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Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program. This can be:Physiologic: pre-programmedPathologic: associated with necrosis Apoptosis has the following characteristics:Decrease in cell sizeShrinkageIncrease in chromatin concentrationHyperchromasia: the nucleus becomes small and darkPyknosis → karyohexis → karyolysisPyknosis = shrinkageKaryohexis/karyolysis = nuclear fragmentationIncrease in membrane blebsThis is a very organized process → parts are recycled for the body to reuse. Apoptosis always results in phagocytosis, which is done by macrophages. During apoptosis, the following processes take place:Protein digestionThis is done by a family of caspases that ensure that the pre-programmed suicide happens in an organized wayA family of enzymesDNA-breakdownPhagocytic recognitionThere are several subcellular responses to caspase activation:Lysosomal response → auto-digestionSmooth endoplasmic reticulum (SER) activationMitochondrial swellingCytoskeleton breakdownThin filamentsActin, myosinMicrotubulesIntermediate filamentsKeratin, desmin, vimentin, neurofilaments, glial filaments 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 cellNeutrophils are attracted to the cell → inflammatory responseMacrophages travel to the cell after a while It is important to differentiate between necrosis and apoptosis:Apoptosis: normal death/replacementsShrinkage → reduced cell sizeFragmented nucleusIntact plasma membraneCellular content may be intactNo adjacent inflammationOften physiologicNecrosis: premature death due to causesSwelling...
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There are 7 basic mechanisms of disease:
Narcolepsy is a neurological disorder linked to HLA and autoimmunity. When a narcolepsy-patient is excited, his muscles relax and he passes out.
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:
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:
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.
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 are white blood cells. Blood usually contains 4,5-109leukocytes/L. The morphology and normal distribution of leukocytes in blood has certain properties:
White blood cells can be created in 3 different ways. All leukocytes originate from hematopoietic stem cells, which reside in the bone marrow:
There are 3 barriers that form the body's defense mechanism:
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.
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 |
Innate immunity has different components divided into 3 categories:
An innate immune response has 5 stages:
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:
Pathology always starts with tissue:
3 techniques can be combined to make a final diagnosis:
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:
This is a general mechanism that can be applied in all tissues → the same process can happen in inflamed skin or lung tissue.
Inflammatory cells have a distinct histomorphology:
Some questions cannot be answered by "just" looking at light microscopy:
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 moreA diverse repertoire is necessary because humans are exposed to many different pathogens:
B- and T-cells play a very important part in adaptive immunity. The difference between B-cells and T-cells is obvious:
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.
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:
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 has 2 main functions:
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:
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.
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:
There are several types of lymphocytes:
There are 2 types of MHC molecules, which are distinguished by their peptides being produced in 2 different cellular compartments:
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:
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:
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.
On the surface of B-cells, there are antibodies → membrane bound immunoglobulins which serve as B-cell receptors:
Globally, B-cell activation goes as follows:
Plasma cells may derive from B-cells, but they have different properties:
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:
Antibodies have different domains and nomenclature:
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 moreThe 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:
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:
Somatic hypermutation takes place in the gene segments that coat particles for the variable domains:
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:
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.
In total, there are more than
.....read moreAll diseases are results of visible cell abnormalities. There are 4 kinds of cell adaptations:
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:
Hypertrophy has a specific mechanism:
Atrophy is a reduction in cell size, resulting in a decrease in the size of the organ. This also can be physiologic of pathologic:
The main causes of atrophy are:
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:
Pathologic hyperplasia is distinct from cancer, but it will constitute a fertile soil in which cancerous proliferation may eventually rise.
Metaplasia is a reversible change in which one differentiated cell is replaced by another type, for example:
The body is divided in an inside and an outside world. Between these "worlds", there are junctions, for example:
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.
Death is defined by an irreversible injury:
Some injuries can lead to death if they're prolonged and/or severe enough:
Many things can cause cell
.....read moreApoptosis is a pathway of cell death that is induced by a tightly regulated suicide program. This can be:
Apoptosis has the following characteristics:
This is a very organized process → parts are recycled for the body to reuse. Apoptosis always results in phagocytosis, which is done by macrophages.
During apoptosis, the following processes take place:
There are several subcellular responses to caspase activation:
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:
It is important to differentiate between necrosis and apoptosis:
The pathway of apoptosis is activated in graft versus host disease. This is cytotoxic T-lymphocyte-mediated 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.
In a case of endometrial cancer, grade 1 and stage I, the following is visible:
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.
