infection in the lung, it most definitely is a case of TBC. Caseous necrosis are cavities in the lung made of dead cells, which is very common for TBC.
Testis
The testis is very difficult to biopsy, but the probability of malignancy in the testis is very high. It can be confused with TBC, which can also occur in the testis → it enters the blood stream and lymph nodes via the lungs. However, this is super rare.
Caveating/cystic lesion in the lung
An infection can lead to a caveating or cystic lesion in the lung. This is done by the echinococcus parasite, which can make cystic walls around itself and create holes in the lungs → echinococcus cysts. If the cyst is ruptured, new larvae can be made everywhere.
Graft versus host disease
Graft versus host disease can happen after a bone marrow transplant. It is a form of immunodeficiency. It can cause cytopathic or cyto-proliferative patterns → virus infections, for instance HPV or CMV associated pneumonitis. Usually, this virus can be destroyed by a well-functioning immune system. However, this can be dangerous in case of bone marrow transplantation → it can cause Graft versus host disease.
POX-virus
POX-virus can cause molluscum contagiosum ("waterwratten"). This is very contagious, but usually goes away by itself.
Herpes simplex
In case of herpes simplex ("koortslip") there is an excessive amount of cells, paired with blisters. It is cyto-proliferative.
Syphilis
Ulcerating skin lesions can be caused by plasma cell infiltrations → mononuclear infiltrations. This disease is called syphilis, which is caused by spirochetes.
Hyphen invading vessel walls
Aspergillus fumigatus is a fungus that not only can spread through the body via blood vessels, but also can destroy the vessel wall → hyphen invading vessel walls. This way, the fungus can spread through the entire human body. It is very rare and only happens when one is immunodeficient.
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Mechanisms of Disease 1 HC20: Diagnostics of infectious diseases
HC20: Diagnostics of infectious diseases
Gram-staining
The Gram-stain test was developed by Hans Christian Gram (1853-1938). It works as follows:
- Fixation of the bacteria on a glass slide
- Crystal violet staining → slides through the cell wall
- Iodine treatment → forms crystal complexes
- Decolorization → the crystal complexes disappear from the gram-negative bacteria
- Counter stain safranin
Streptococcus pneumoniae:
A 70-year-old woman who smokes has an increased cough with sputum. Gram-stains are made and show Gram-positive duplex cocci. She is infected by the streptococcus pneumoniae bacteria.
Ziehl-Neelsen
Ziehl-Neelsen staining is used to color acid-fast bacteria, for instance mycobacterium tuberculosis. These bacteria have a lipid in their layer which can specifically be colored to identify it as an acid-fast bacterium.
Other colorization methods
Some other colorization methods are:
- Auramine: can also stain acid-fact bacteria
- Has a higher sensitivity but a lower specificity than Ziehl-Neelsen
- Giemsa stain: used to diagnose plasmodium falciparum in a thin blood smear
- Plasmodium falciparum causes malaria
Rapid antigen tests
Rapid antigen tests can be useful because they are indeed rapid, however they have a very low sensitivity → the practical value is limited. SARS-CoV-2 immunochromatographic tests, for instance, have a sensitivity of 30-80%. There is a specific antibody on a piece of paper, and it is tested whether an antigen attaches to it. Immunochromatographic tests are based on pregnancy tests.
Culture of microorganisms
There is methodology based on culture of microorganisms. This is usually used for research of bacteria and viruses, but these days hardly for diagnostics. Culturing has certain characteristics:
- Time-dependent
- Specimen quality is important
- Further analysis is required
- Morphology
- Metabolism
- Antigens
- Some bacteria and many viruses cannot be cultured
In contrary to bacteria, viruses can only be cultured on living cells.
Staphylococcus aureus endocarditis:
A 21-year-old man has fever, chills and a heart murmer. He has suffered from intravenous drug abuse. The doctor decides to take a blood culture:
- The blood culture is taken and put in a bottle
- The blood culture is left to grow
- The culture is taken out of the bottle and put on agar
- Gram staining and determination
This process takes a while.
Afterwards, further analysis is done:
- Rapid simple tests
- Catalase test: the bacteria is a gram-positive staphylococcus
- Coagulase test: positive → the bacteria is staphylococcus aureus
- Biochemical properties
- MALDI-TOF
- Antibiotic susceptibility testing
MALDI-TOF mass spectrometry
MALDI-TOF (Matrix-Assisted Laser Desorption/Ionization Time of Flight) is a mass spectrometry test. Several steps are followed:
- A colony of an unknown organism is selected
- The organism is prepared onto a MALDI target plate
- Different organisms spend a different time in the tubes
- The MALDI-TOF profile spectrum is generated
- The data is interpreted
- The species are identified
PCR
PCR is a main diagnostic method these days. Cycles of heating and cooling are used to multiply DNA → PCR is a form of nucleic acid amplification:
- Target DNA strands are selected
Mechanisms of Disease 1 HC21: Essential microorganisms
HC21: Essential microorganisms
Clinical symptoms
One microorganism can cause 1, 2, 3 or many more clinical symptoms.
Vibrio cholera
The bacteria vibrio cholerae is a curved gram-negative bacteria that causes cholera. Cholera is an epidemic in many countries, mainly where hygiene is a problem. The bacterium has several characteristics:
- Is a vibrio → is curved
- Has a flagellum → makes rapid movements possible
The bacterium is spread by drinking contaminated water or direct contact between people. Not everyone who is a carrier becomes sick, but people with acid-inhibitors, elderly and children are more susceptible.
It is a non-invasive micro-organism → it doesn't cause inflammation or fever. There is no host response involved, but it does produce a cholera toxin. It is a toxin-mediated disease, which causes hyperactivity of the cell → pumps which pump water and elektrolytes out of the cell are activated:
- The cholera toxin can bind to the membrane of the villi via a G-protein
- cAMP is activated irreversibly in the cell
- cAMP leads to an active secretion of kalium, natrium, chloride, bicarbonate and water → results in a watery diarrhea
- This is called rice water stool
The pumps can pump up to 15 L a day. This can cause dehydration and a low blood pressure, especially among children.
Taenia saginata
The taenia species is a species of tapeworms in the bowel. Humans are the definitive host. The worms make eggs, which can be eaten by cows, causing the taenia to reproduce. Cows are the intermediary host → when a person eats raw cow meat, they can become infected. Another taenia species is taenia solium.
Legionella pneumophila
The legionella bacterium is a gram-negative bacterium that is very small. Legionella pneumophila can lead to 2 diseases:
- Pneumonia
- If someone is T-cell immunocompromised
- Pontiac fever
Legionella survives in the cell → it needs help from T-cells to be destroyed
The legionella bacteria thrive in warm water → they mainly reside in man-made water systems like air conditioning, saunas, showers and hot tubs. Transmission goes via air particles → aeriosoles. One person cannot infect another with it.
Treponema pallidum
The bacteria treponema pallidum can cause Syphilis. The bacteria is gram-negative and is mainly spread via genital or oral mucosal contact. The disease comes in phases:
- Ulcer on the genital organs (or somewhere else)
- The ulcer disappears for a while
- Fever and skin rash
- The symptoms disappear again
- Gumma (a swelling)
- This only happens in a few cases
- Can also occur in the brain
Treponema pallidum came to Europe for the first time after Columbus returned from the Americas. It usually is diagnosed with serology.
Schistosoma
Schistosoma is a worm that lives in the water, mainly in Africa. Humans are definitive hosts, snails are intermediate hosts. People are exposed to it by being in infected water:
- The worm enters the body via the skin and causes swimmers itch
- The worm migrates and starts
Mechanisms of Disease 1 HC extra: Mycobacterial infections (tuberculosis)
HC extra: Mycobacterial infections (tuberculosis)
Mycobacterium tuberculosis epidemiology
Mycobacterium tuberculosis is characterized by:
- Droplet nuclei
- Alveolar macrophage
- Intracellular survival
- Spread to lymph nodes
- Hematogenous spread
- T-cell immunity → latent stage
- Reactivation
In regions such as southern Africa, 50% of patients with TB have HIV. HIV affects the CD4 cells, which increases the chance of getting TB enormously.