Due to metabolic scenarios of cellular stress
.....read moreInflammation 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:
Inflammation can be divided into 3 categories:
Inflammation is necessary to fight pathogens. However, too much inflammation has negative consequences. This is the case in autoimmune diseases.
In the process of inflammation, 4 particles play an important part:
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:
Inflammation starts with vascular changes:
Bacteria form an essential part in the development of higher organisms:
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.
Bacteria can be classified based on the structure of the cell wall
Gram negative and positive bacteria can be distinguished with gram stains:
Virulence factors describe what the bacterium does with the host (the human). Defense mechanisms describe how the host reacts to the bacterium.
Streptococcus pyogenes is a gram-positive bacteria. They are called extracellular bacteria → cannot survive in a cell. Virulence factors of S. pyogenes are:
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.
There are 2 blood tests which can be used to test for inflammation:
Both are blood tests that aren't specific for a specific bacterium. CRP is an acute marker, ESR is a chronic marker.
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:
Trophozoites: doesn't survive in the environment → dies within seconds/minutes
The complexity of an organism is based on its amount of base pairs:
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.
A eukaryotic cell has a:
Eukaryotic pathogens are protozoa, fungi and helminths.
A prokaryotic cell, like a bacterium lacks a nucleus and cells organelles, but does consist of:
The cell wall is very important for bacteria:
Gram stains can be used to look at the cell walls of bacteria. A bacterium can be gram positive or gram negative:
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:
Viral infections are much more common than bacterial infections. Viruses are a major cause of human disease:
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:
Viruses are classified by comparing morphology and replication cycles. This provides common basis for naming and allows common clinical approach.
There are very large and very small viruses. Viruses with a larger genome are more complex.
A virus can be naked or enveloped:
A few important terms that are used to determine the structure of a virus:
Capsid viruses have a symmetrical arrangement:
Capsid functions are:
The basic structure of an enveloped virus is as follows:
Capsid and enveloped viruses differ from each other in multiple ways:
A virus is either a DNA or an RNA virus. It never can have DNA and RNA simultaneously.
General properties of DNA viruses are:
Parasites and fungi are eukaryotes. They are a mixture of single-cell and multi-cellular species and are more complex than viruses and bacteria.
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.
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:
A fungal (yeast) cell is a eukaryotic cell, which consists of:
Fungi have different ways of reproducing:
The cellular immune system is very important to combat fungi:
There are many important types of fungi, of which 2 are relevant for this course:
Parasites have a very complex structure. Their life cycle depends on hosts:
Parasites can be divided into 2 groups:
The diagnosis of a parasitic infection can be made directly or indirectly:
A protozoa is a eukaryotic cell containing the following
.....read moreAll 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.
A virulence factor is any component, product or characteristic that contributes to the ability of a micro-organism to cause disease:
These factors help the virus to:
It isn't necessary to memorize these factors.
Streptococcus pyogenes is a primary pathogen. It acts via a transient carrier in the throat.
Diagnostics show that it is a:
Symptoms of an infection with streptococcus pyogenes are:
S. pyogenes has little hairs on its cell wall that touch the epithelial cell. The cell wall of s. pyogenes contains:
Several other virulence factors pay an important role:
A host has both sterile and non-sterile areas:
The human body has 1014-15 bacteria and 1013 body cells. Most bacteria reside in the intestines.
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.
Humans have colonization resistance → bacteria are present on skin and mucosae to protect against adherence by other microorganisms.
The human body has different measures to achieve sterility:
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:
Fever can have many causes, but more often than not it is caused by infection. The body temperature is regulated in the hypothalamus:
There are many forms of exposure:
Exposure to micro-organisms leads to:
There are 2 groups of pathogens which can cause infections:
Infection can be acquired endogenously or exogenously:
There are 6 components of host defense:
There are many causes of an impaired barrier function:
Various microorganisms can cause an impaired barrier function:
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 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:
This works in 80-90% of the cases.
Causes of complement deficiency are mainly genetic:
One pathway can comprise for the falling out of the other. However, one is very essential to function correctly:
In case of hypogammaglobulinemia, there is an immunoglobulin deficiency. Causes are:
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.
There is a spectrum of inflammatory responses to infection, which consists of 5 forms of inflammation:
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.
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.
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 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 can cause molluscum contagiosum ("waterwratten"). This is very contagious, but usually goes away by itself.
In case of herpes simplex ("koortslip") there is an excessive amount of cells, paired with blisters. It is cyto-proliferative.
Ulcerating skin lesions can be caused by plasma cell infiltrations → mononuclear infiltrations. This disease is called syphilis, which is caused by spirochetes.
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.