Pathogen and pathogenesis
Mycobacterium tuberculosis can have 6 different clinical manifestations:
- Latent
- Many patients don't have symptoms but are carriers
- Subclinical
- Cannot only be transmitted during forceful coughs
- Limited disease
- Pneumonia in 1 lung lobe
- Extensive disease
- Pneumonia in both lungs
- Multi-organ
- Spread by macrophages migrating everywhere in the body
- For example masses in the abdomen
- Miliary TBC
- Very rare
- Granulomas all over the body
- The granulomas are visible as speckles
- The necrosis breaks through to the vessel wall → the bacteria are spread via the blood stream
Diagnosis and treatment
Testing:
TB can be diagnosed clinically or via diagnostic tests:
- Clinical
- Complaints
- Cough for longer than 2 weeks
- Fever, night sweats, weight loss
- Depends on organ involvement
- Physical examination
- Complaints
- Diagnostic tests
- Radiography: never specific for TBC
- Histology: unusual
- Granulomas
- Central necrosis
- Looks like cottage cheese
- Multinucleate giant cells
- Microbiological tests: essential for a correct diagnosis
- Acid fast staining
- For example Ziehl-Neelsen
- The cell wall has a high content of complex lipids → mycolic acids
- Acid fast bacteria stay pink, non-acid fast bacteria become blue after decoloring
- PCR
- Culture
- Takes 2 weeks to 2 months until the bacteria have grown
- Antibiotic susceptibility testing
- Genotyping
- Acid fast staining
- Indirect
- Tuberculin skin test
- A small amount of antigens is injected → the T-cell response is measured
- Positive mantoux test → the T-cells respond in the skin
- These tests are not specific for TBC
- Interferon gamma release assay
- Tuberculin skin test
- A small amount of blood is put in 1 positive and 1 negative control tube
- Antigens specific for mycobacterium tuberculosis are put in the tube
- If the cells have produced the cytokine interferon g, the person has been exposed to mycobacterium tuberculosis in the past or present
Therapy:
The treatment of TBC depends on whether it is active or latent. Multiple drugs are prescribed → a patient has to take at least 2 drugs at the same time:
- Active TBC → treatment has to be a combination of:
- Isoniazide
- For 6-9 months
- Rifampicin
- For 6-9 months
- Pyrazinamide
- For 2 months
- Ethambutol
- For 2-9 months
- Latent TBC → it is acceptable to treat with 1 or 2 drugs:
- Isoniazide
- Rifampicin
- Isoniazide and rifampicin
It isn't necessary to remember the names of
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Mechanisms of Disease 1 HC22: Antimicrobial therapy
HC22: Antimicrobial therapy
Discovery of antibiotics
The first antibiotic was saharsan, to cure Syphilis. This was a very toxic drug. Alexander Fleming discovered penicillin. He came back from a holiday and saw that on the dirty plates he left behind there were certain parts that weren't covered by bacteria. Here, a certain fungus was growing → penicillin. Penicillin was making a molecule which was able to kill bacteria. It took about 10 years until penicillin was used on an industrial level. After the 1980's, there was no new discovery of antibiotics.
Interactions
Antimicrobial therapy should be active against the microorganisms. There are several interactions necessary:
- Antimicrobial therapy «host
- Host «microorganism
- Microorganism «antimicrobial therapy
Antibiotics need to shift this balance in favor of the host. Two terms are very important to describe their effect:
- Pharmacodynamics describe this effect the drug has on the microorganism
- Pharmacokinetics describe the effect the host has on the drug
Pharmacodynamics
Classes of antibiotics
The correct antibiotic depends on the bacterium. Bacteria can be divided in groups:
- Gram positive versus gram negatives
- Aerobe versus anaerobe
Based on this, correct antibiotics can be prescribed:
- Penicillin
- Gram positive
- Aerobe and anaerobe
- Meropenem → broad spectrum
- Gram positive and gram negative
- Aerobe and anaerobe
- Cefuroxim
- Gram positive and gram negative
- Aerobe
- Metronidazol
- Gram positive and gram negative
- Anaerobe
- Ciprofloxacin
- Gram positive and gram negative
- Aerobe and anaerobe
Mechanism of action:
Different classes of antibiotics influence different parts of the bacteria:
- Antibiotics active on the cell wall: inhibit the crosslinking of peptidoglycans → inhibit the integrity of the cell wall → bacteria can't divide
- Penicillin
- Cephalosporine
- Carbapenem
- Glycopeptides
- Vancomycin
- Antibiotics active on the cell membrane
- Colistin
- Daptomycin
- Antibiotics active on ribosomes: inhibit protein synthesis
- Aminoglycosides
- Tetracycline
- Macrolides
- Clindamycin
- Antibiotics that effect DNA synthesis
- Quinolones/ciprofloxacin
- Effect DNA gyrase, an enzyme that is important for reading DNA
- Sulfonamides
- Blocks folic acid synthesis, an essential building block for bacteria
- Quinolones/ciprofloxacin
- Antibiotics active in the cytoplasm
- Metronidazole/imidazole
Beta-lactams:
There are several beta-lactam antibiotics:
- Penicillin derivatives
- Penicillin G
- Flucloxacillin
- Amoxicillin
- Amoxicillin + clavulanic acid
- Cephalosporins
- Cephuroxim
- Many others
Gram-negative bacteria have a different cell wall than gram-positive bacteria → have a much thinner peptidoglycan layer which cannot contain the colored fluid. Beta-lactams affect the synthesis of peptidoglycans of both gram-positive and gram-negative bacteria → the antibiotics mainly form a problem for bacteria when they are dividing.
The molecular mechanism is as follows:
- Peptidoglycan chains need to be crosslinked
- Penicillin is blocking transpeptidase
- The peptidoglycan chains cannot be crosslinked any longer
Low dosages of penicillin won't affect the bacteria. At a certain dose, there suddenly will be an effect. However, if the dose is increased again, the effect
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Mechanisms of Disease 1 HC23: Principles of antibiotic pharmacotherapy
HC23: Principles of antibiotic pharmacotherapy
Goal of drug treatment
The main goal of drug treatment is to achieve a drug concentration within the body that is therapeutically relevant and appropriate. Knowledge about pharmacokinetics is relevant to determine the appropriate dose and to maintain drug concentrations within the therapeutic index. The most prescribed antibiotic is amoxycillin.
To describe the route of a drug, the ADME aspects are used:
- Absorption
- Distribution
- Metabolism
- Excretion
The processes of metabolism and excretion together form elimination.
Absorption
Absorption consists of the passage of a drug from its site of administration into the circulation. There are 3 main routes of administration for antibiotics:
- Oral
- Epithelial surfaces
- Intravenous injection
Transport:
During absorption, drug molecules are transported across the cell membranes. This can happen via:
- Passive transport → diffusion
- Active transport → carrier-mediated transport using energy (ATP)
Which form is used, depends on the physicochemical properties of the drug molecule:
- Molecular size
- Drugs with a size smaller than 1000 dalton can be diffused over membranes
- Bigger drugs need to be injected intravenously
- Drugs with a size smaller than 1000 dalton can be diffused over membranes
- Relative lipid solubility
- Drugs with a high lipid solubility can cross the membrane by diffusion
- Hydrophilic drugs cross the membrane via carriers
Concentration-time curve:
Absorption can be shown in a concentration-time curve. 2 relevant parameters are:
- Cmax: the maximal plasma concentration
- tmax: time when the concentration is maximal
The therapeutic range of a drug lies between the MEC (minimal effective concentration) and MTC (maximal toxic concentration). A drug with a wide therapeutic range is preferable. Penicillins, for instance, are antibiotics with a very wide therapeutic range, while gentamycins have a narrow therapeutic range.
The concentration can be influenced by:
- The dose
- The dose frequency
Case:
A 21-year-old patient is treated with ciprofloxacin (chinolon) because of a severe and complicated cystitis. Ciprofloxacin should not be taken in combination with dairy products, like milk or yoghurt, because:
- It forms a complex with calcium, magnesium, zinc and iron
- The drug will be too large to be transported across the cell membrane
- The absorption reduces
- The effectiveness reduces
Factors:
Several factors can influence absorption:
- Food intake
- Gastrointestinal motility
- pH at absorption site
- Drug-drug interaction
Bioavailability:
The bioavailability (F) is the fraction of an administered dose that reaches the systemic circulation as an intact drug. This typically is less than 100%, due to:
- Poor absorption
- Metabolic degradation → first pass effect
- If the drug is in the portal vein, it has to pass the liver before it reaches the systemic circulation
The bioavailability of oral drugs is less than 100%, while the bioavailability of intravenous drugs is 100%.
Distribution
It is relevant to know the distribution of a drug to determine whether a drug is able to reach the site of infection and to determine the effective dose.
Fluid:
Once administered, drugs are distributed over different body fluid
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Mechanisms of Disease 1 HC24: Introduction MOOC
HC24: Introduction MOOC
Lectures
Mandatory MOOC lectures:
- The kidney in health and disease
- Options if kidneys fail
- Immunogenetics
- Histocompatibility
- The diabetic patient
- SPK and islet cell transplantation
- Introduction and overview of early challenges (from 1,15 to the end)
- Cellular rejection
- Antibody mediated rejection
- Cases from daily practice A: patient cases with early challenges
- Cases from daily practice B: patient cases with early challenges
- Introduction and overview of late challenges (from 0,56 to the end)
- Infections: overview and CMV infection
- Infections: BK and EBV infection
- Cases from daily practice A: patient cases with late challenges
- Cases from daily practice B: patient cases with late challenges
- MOOC module 1: Etivity, which treatment do you advise?
- MOOC module 2: Etivity, which donor do you advise?
Functions
The kidney has several functions:
- Clearance of toxins
- Ureum
- Creatinine
- Potassium
- Acid
- Regulation
- Water
- Salt
- Blood pressure
- Production
- Erythropoietin
- Vitamin D
Renal failure
Renal failure can have multiple causes:
- Prerenal
- For example a very low blood pressure
- Renal
- Lie within the kidney
- Postrenal
- For example a tumor which presses on the urinary tract
There are many types of chronic renal failure:
- Diabetic
- Non-diabetic
- Vascular: nephrosclerosis
- Glomerular
- Primary: IgA nephropathy
- Secondary
- Interstitial: reflux nephropathy
- Cystic kidneys
- Chronic transplant dysfunction
Renal replacement therapy
There are several options if the kidneys do not work:
- Dialysis
- Hemodialysis (1960)
- Peritoneal dialysis (1970)
- Transplantation (1966)
- Deceased donor
- Living donor
Diabetes
Diabetes leads to severe vascular complications:
- Microvascular
- Adenopathy
- Nephropathy
- Neuropathy
- Macrovascular
- Cerebral artery disease
- Cardiac disease
- Peripheral artery disease
Simultaneous pancreas kidney transplantation:
In case of diabetes type 1, a simultaneous pancreas and kidney transplantation can be made. This way, the patient can make new insulin.
Problems after transplantation
A kidney transplantation isn't always succesful:
- Week 1 post-transplantation
- Acute tubular necrosis
- Hyperacute rejection
- Urologic
- Obstruction
- Urine leak
- Vascular thrombosis
- Renal artery
- Renal vein
- <12 weeks post-transplantation
- Acute rejection
- Calcineurin inhibitor toxicity
- Volume contraction
- Urologic
- Obstruction
- Infection
- Pyelonephritis
- Viral infections
- Interstitial nephritis
- Recurrent disease
- >12 weeks post-transplantation
- Acute rejection
- Volume contraction
- Calcineuron inhibitor toxicity
- Urologic
- Obstruction
- Infection
- Pyelonephritis
- Viral infections
- Chronic allograft nephropathy
- Decline in renal function
- Recurrent disease
- Renal artery stenosis
- Post-transplantation lymphoproliferative disorder
Infections following renal transplantation:
- 1st month after transplantation: mostly due to the operation
- Long term: opportunistic infections
- Important factor for later renal failure
Rejection
Diagnosis:
In case of rejection, donor antigen presenting cells present an antigen, which triggers reactions of T-cells.
Clinical signs of rejection are:
- Malaise
- Fever
- Oliguria
- Hypertension
- Graft tenderness
Diagnosis hinges on serial creatinine measurements. Elevation of 20%
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Mechanisms of Disease 1 HC25: Epidemiology
HC25: Epidemiology
Definition of epidemiology
Epidemiology is the study of the occurrence and determinants of illnesses and their spread in the population. It is about the effects between:
- Environment
- Host
- Microorganism
Incidence, prevalence and attack rate
The 3 most important terms in epidemiology are:
- Incidence: the part of the population which develops the disease in a certain time period
- Number of new cases (n)/(population number (N) x time period)
- Prevalence: the part of the population which has the disease at a certain time point
- Number of existent cases (n)/population number (N)
- Attack rate: the percentage of "attacked" people
- Number of people affected/population number (N)
Case:
The following data is available:
- 10 beds, 10 days
- 5 surgical site infections
- 24 patients
- 95 patient days
The following calculations can be done:
- The prevalence on day 3 is: 1/9 = 11%
- The prevalence on day 10 is: 2/8 = 25%
- The incidence is 5/95 patient days
- 100 patient days is 1 patient staying in the hospital for 100 days, or 4 patients staying for 25 days
- The attack rate is 5/24 = 21%
Endemic, epidemic and pandemic
3 important terms that describe to what extent a disease has spread are:
- Endemic: the disease occurs continuously in a certain part of the population, but doesn't spread any further
- For example malaria in sub-Saharan Africa
- Epidemic: the disease occurs more frequently than normal and there are more patients than expected
- For example Ebola in 2015/2016
- Pandemic: an epidemic on worldwide level
- Can be caused by a DNA-shift → a part of the genome of the pathogen changes
Filoviruses
Currently the Ebola virus is causing an epidemic. In Africa, confirmed cases of Ebola HF have been reported in many countries.
Structure:
Marburg and Ebola are filoviruses, which have a distinguishing structure:
- Negative-stranded RNA virus
- Envelope
- Threadlike structure
- Very broad cell tropism → can infect nearly every cell in the body
Transmission:
Fruitbats form the normal reservoir of Ebola. The hosts are reindeers and monkeys → these animals are infected, but the virus normally stays inside the rainforest. People living around the rainforest can get infest by eating meat of these animals. In conclusion, filoviruses can be transmitted in multiple ways:
- Primary transmission: contact with fruitbats/infected mammals
- Bushmeat
- Interhuman transmission: contact between body secretions
- Sweat, mucosae, bloodstream, non-intact skin, aerosols (limited)
- Nosocomial transmission: inadequate sterilization of materials
- One of the biggest outbreaks of Ebola was caused by hospital needles not being properly sterilized
Incubation period:
The incubation period is the moment of infection up to the moment of the first symptoms. It is important to know the incubation period to determine how long a patient has to be isolated. In this period, the patient has a clinical disease.
Both Ebola and Marburg
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Mechanisms of Disease 1 HC26: Prevention and control
HC26: Prevention and control
Preventive measures
There are many ways a source can infect a host, which means there also are many preventive measures:
- Reservoir
- Elimination: everything that can be done to eliminate a microorganism
- Cleaning
- Disinfection
- Sterilization
- Pasteurization
- Water purification
- Sewage treatment
- Adequate heating of food
- Screening of blood products
- Social development
- Elimination: everything that can be done to eliminate a microorganism
- Source
- Elimination
- Cleaning
- Disinfection
- Sterilization
- Pasteurization
- Water purification
- Sewage treatment
- Adequate heating of food
- Screening of blood products
- Social development
- Source isolation
- Elimination
- Transmission
- Interruption of transmission
- Hand hygiene
- Vector control
- Asepsis
- Use of gloves, gowns and face masks
- Protection against insect bites
- Safe handling of sharps
- Safe sex
- Interruption of transmission
- Host
- Protective isolation
- Protection of the host
- Vaccination
- Passive immunization
- Antimicrobial prophylaxis
- Social development
Outbreaks
Whether something is called an outbreak depends on how often a certain disease normally occurs. If a disease usually rarely occurs, but suddenly the prevalence rises, there is an outbreak.