.....read moreThe Gram-stain test was developed by Hans Christian Gram (1853-1938). It works as follows:
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 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.
Some other colorization methods are:
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.
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:
In contrary to bacteria, viruses can only be cultured on living cells.
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:
This process takes a while.
Afterwards, further analysis is done:
MALDI-TOF (Matrix-Assisted Laser Desorption/Ionization Time of Flight) is a mass spectrometry test. Several steps are followed:
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:
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:
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 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:
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.
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:
Treponema pallidum came to Europe for the first time after Columbus returned from the Americas. It usually is diagnosed with serology.
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:
Mycobacterium tuberculosis is characterized by:
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.
Mycobacterium tuberculosis can have 6 different clinical manifestations:
TB can be diagnosed clinically or via diagnostic tests:
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:
It isn't necessary to remember the names of
.....read moreThe 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.
Antimicrobial therapy should be active against the microorganisms. There are several interactions necessary:
Antibiotics need to shift this balance in favor of the host. Two terms are very important to describe their effect:
The correct antibiotic depends on the bacterium. Bacteria can be divided in groups:
Based on this, correct antibiotics can be prescribed:
Different classes of antibiotics influence different parts of the bacteria:
There are several beta-lactam antibiotics:
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:
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
.....read moreThe 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:
The processes of metabolism and excretion together form elimination.
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:
During absorption, drug molecules are transported across the cell membranes. This can happen via:
Which form is used, depends on the physicochemical properties of the drug molecule:
Absorption can be shown in a concentration-time curve. 2 relevant parameters are:
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:
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:
Several factors can influence absorption:
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:
The bioavailability of oral drugs is less than 100%, while the bioavailability of intravenous drugs is 100%.
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.
Once administered, drugs are distributed over different body fluid
.....read moreMandatory MOOC lectures:
The kidney has several functions:
Renal failure can have multiple causes:
There are many types of chronic renal failure:
There are several options if the kidneys do not work:
Diabetes leads to severe vascular complications:
In case of diabetes type 1, a simultaneous pancreas and kidney transplantation can be made. This way, the patient can make new insulin.
A kidney transplantation isn't always succesful:
Infections following renal transplantation:
In case of rejection, donor antigen presenting cells present an antigen, which triggers reactions of T-cells.
Clinical signs of rejection are:
Diagnosis hinges on serial creatinine measurements. Elevation of 20%
.....read moreEpidemiology is the study of the occurrence and determinants of illnesses and their spread in the population. It is about the effects between:
The 3 most important terms in epidemiology are:
The following data is available:
The following calculations can be done:
3 important terms that describe to what extent a disease has spread are:
Currently the Ebola virus is causing an epidemic. In Africa, confirmed cases of Ebola HF have been reported in many countries.
Marburg and Ebola are filoviruses, which have a distinguishing structure:
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:
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
.....read moreThere are many ways a source can infect a host, which means there also are many preventive measures:
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.
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:
Q-fever is mainly diagnosed based on antibodies in the serum → aren't visible with microscopy.
The infection chain of Q-fever consists of:
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 take many measures to prevent and control infections. There is a high risk of nosocomial infections such as:
Prevention and control of these infections mainly consists of hand hygiene and isolation.
Ignaz Semmelweis (1815-1865) worked in 2 different wards of the General Hospital of Vienna in the 1840's:
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
.....read moreCOVID-19 originates from Wuhan, in the province Hubei in China. Over 11 million people live there.
Important numbers to know are:
In case of COVID-19, almost all numbers aren't correct:
The transmission chain of COVID-19 consists of:
Transmission happens via different routes:
From January to May 2020, there were 1,320,488 laboratory-confirmed COVID-19 cases, of which:
These percentages are only based on the confirmed COVID-19 cases → aren't realistic.
Symptoms of COVID-19 are:
Complications of COVID-19 can be:
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.
There are 3 treatment options to treat COVID-19:
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
.....read moreThere are 3 types of immunopathology:
A common feature is loss of (self)tolerance and lack of control of the immune response resulting in (chronic) inflammation.
Inflammation is a protective response aimed to eliminate cause of injury, clear damaged tissue and initiate repair. Classical signs of inflammation are:
Chronic inflammation contributes to a wide variety of diseases like cancer, diabetes and Alzheimer.
Characteristics of hypersensitivity reactions are:
There is a classification that distinguishes hypersensitivity reactions in 4 types:
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 is IgE-mediated. Examples are:
Atopy is the predisposition to make IgE antibodies that specifically target innocent substances in the environment.