Q-fever
Clinical presentation:
A while ago there was an outbreak of Q-fever. Q-fever is caused by coxiella burnetti, an intracellular bacterium which lacks a cell wall. The clinical presentation of Q-fever is:
- Fever, headache
- Sometimes:
- Coughing
- Pleural pain
- Rarely:
- Granulomatous hepatitis
- Chronic Q-fever: endocarditis, infections of vascular prostheses of prosthetic valves
Q-fever is mainly diagnosed based on antibodies in the serum → aren't visible with microscopy.
Infection chain:
The infection chain of Q-fever consists of:
- Reservoir: very complex → zoonosis mainly started by ticks
- Source: animal products or animal abortions
- Especially from goats and sheep
- Abortion products form spores that can survive for years
- Transmission: inhalation
- Transmission from host to source is very unlikely → humans are final stadium hosts
- Host: humans
The only way to fight Q-fever is to destroy the reservoir → all involved animals have to be killed. Subsequently, all sheep and goats need to be vaccinated.
Hospitals
Hospitals take many measures to prevent and control infections. There is a high risk of nosocomial infections such as:
- Postoperative wound infection
- Catheter-related bloodstream infections
- Urinary tract infection
- Hospital acquired pneumonia
Prevention and control of these infections mainly consists of hand hygiene and isolation.
Hand hygiene:
Ignaz Semmelweis (1815-1865) worked in 2 different wards of the General Hospital of Vienna in the 1840's:
- Ward 1: doctors and medical students
- Ward 2: midwives
In ward 1, there was much more maternal mortality caused by fever than in ward 2. Semmelweis noticed that the doctors and students didn't wash their hands with chlorine solution, while the midwives did. In ward 1, microorganisms from corpses were transmitted to the next mothers causing them to die.
The hands can transmit resident and transient microorganisms. Resident microorganisms reside in cracks in the skin and transient microorganisms on the surface → after handwashing, only the transient microorganisms disappear. After using soap, the
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Mechanisms of Disease 1 HC extra: COVID-19
HC extra: COVID-19
COVID-19 epidemiology
The start of a pandemic:
COVID-19 originates from Wuhan, in the province Hubei in China. Over 11 million people live there.
Numbers:
Important numbers to know are:
- Incidence: new number of cases/population
- Case fatality rate: number of deceased/total number infected
- R0reproductive number: average number of new cases infected by 1 infected person
In case of COVID-19, almost all numbers aren't correct:
- Only what is tested is known
- What isn't tested, isn't known
- Misclassification
- There is always delay
- Reports are never up to date
- Disease in specific subgroups can be underreported
- There are always aberrations
- R0represents the average number, but not the real patterns of transmission
Transmission:
The transmission chain of COVID-19 consists of:
- Reservoir: bats
- Source: humans
- Host: humans
Transmission happens via different routes:
- Droplet-borne route: droplets cannot travel very far because they sink to the ground due to gravity
- Short-range airborne route: transmitted by aerosols
- Long-range airborne route: transmitted by aerosols
- Fornite route: via surface contact or contact between people
Clinical aspects
Clinical course:
From January to May 2020, there were 1,320,488 laboratory-confirmed COVID-19 cases, of which:
- 14% were hospitalized
- 2% were admitted to the intensive care unit
- 5% died
These percentages are only based on the confirmed COVID-19 cases → aren't realistic.
Symptoms of COVID-19 are:
- Cough (50%)
- Fever (43%)
- Myalgia (36%)
- Headache (34%)
- Dyspnea (29%)
- Sore throat (20%)
- Diarrhea (19%)
- Nausea/vomiting (12%)
- Loss of smell or taste, abdominal pain, rhinorrhea (10% each)
Complications of COVID-19 can be:
- Pulmonary embolism
- Acute respiratory distress syndrome
- Possibly due to a cytokine-storm → hyper-inflammatory state
Diagnosis:
COVID-19 can be diagnosed with molecular techniques → the SARS-CoV2 viral load is highest in respiratory samples. For instance, in case of PCR, the sensitivity is the highest in lower airway samples.
COVID-19 diagnosis can also be done using serology. This is useful when the patient has had the virus for a while → antibodies can be detected around day 10.
Lastly, diagnosis of COVID-19 can be done using radiology. COVID-19 has a specific pattern on a CT-scan. A score is given to the images → a CO-RAD score of 4 or 5 indicates that there is a COVID-19 infection and a CO-RAD score of 1 or 2 indicates that an infection by this virus is unlikely.
Treatment:
There are 3 treatment options to treat COVID-19:
- Supportive care
- Anti-viral
- Remdesivir
- Convalescent plasma
- Anti-inflammatory
- Corticosteroids
- Dexamethasone
- Anti-IL6 (tocilizumab)
- Anti-IL1 (anakinra)
- Bradykinine-inhibitor (Icatibant)
- Anti-CD147 (meplazumab)
- JAK-inhibitor (ruxolitinib)
Remdesivir is an anti-viral way to treat COVID-19. It was originally designed for the Hepatitis C virus, and later used for Ebola and Marburg. It is a ribonucleotide analogue inhibitor of viral RNA polymerase. It gives a faster clinical improvement but no difference in mortality. Usually it is prescribed 10 days after the symptoms start, so it may be more
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Mechanisms of Disease 1 HC27: Mechanisms of hypersensitivity reactions
HC27: Mechanisms of hypersensitivity reactions
Immunopathology
There are 3 types of immunopathology:
- Immunodeficiency: an ineffective immune response
- Hypersensitivity: an overactive immune response
- Autoimmunity: an inappropriate reaction to self-antigens
A common feature is loss of (self)tolerance and lack of control of the immune response resulting in (chronic) inflammation.
Inflammation:
Inflammation is a protective response aimed to eliminate cause of injury, clear damaged tissue and initiate repair. Classical signs of inflammation are:
- Pain
- Heat
- Redness
- Swelling
Chronic inflammation contributes to a wide variety of diseases like cancer, diabetes and Alzheimer.
Hypersensitivity:
Characteristics of hypersensitivity reactions are:
- Undesirable reactions of the normal immune system in pre-sensitized hosts
- The reaction is not abnormal
- Pre-sensitized hosts → there has been contact with the antigen before
- Mechanisms are similar to those operative in the normal immune response
- Abnormal because of the exaggerated or otherwise inappropriate form resulting in tissue injury
There is a classification that distinguishes hypersensitivity reactions in 4 types:
- Type I reactions: immediate hypersensitivity
- Type II reactions: antibody-mediated diseases
- Type III reactions: immune-complex mediated diseases
- Type IV reactions: T-cell mediated diseases
Type I, II and III reactions are mediated by antibodies → the reactions are immediate. Type IV reactions are mediated by T-cells → the reactions are delayed.
Type I hypersensitivity
Examples:
Type I hypersensitivity is IgE-mediated. Examples are:
- Atopic rhinitis
- For example seasonal hayfever
- Atopic conjunctivitis
- Atopic asthma
- Allergy and bronchial hyperresponsiveness
- Atopic dermatitis
- Food allergy
- Systemic anaphylaxis
Atopy:
Atopy is the predisposition to make IgE antibodies that specifically target innocent substances in the environment.
Process:
In case of IgE-mediated hypersensitivity (type I), 3 particles are involved:
- IgE
- Eosinophils
- Mast cells
IgE-mediated hypersensitivity has 2 phases:
- Allergic sensitization
- A dendritic cell phagocytoses an allergen
- The dendritic cell presents a fragment of the pathogen to a Th0-lymphocyte
- The Th0-lymphocyte evolves to a Th2-lymphocyte
- The Th2-lymphocyte starts to produce IL-4 and IL-13 → B-cells differentiate to plasma cells and class-switch to the production of IgE
- Symptomatic phase
- Dendritic cells present antigens to memory Th2-cells → release IL-4, IL-5 and IL-13 → results in characterizing symptoms
- IL-4 and IL-13 activate the epithelia → mucus production and fibroblast activation
- IL-5 produces and activates eosinophils in the bone marrow
- Sensitization has already taken place → the allergen binds to mast cells with high affinity IgE-receptors
- Activation of mast cells results in cross-linking of IgE-receptors → 2 receptors bind 1 antigen
- Degranulation of the mast cell → histamine and protease release
- There molecules are already present → reactions occur immediately
- De novo-synthesis and secretion of lipid mediators in the mast cell
- Important for continuation of the inflammatory reaction
- Degranulation of the mast cell → histamine and protease release
- Vasodilatation → increased vascular permeability → contraction of smooth muscle cells → chemotaxis of leukocytes
- Dendritic cells present antigens to memory Th2-cells → release IL-4, IL-5 and IL-13 → results in characterizing symptoms
Because of the interplay of all the immune cells locally, they all produce mediators
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Mechanisms of disease 1 HC28: Pathology of allergy
HC28: Pathology of allergy
Classification
Classification is the act of forming a distribution into groups, classes, orders and families according to some common relations or attributes. A classification system is used to:
- Enhanced the quality of communication
- Especially between experts involved in the field
- Provide a logical structure for categorization
- For epidemiologic, prognostic or interventional studies
- Assist in the management of individual patients
- To this extent, categories should be mutually exclusive and predictive of the subsequent behavior of the disease
Conjunctivitis
Conjunctivitis is a type I hypersensitivity reaction. In case of direct hypersensitivity reactions, there is a fast immunological reaction in a sensitive individual, often called an allergy.
Morphology:
Histological images of conjunctivitis are different from most images of type I hypersensitivity reactions:
- Eosinophils are strongly present
- IgE is hard to find in a histological image
- Mast cells are present, but are hard to distinguish
Symptoms:
Conjunctivitis is an ocular allergy caused by pollen release spores. Symptoms are:
- Itching
- Watery discharge
- Redness
The upper ENT may also be involved.
Therapy:
Therapy consists of:
- Antihistamines
- Mast cell stabilizers
- Non-steroidal anti-inflammatory agents
Anti-GBM nephritis
Anti-GBM nephritis is an example of Type II hypersensitivity. GBM stands for glomerular basal membrane. Type II hypersensitivity reactions are mediated by antibodies directed to antigens on the cell-surface in the extracellular matrix. It is caused by cell destruction, an inflammatory reaction or intervention with the normal function. Deposited IgG-antibodies activate the complement system → inflammatory reaction.
Process:
In case of anti-GBM nephritis, the following happens:
- Anti-GBM antibodies bind to the basal membrane of capillaries
- Leukocytes (such as neutrophils) are activated and attack the vessel walls → the basal membrane breaks
- The vessel walls become infected → glomerulonephritis and alveolar capillaritis
- Capillary loops are destroyed
- Inflammatory mediators come into Bowman’s space → lining epithelium starts to proliferate → crescent formation
- Histological images of glomerulonephritis show a crescent
The IgG antibodies work against the alpha-3 chain of collagen type IV, a complement of GBM. The alpha-3 chain is part of the basement membrane in the kidney and the lung. This causes leukocytes to attack the membrane with antigens. Anti-GBM nephritis typically occurs in the kidneys and lungs.
Goodpasture syndrome:
About 50% of anti-GBM nephritis cases occurs without the lungs being involved. In case of Goodpasture-syndrome, both kidneys and lungs are involved. This usually is paired with hemorrhagia (bleeding). The alveolar walls are inflamed and pneumocytes are clearly visible.
Smokers:
Glomerulonephritis typically occurs in smokers → smoking destroys the alveolar epithelia → antibodies travel from the lungs to the kidneys. This can be diagnosed with serology for anti-GBM antibodies.
Fibrinoid necrosis
Fibrinoid necrosis is a type III hypersensitivity reaction. An important difference between type II and III hypersensitivity is that in case of type III the antibodies bind to solubles.
Morphology:
Histological images of fibrinoid necrosis show:
- Fibrine
- Necrosis
- Inflammation
Process:
Fibrinoid
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Mechanisms of Disease 1 HC29: Asthma
HC29: Asthma
Symptoms
Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation (not every patient has this). It is defined by the history of symptoms such as:
- Wheeze
- Shortness of breath
- Chest tightness and cough
These symptoms occur together with variable expiratory airflow limitation and vary over the time and in intensity. Eosinophils are prominently present. In case of fatal asthma, the airways are filled with mucus.
Phenotypes
Symptoms of asthma can vary greatly → asthma ≠ asthma. There are many pnenotypes of asthma:
- Allergic asthma
- Work related asthma
- Asthma in obesity
- Exercise induced asthma
- Recurrent infectious asthma
- Severe eosinophilic asthma
- Et cetera
Patients can have severe disease and absence of eosinophils, or presence of eosinophils but hardly any symptoms → the asthma spectrum is very broad. For this reason, obstructive lung disease may be a better definition for the disease.
Treatment
Asthma has the following characteristics, which can be treated with:
- Remodeling
- Hypertrophy of the muscles → thicker wall, narrow lumen
- Cannot be treated
- Mucus production
- Inhaled steroids
- Antibiotics
- Azithromycin changes the environment of the airways → removes microorganisms
- Inflammation
- Inhaled steroids
- Have many side effects such as obesity
- Monoclonal antibodies
- Reduce the dose of steroids
- Inhaled steroids
- Smooth muscle contraction
- Bronchodilators
- b2-agonists → stimulate the sympathetic nervous system
- Anticholinergics → reduce the parasympathetic nervous system
- Relieve the muscle contraction, but don’t treat the inflammatory process
- Bronchodilators
Treatment of mild asthma:
There has been a historical change in treatment of “mild” asthma. At first there was only treatment with bronchodilators, but it appears patients with apparently mild asthma are at risk of serious adverse events:
- 30-37% of adults with acute asthma had symptoms less than weekly in the previous 3 months
- 16% of patients with near-fatal asthma had symptoms less than weekly in the previous 3 months
- 15-20% of adults dying of asthma had symptoms less than weekly in the previous 3 months
Exacerbation triggers are variable:
- Viruses
- Pollens
- Pollutions
- Poor adherence
Inhaled SABA has been first-line treatment for asthma for 50 years:
- This dates from an era when asthma was thought to be a disease of bronchoconstriction
- Patient satisfaction with, and reliance on, SABA treatment is reinforced by its rapid relief of symptoms, its prominence in ED and hospital management of exacerbations, and low cost
- Patients commonly believe that “my reliever gives me control over my asthma” → they often don’t see the need for additional treatment
In 2020, GINA constated that the first line treatment for mild asthma is ICS-formoteral as needed. b2-agonists are no longer the first treatment for mild asthma.
Diagnosis
There are 2 ways to diagnose asthma:
- History of characteristic symptoms: vary over the time and in intensity
- Wheeze
- Shortness of breath
- Chest tightness and cough
- Evidence of variable airflow limitation
Allergic asthma
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Mechanisms of Disease 1 HC30: Pathology of autoimmunity
HC30: Pathology of autoimmunity
Autoimmune diseases and hypersensitivity
Hypersensitivity reactions and autoimmune diseases correlate with each other:
- Hypersensitivity reactions
- Mechanisms show that the immune system overreacts to certain stimuli
- Are present in many autoimmune diseases
- Type I hypersensitivity forms an exception
- Autoimmune diseases
- Have a hypersensitivity reaction as part of their pathogenesis
Autoimmunity and infection
Patients with a variety of auto-immune diseases report that an infectious disease seems to precede the development of their auto-immune disease. In these cases, an infection can be:
- A trigger
- For the production of antibodies that cross-react with autoantigens
- An enhancer
- For activating the immune system by activating inflammatory cells
- A second, third of fourth hit in a complex pathogenesis
Examples are:
- Many patients with IgA nephropathy report flu-like episodes with gastrointestinal and upper airway involvement before the occurrence of hematuria
- Patients with ANCA-associated vasculitis often report that their initial symptoms consisted of upper airway disease with sinusitis
Koch’s postulates:
The association of specific microorganisms with diseases came about as a consequence of the work of the German physician Robert Koch. He formulated a set of criteria that could be used to identify the pathogen responsible for a specific disease. These criteria came to be known as Koch’s postulates:
- The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms
- It must be possible to identify microorganism from a diseased organism
- The microorganism should then cause disease upon introduction into a healthy organism
- The microorganism should be identified as being identical to the original specific causative agent
- If detection of the microorganism predates disease and/or if its quantity correlated with disease severity a causal relationship becomes more likely
In case of autoimmunity, the microorganism is replaced by a factor such as an antibody. The criteria are a little less strict than for infectious diseases → for instance, the factor must be present in most organisms.