In case of IgE-mediated hypersensitivity (type I), 3 particles are involved:
IgE-mediated hypersensitivity has 2 phases:
Because of the interplay of all the immune cells locally, they all produce mediators
.....read moreClassification 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:
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.
Histological images of conjunctivitis are different from most images of type I hypersensitivity reactions:
Conjunctivitis is an ocular allergy caused by pollen release spores. Symptoms are:
The upper ENT may also be involved.
Therapy consists of:
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.
In case of anti-GBM nephritis, the following happens:
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.
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.
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 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.
Histological images of fibrinoid necrosis show:
Fibrinoid
.....read moreAsthma 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:
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.
Symptoms of asthma can vary greatly → asthma ≠ asthma. There are many pnenotypes of asthma:
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.
Asthma has the following characteristics, which can be treated with:
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:
Exacerbation triggers are variable:
Inhaled SABA has been first-line treatment for asthma for 50 years:
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.
There are 2 ways to diagnose asthma:
Hypersensitivity reactions and autoimmune diseases correlate with each other:
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:
Examples are:
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:
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.
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:
In some patients, antibodies can be present long before they have symptoms or the disease is diagnosed.
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.
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
.....read moreCommunication between 2 cells takes place via surface contact. This is made possible by:
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.
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.
Normally, there are 2 important signal transduction cascades in the synapse, where
vesicles with acetylcholine play an important part:
Myasthenia gravis is caused by acetylcholine receptors not clustering.
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 mainly occurs in:
The disease is associated with a tumor in the thymus:
MuSK myasthenia gravis only occurs in women. In this case, there is no tumor-association.
4% of Myasthenia patients have Lambert-Eaton Myasthenia (LEMS). In this case, antibodies for the voltage gated calcium channels (VGCC) are present.
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.
.....read moreVasculitis 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.
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:
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.
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:
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.
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 polyangitis (GPA) is type of vasculitis that used to be known as Wegener’s granulomatosis. It is a combination of:
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.
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:
The ANCA-test is used a lot for diagnostics. It is a type of indirect immunofluorescence:
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:
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.
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.
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:
The is a wide spectrum of autoantibodies in SLE → there are antibodies against:
It is peculiar that there can be antibodies against components of a cell. There are many hypotheses on etiological factors:
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
.....read moreInfection, inflammation and autoimmune diseases can overlap, but this isn’t necessary:
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.
A 9-year-old boy of Turkish descent acutely falls ill:
The diagnosis is acute rheumatic fever (ARF).
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:
Not the bacteria, but the immune response causes symptoms. ARF is a syndrome → a combination of symptoms and signs:
ARF mainly occurs in developing countries. Recurrent ARF may lead to rheumatic heart disease (RHD):
ARF mainly occurs in children of young age, while RHD is more common among elderly. Approximately 3-6% of the population is susceptible.
Pathogenesis is made up out of:
The prognosis of the first episode is quite good → 27% has no abnormalities after 1 year. Therapy consists of:
To diagnose ARF, the Jones criteria are used:
Rheumatoid arthritis (RA) is a rheumatic autoimmune disease characterized by inflamed joints:
There are several stages of rheumatoid arthritis:
The time frame in which this happens is unknown. It may be longer than 10 years.
Rheumatoid arthritis is a heterogenous disease → it is difficult to diagnose. The following classification criteria is used to diagnose rheumatoid arthritis:
In case 6 or more points are present, RA is definite.
Rheumatoid arthritis is inflammation of the synovial membrane of the joint, characterized by:
Inflammation is a reaction of the immune system to triggers. It is characterized by:
The aim of inflammation is to remove harmful agents and repair the damage.
Healthy skin is not inflamed. Inflammation starts as follows:
The inflammation stops when the harmful agent is removed. This also is the case in allergies.
Rheumatoid arthritis is also an inflammation.
.....read moreImmunosuppressive 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:
Examples of such cases are acute Graft versus Host disease and systemic lupus erythematosus. Glucocorticosteroids are examples of immunosuppressive drugs.
The history of immunosuppression is a successful story:
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 and ID can overlap:
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 are:
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:
Immunosuppression can be achieved by blocking the immune system. The adaptive immune system can be targeted at multiple sites:
Immunosuppressants can be classified in 3 groups:
A transplantation is successful if:
There are 2 types of rejection:
T-cell mediated acute rejection is a type of type IV hypersensitivity. This type of hypersensitivity reaction is important in:
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.
In case of acute rejection of the kidney, the following is visible:
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.
In the BENF classification, severity of acute rejection is graded from 0-3:
This is applied as follows:
It isn’t necessary to know this by heart.
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:
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.
Histomorphological features of chronic changes in the allograft show:
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