ANCA-associated vasculitis:
Anti-neutrophil cytoplasmic autoantibodies (ANCA) pass these criteria. The antibodies are directed against components in granules of neutrophils, for example against proteinase-3, myeloperoxidase and elastase. Most patients with systemic vasculitis have high values of these antibodies, while healthy patients hardly have any of them.
Other immune mediated diseases are:
- Rheumatoid arthritis
- Sjögren’s disease
- Systemic sclerosis
- Idiopathic interstitial fibrosis of the lung
In some patients, antibodies can be present long before they have symptoms or the disease is diagnosed.
Rheumatoid Arthritis
Rheumatoid Arthritis is a systemic, chronic inflammatory disease, affecting many tissues but principally the joints → hand-knuckles start to swell. A typical patient is a 40-year-old woman. It is relatively frequent in the population, but there are many treatment options.
Histology:
Histological images show a proliferating synovitis that frequently destroys the cartilage or bone, with disabling arthritis. There are villous projections of granulation tissue with inflammatory infiltrate and proliferation of synovial lining
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Mechanisms of Disease 1 HC31: HLA and autoimmunity
HC31: HLA and autoimmunity
Communication
Communication between 2 cells takes place via surface contact. This is made possible by:
- Neurons
- Muscles
- Immune cells
Many processes use synapses to communicate. This communication is specific → HLA molecules (MHC molecules) are present on antigen-presenting cells. There are many different HLA-molecules and the T-cell receptors know exactly which molecule it is.
Myasthenia gravis
In case of myasthenia gravis (MG), there is a defect of neuro-muscular synapses where the motor neuron informs the muscle whether or not to contract. 99% of myasthenia gravis cases are caused by an auto-immune disease → develop during life. Several subtypes of myasthenia gravis exist, each caused by autoantibodies against the neuromuscular synapse.
Process:
Normally, there are 2 important signal transduction cascades in the synapse, where
vesicles with acetylcholine play an important part:
- Voltage gated calcium channels (VGCC) release acetylcholine → binds to the acetylcholine receptors on the post-synaptic membrane → depolarization
- Muscle specific kinase (MuSK) and lipoprotein-related protein 4 (Lrp4) bind acetylcholine to the receptor
- The nerve secretes argin
- Argin binds to Lrp4
- The muscle knows that there is a nerve
- Lrp4 interacts with MuSK
- Gives feedback to the nerve
- MuSK dimerizes → autophosphorylation
- A signaling cascade to the clustering acetylcholine receptor (AChR)
Myasthenia gravis is caused by acetylcholine receptors not clustering.
Symptoms:
Myasthenia gravis is characterized by fluctuating muscle weakness which improves during rest. Patients with myasthenia gravis have antibodies against AChR, MuSK or Lrp4, which cause different symptoms:
- AChR myasthenia gravis
- 80% of myasthenia cases
- Asymmetric
- One eye is more affected than the other
- Fluctuating ptosis
- Ophtalmoplegia with diplopia
- Descending weakness
- Starts in the upper body parts and slowly spreads downwards
- May ultimately affect all skeletal muscles
- MuSK myasthenia gravis
- 4% of myasthenia cases
- Asymmetric
- Bulbar weakness
- Speaking problems
- Swallowing problems
- Neck weakness
- Up to 50% have respiratory insufficiency at some point
- Lrp4 myasthenia gravis
- 2% of myasthenia cases
Epidemiology:
AChR myasthenia gravis mainly occurs in:
- Young women
- A non-tumor and early onset is more common
- Old men
- A non-tumor and late onset is more common
- A small cell lung carcinoma is more common
The disease is associated with a tumor in the thymus:
- 15% of myasthenia gravis cases are paired with a thymoma
- The thymus may also be enlarged
- 40% of thymoma cases are paired with myasthenia gravis
MuSK myasthenia gravis only occurs in women. In this case, there is no tumor-association.
Lambert-Eaton Myasthenia
4% of Myasthenia patients have Lambert-Eaton Myasthenia (LEMS). In this case, antibodies for the voltage gated calcium channels (VGCC) are present.
Symptoms:
LEMS is characterized by ascending weakness → starts in the legs and slowly spreads upwards. For instance, patients have trouble standing up without using their hands. There mainly is an autonomic dysfunction.
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Mechanisms of Disease 1 HC32: Vasculitis
HC32: Vasculitis
Vasculitis
Vasculitis is a hypersensitivity reaction. It is a systemic disease. There is an inflamed blood vessel and fibrinoid necrosis caused by white blood cells that have been stimulated by ANCA. Every blood vessel can be damaged and eventually lead to death.
Peri-arteritis nodosa
In the 19th century, many descriptions of similar patients appeared. The general name given to their symptoms was periarteritis/polyarteritis nodosa. There was an inflammation of the blood vessels → arteritis, which was arranged in a nodular fashion → nodosa. Both similarities and variations were noticed:
- Similarities
- Illness of the vessels
- Rapid course
- Death
- Variations
- Organ involvement
- Differences in histology
This mainly occurred in combination with kidney disease and progressive muscle weakness. Several hypotheses on the etiology of vasculitis were made based on environmental factors, viruses and genetics.
Subtypes
Henoch Schonlein purpura:
Henoch Schonlein purpura is a subtype of vasculitis mainly affecting the skin and gut, but other organs may be affected as well. Patients are mainly children and elderly. The disease is characterized by:
- Abdominal pain
- Purpura on the legs
- Purple point bleedings
Henoch Schonlein can also affect the kidneys → deposition of IgA in the glomeruli of the kidneys. It is possibly related to IgA nephropathy, which is the most common immune mediated disease in the western world. Therefore, IgA vasculitis is a suggested alternative name for Henoch Schonlein purpura. In other subtypes of vasculitis, no glomerular disposition is visible → the ANCA-test is negative.
Churg-Strauss syndrome:
In 1951, Jacob Churg and Lotte Strauss published on 13 patients with vasculitis who had prominent lung involvement and were previously known with asthma. This typical combination of the lung with eosinophilia became known the Churg-Strauss Syndrome.
Churg-Strauss syndrome is a vasculitis typically involving the lungs with an eosinophilic infiltrate, in patients previously known with asthma. Both asthma and in this case also vasculitis are strongly related to eosinophilic granulocytes. The disease is also known as EGPA (eosinophilic GPA).
Granulomatosis with polyangiitis:
Granulomatosis with polyangitis (GPA) is type of vasculitis that used to be known as Wegener’s granulomatosis. It is a combination of:
- Upper airway vasculitis
- Renal involvement
- Histologically proven presence of granulomas
Typical for people with GPA is the “saddle nose”. This is chronic and is caused by vasculitis destroying the cartilage in the nose → there is no tissue left in the middle of the nose. This may be associated with staphylococcus aureus infections.
Anti-neutrophilic cytoplasmatic auto-antibodies
In case of systemic ANCA-associated vasculitis, anti-neutrophilic cytoplasmic auto-antibodies (ANCA) are detected. These antibodies are a form of IgG and are directed against components in the primary granules of neutrophils, for example:
- Proteinase-3
- Myeloperoxidase
- Elastase
- Other components
ANCA-test:
The ANCA-test is used a lot for diagnostics. It is a type of indirect immunofluorescence:
- Granulocytes (neutrophils) from healthy donors are put on a glass slide
- Patient serum is put on the slide
- ANCA directed towards neutrophils binds to the neutrophils
Mechanisms of Disease 1 HC33: Systemic Lupus Erythematosus
HC33: Systemic Lupus Erythematosus
Clinical image
Systemic lupus erythematosus (SLE) is the prototype of a multisystem disease of auto-immune origin. It is a type III hypersensitivity reaction characterized by a broad spectrum of autoantibodies and butterfly rash (erythematosus). The clinical course is extremely variable → there are remissions and relapses.
SLE affects many different organs:
- Skin
- Kidneys
- Joints
- Heart
- Serosal membranes
Epidemiology:
The disease is fairly common in certain populations → in Asia, 1 in 2500 persons are affected. There is a strong female preponderance. Peculiarly, in areas where the disease is more common, the symptoms are less severe → the disease only manifests in 1 organ. In areas where the disease is rare, the symptoms are more severe → more organs are involved.
Lupus nephritis
Up to 60% of patients with SLE develop lupus nephritis. Lupus nephritis has a considerable morbidity and poor survival. The histopathological findings in lupus nephritis vary considerably → classification of lupus nephritis is essential for treatment decisions.
Diagnostics
There is a mnemonic to diagnose SLE → the symptoms together form “SOAP BRAIN MD”. SLE can be diagnosed when 4 of these symptoms are present during any amount of time:
- Serositis
- For example pleuritis
- Many organs have a thin layer of serosa → can be inflamed
- Oral ulci
- Arthritis
- Photosensitivity
- Can cause rash after exposure to the sun
- Blood changes
- Of any kind
- Renal involvement
- Of any kind → nephrotic or nephritic syndrome
- ANA (anti-nuclear antibodies)
- Immunological changes
- Low C3 levels
- Caused by high activity of the complement system in this disease
- Low C3 levels
- Neurological signs
- Neuro-lupus and the fog
- A vasculitis-like lesion is visible in the brain
- Fog: patients feel like they’re in a surrealistic surrounding
- Neuro-lupus and the fog
- Malar rash
- Butterfly rash
- Discoid rash
- Rash on body parts other than the face
Serology
The is a wide spectrum of autoantibodies in SLE → there are antibodies against:
- Cytoplasmic components
- Surface antigens of blood cells
- Proteins in complex with phospholipids
- Nuclear components
- Antibodies to DNA
- Antibodies to histones
- Antibodies to nonhistone proteins
- Antibodies to nucleolar antigens
Etiology
It is peculiar that there can be antibodies against components of a cell. There are many hypotheses on etiological factors:
- Modification of a self-antigen
- By a virus or drug
- Polyclonal B- or T-cell activation
- Genetically determined
- May be triggered by:
- Viruses
- Drugs
- Bacteria
- Defective thymus
- Dysregulated apoptosis and/or clearance of apoptotic cells
- Chimerism
Apoptotic cells:
Apoptotic cells are present in the tissue. SLE causes the production of anti-nuclear antibodies (ANAs), which can be detected by indirect immunofluorescence. ANAs presumably destroy parts of the nucleus → cause apoptosis. This is called nuclear dust.
There is a hypothesis that because of a macrophage dysfunction, there is a defective clearance of nuclear antigens from
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Mechanisms of Disease 1 HC35: Infections and autoimmunity
HC35: Infections and autoimmunity
Overlap
Infection, inflammation and autoimmune diseases can overlap, but this isn’t necessary:
- In case of rheumatoid arthritis, there is inflammation but no infection
- In case of cholera and tetanus, there is infection but no inflammation
- In case of myasthenia gravis, there is autoimmunity but no inflammation
From infection to autoimmunity:
Infection can lead to autoimmunity. An infection induces a normal immune response, but the immune molecules or cells react with self-antigens which are similar to those of the pathogens → cross-reactivity. This can be caused by some microorganisms having qualities that resemble human qualities → normally the body doesn’t react to self-antigens due to positive and negative selection. This is called tolerance, which is expressed by the regulatory T-cells.
Acute rheumatic fever
Case:
A 9-year-old boy of Turkish descent acutely falls ill:
- Fever
- Arthritis of right knee, later of both knees
- Heart murmur
- High inflammation
- ESR: 140 mm/hour
- C-reactive protein: 160
- Normally this is <3
- ECG: prolonged PR interval
- Echocardiography: mitral valve abnormalities
The diagnosis is acute rheumatic fever (ARF).
Clinical presentation:
ARF is an infection and an autoimmune reaction. It is a result of throat infection, but not of skin infection, by streptococcus pyogenes. Immunological effects of this bacteria are:
- Acute rheumatic fever
- An autoimmune response
- Acute glomerulonephritis
- A type III hypersensitivity reaction
Not the bacteria, but the immune response causes symptoms. ARF is a syndrome → a combination of symptoms and signs:
- Heart: carditis
- Joints: arthritis
- Neurological: chorea
- Skin: nodules and/or erythema marginatum
Epidemiology:
ARF mainly occurs in developing countries. Recurrent ARF may lead to rheumatic heart disease (RHD):
- Incidence of ARF: 0,5 million/year → 300.000 develop RHD
- Prevalence of RHD: 15 million
- Mortality of RHD: 233.000/year
ARF mainly occurs in children of young age, while RHD is more common among elderly. Approximately 3-6% of the population is susceptible.
Pathogenesis:
Pathogenesis is made up out of:
- Molecular mimicry: auto-immune hypersensitivity
- Type II reaction: initial damage → exposes self-antigens
- IgG formed against streptococcus pyogenes reacts with an M-protein (and possibly group A carbohydrates) on the bacterium
- M-proteins prevent opsonization
- Have 3 parts: the response is directed against middle components which have rheumatoid epitopes
- M-proteins prevent opsonization
- IgG formed against streptococcus pyogenes reacts with an M-protein (and possibly group A carbohydrates) on the bacterium
- The complex cross reacts with:
- Myosin
- Heart sarcolemma
- Synovium
- Articular cartilage
- Subsequent type IV response: Th1 cellular responses
- The myocardium contains Aschoff bodies
- Type II reaction: initial damage → exposes self-antigens
- Genetic predisposition
The prognosis of the first episode is quite good → 27% has no abnormalities after 1 year. Therapy consists of:
- Anti-inflammatory drugs
- Slow-releasing penicillin: to prevent re-infection of streptococcus pyogenes
Jones criteria:
To diagnose ARF, the Jones criteria are used:
- 2 major or 1 major and 2 minor manifestations must be present, plus evidence of antecedent group A streptococcus infection
- Chorea and indolent carditis do not require evidence of antecedent group
Mechanisms of Disease 1 HC36: Immune cells in rheumatoid arthritis
HC36: Immune cells in rheumatoid arthritis
Rheumatoid arthritis
Symptoms:
Rheumatoid arthritis (RA) is a rheumatic autoimmune disease characterized by inflamed joints:
- Painful joints
- Swollen, warm joints
- Impaired functioning
- Stiffness
- Tiredness
Process:
There are several stages of rheumatoid arthritis:
- Normal
- Arthralgia
- Painful joints
- Onset arthritis
- Joints become inflamed
- Undifferentiated arthritis → doesn’t necessarily lead to rheumatoid arthritis
- Established rheumatoid arthritis
- Leads to either slowly or rapidly progressive rheumatoid arthritis
- Slowly progressive rheumatoid arthritis
- Rapidly progressive rheumatoid arthritis
The time frame in which this happens is unknown. It may be longer than 10 years.
Diagnosis:
Rheumatoid arthritis is a heterogenous disease → it is difficult to diagnose. The following classification criteria is used to diagnose rheumatoid arthritis:
- Joint distribution (0-5)
- 1 medium/large joint → 0
- 2-10 medium joints → 1
- 1-3 small joints → 2
- 4-10 small joints → 3
- >10 joints, of which at least 1 is small → 5
- Serology (0-3)
- Neither Rf nor ACPA positive → 0
- At least one test is low positive → 2
- At least one test is high positive → 3
- Symptom duration (0-1)
- <6 weeks → 0
- >6 weeks → 1
- Acute phase reactants (0-1)
- Neither CRP nor ESR abnormal → 0
- Abnormal CRP or abnormal ESR → 1
In case 6 or more points are present, RA is definite.
Pathophysiology:
Rheumatoid arthritis is inflammation of the synovial membrane of the joint, characterized by:
- Influx of adaptive and innate immune cells
- Extensive angiogenesis
- New blood vessels are formed
- Synovial hyperplasia
Inflammation
Symptoms:
Inflammation is a reaction of the immune system to triggers. It is characterized by:
- Dolor
- Calor
- Rubor
- Tumor
- Loss of function
The aim of inflammation is to remove harmful agents and repair the damage.
Process:
Healthy skin is not inflamed. Inflammation starts as follows:
- Macrophages in tissues recognize pathogens
- Pro-inflammatory cytokines are secreted by the macrophage
- IL-1b→ fever and production of IL-6
- TNF-a→ fever, mobilization of metabolites and shock
- IL-6 → fever and induces acute-phase protein production by hepatocytes
- CXCL8 → chemotactic factor, recruits neutrophils and T-cells to the site of infection
- IL-12 → activates NK-cells and induces the differentiation of CD4 T-cells into Th1-cells
- Vasodilation and increased vascular permeability allow fluid, proteins and inflammatory cells to leave and enter tissue
- The infected tissue becomes inflamed, causing redness, heat, swelling and pain
- Activated inflammatory cells undergo apoptosis and clearance
- This is a tightly regulated event to prevent chronic inflammation
- Apoptotic neutrophils promote the recruitment of monocytes
- Monocytes are attracted to the tissue by lipid mediators → differentiate to macrophages
- Macrophages digest apoptotic neutrophils and produce anti-inflammatory cytokines → no new immune cells enter the tissue
The inflammation stops when the harmful agent is removed. This also is the case in allergies.
Immune cells
Rheumatoid arthritis is also an inflammation.
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Mechanisms of Disease 1 HC37+38: Pharmacology: immunosuppression
HC37+38: Pharmacology: immunosuppression
What is immunosuppression?
Immunosuppressive drugs are drugs that lower the body’s normal immune response → they interfere with the immune system homeostasis. They are a variety of drugs that prevent the production of antibodies. Commonly, they are used to prevent rejection of the recipient’s body of an organ transplanted from a donor.
Immunosuppression is needed in case of:
- Autoimmune disease
- Transplantation
Examples of such cases are acute Graft versus Host disease and systemic lupus erythematosus. Glucocorticosteroids are examples of immunosuppressive drugs.
History
The history of immunosuppression is a successful story:
- 1954: the first successful renal transplant
- Identical twin donor without immunosuppression
- 1959: the first successful allograft
- Non-identical twin
- Sublethal body irradiation
- 1962: the first successful allograft with an unrelated donor
- Azathioprine
- > 1 year survival
- 1963: reversal of rejection with steroids
- 1967: the first heart transplant
- Died of rejection in several days
Immunosuppressive theory
In reality, transplantation trades 1 set of problems for the other. Immunosuppressive drugs shift balances → new problems arise. Transplantation-patients have a multi-drug therapy of drugs with a low therapeutic index which very susceptible to side effects. Multidrug regimens allow for lower doses of each drug → minimize toxicity while providing adequate immunosuppression. They work at different signals/pathways of immune activation.
Acquiring the desired effect is always paired with toxic effects. Every drug has a certain toxicity:
- NIT: non-immune toxicity
- Give side effects like nephrotoxicity
- Side effects that aren’t immune related but organ related
- A drug doesn’t affect primary action mechanisms
- Give side effects like nephrotoxicity
- ISE: immunosuppressive effect
- Effective level
- Risk of infections is higher
- ID: immunodeficiency
- Infections, hospitalization
NIT and ID can overlap:
- Positive effects have a trade-off
- There already is toxicity at low levels
For this reason, drug concentrations have to be measured continuously → TDM (therapeutic drug monitoring) is necessary. Blood samples are continuously taken to measure the drug concentration.
Goals of immunosuppression
Goals of immunosuppression are:
- Providing adequate immunosuppression
- Minimizing adverse effects
- Treating adverse effects and chronic, drug-related problems
- Screening for drug-related complications
Current drugs are good for preventing acute rejections, but not chronic antibody mediated rejections → there is a recent improvement in short-term outcomes but less improvement in long-term outcomes. Rejections are often chronic.
The focus is on different combinations:
- Reducing doses of each individual drug to improve outcomes
- Combining of multiple, low-dose drugs is more effective than 1 single drug in its optimal dose
Achieving immunosuppression:
Immunosuppression can be achieved by blocking the immune system. The adaptive immune system can be targeted at multiple sites:
- Belatacept: blocks direct interaction between antigen presenting cells and T-cells
- Cyclosporin and tacrolimus: inhibit T-cell proliferation and block downstream signaling → less IL-2 production
- Rapamycin and MMF/azathioprine → inhibit proliferation of activated T-cells
Classification
Immunosuppressants can be classified in 3 groups:
- Inhibitors of cytokine production
Mechanisms of Disease 1 HC39: Pathology of transplantation
HC39: Pathology of transplantation
Transplantation
A transplantation is successful if:
- There is no rejection
- There is a long graft survival
There are 2 types of rejection:
- Acute rejection: essentially a T-cell mediated response
- Treated with for example cyclosporin → inhibits T-cell activation
- Usually, the graft isn’t lost
- Chronic rejection: refers to scarring of the graft
- Exact mechanism is unknown
- Treatment is not available
T-cell mediated acute rejection
T-cell mediated acute rejection is a type of type IV hypersensitivity. This type of hypersensitivity reaction is important in:
- Graft rejection
- Lysis of virus infected cells
- Tumor immunity
CD8 T-cells kill antigen-bearing target cells → cytotoxic T-cells from the host try to kill the donor cells.
Transplantation patients often develop squamous cell carcinomas, a type of skin tumors. These are caused by the HPV virus which can be activated by immunosuppression.
Histopathology:
In case of acute rejection of the kidney, the following is visible:
- T-cells present in interstitial infiltrates → interstitial (inflammatory) infiltrate
- T-cells present in epithelium of tubes → tubulitis: interstitial rejection
- T-cells present in endothelium of vessels → endothelitis: vascular rejection
T-cells can be stained with a CD4 marker. In case of rejection, many CD4 positive T-cells will be visible by the tubuli → tubulitis. In case of vascular rejection, the lumen is filled with swollen endothelial cells with lymphocytes inside them.
Severity:
In the BENF classification, severity of acute rejection is graded from 0-3:
- 0: nil
- 1: mild
- 2: moderate
- 3: severe
This is applied as follows:
- T-cells present in interstitial infiltrates
- i0-i3
- Depends on the % of the interstitial area affected by the T-cells
- T-cells present in epithelium of tubes
- t0-t3
- Depends on the number of T-cells in a tube
- T-cells present in endothelium of vessels
- v0-v3
- Depends on the extent of inflammatory infiltrate and vascular changes in arteries
It isn’t necessary to know this by heart.
C4d:
C4d is a complement waste product, a footprint of classic pathway activation. C4d-positivity along the endothelium of peritubular capillaries signifies that immune complex formation has been active at the endothelial site. In this case, immune complexes of anti-donor antibodies + donor antigens are made. This signifies that some patients also have humoral rejection instead of only T-cell rejection.
Therapy for antibody-mediated rejection can consist of:
- Plasmaferesis
- Rituximab (anti-CD20)
Chronic rejection
Scarring is the most important cause of allograft loss. This is a chronic process of which the etiology is largely unknown. Beginning stages are present in 90% of protocol biopsies taken 1 year after the transplantation. There is no therapy.
Histomorphology:
Histomorphological features of chronic changes in the allograft show:
- Interstitial fibrosis
- Collagen between the tubes
- IFTA is a combination of interstitial fibrosis and tubular atrophy
- Tubular atrophy
- Tubules become smaller
- The basal membrane becomes irregular and thickened
- Glomerulosclerosis
- Chronic vasculopathy
- Severe intimal
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