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:

1. Physical barriers
2. Innate immune system
3. 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 precursor
  • B-cell → plasma cell
  • NK/T-cell precursor → T cell → effector cell, or NK/T-cell precursor → NK-cell
• Myeloid line: hematopoietic stem cell → common myeloid precursor → granulocyte-macrophage progenitor
  • Macrophage and dendritic precursor → monocyte → macrophage or dendritic cell
  • Unknown precursor → mast cell
  • Neutrophil, eosinophil, basophil
• Erythroid line: common myeloid precursor → erythroid progenitor/megakaryocyte
  • Megakaryocyte → platelets
  • Erythroblast → erythrocyte

Cell-differentiation continuously takes place in the bone marrow ("beenmerg"). The cells originating from the lymphoid and myeloid line are considered leukocytes/white blood cells. These cells are either part of the innate or adaptive immune system:

• Innate immune cells: cells of the myeloid line and the NK-cells
  • NK-cells
  • Macrophage
  • Dendritic cell
  • Neutrophil
  • Eosinophil
  • Basophil
• Adaptive immune cells: most cells of the lymphoid line
  • Plasma cell
  • Effector T-cell

Adaptive immune system

The adaptive immune system responses after 5-6 days because the cells have to ripen, which takes time. It is more variable with numerous highly selective specificities. It improves while responding to pathogens, whereas the innate immune system stays constant.

If the adaptive immune system is lacking, initially the pathogen replication will be under control, because the innate immune system is doing its work. However, after a while, there will be uncontrollable pathogen replication. These types of viral infections are deadly.

Origin of B-and T-lymphocytes:

Primary and secondary lymphoid tissues are major reservoirs of naïve and memory T- and B-cells. B- and T-cells make up an important part of the adaptive immune system:

1. Before the first contact with the pathogen, only a few B- and T-cells which can present a specific antigen are present
2. Once activated, more B- and T-cells which can present specific antigens are created in the bone marrow
3. Unlike mature B-cells, precursor T-cells arise in the bone marrow but require additional maturation in the thymus:
   1. T-cell precursors migrate from the bone marrow to develop in the thymus
   2. Mature T-cells leave the thymus and travel to secondary lymphoid tissue

Lymphoid tissue:

Immune cells can be found in blood, but also in tissue. Most adaptive immune cells are found in secondary lymphoid organs, but can also be found in primary lymphoid organs.

Primary lymphoid tissue is the tissue where B-cells and T-cells are made and mature:

• Bone marrow
• Thymus
  • Recognized as a primary lymphoid organ because it plays an essential role in the recognition and maturation of T-lymphocytes

Most secondary lymphoid tissue is localized in the gastro-intestinal tract:

• Gut-associated lymphoid tissue (GALT): tonsils, adenoids, appendix, mesenteric lymph nodes and Peyer's patches
  • Adenoids: the end of the tongue
  • Waldeyer's ring: tonsils on both sides of the mouth
• Bronchial-associated lymphoid tissue (BALT): all lymph nodes draining respiratory epithelium
• Mucosa-associated lymphoid tissue (MALT): remaining more diffusing organized lymphoid structures at all mucosal surfaces

Lymph nodes:

There are many lymphoid nodes, which are mainly located in the GI, oral cavities and respiratory tracts. All lymph nodes are connected via lymphatic vessels. Eventually, all lymph will be connected in the ductus thoracicus and thrown into the circulation.

In case of a wound, pathogens can enter the body through the lesion. The pathogens travel via the afferent lymph vessel to the lymph node. A lymph node is shaped like a kidney bean. It consists of a:

• Subcapsular sinus: lymph arrives in the afferent vessel
  • Collects the lymph
  • Contains the macrophages
    • Filter the incoming lymph → filter, engulf and destroy the pathogens
    • The first parts which come into contact with pathogens
    • Split the pathogens into small fragments which are presented to the B-cells
      • B-cells are located under the macrophage
• Cortex: lymph travels in between the T- and B-cells to the medulla
  • Contains T-cells on the inside
    • Located in between the follicles
  • Contains B-cells inside the follicles
    • Produce antibodies that are deposited in the medulla
    • Germinal centers: hotspot area where B-cell activation takes place
• Medulla: lymph travels to the efferent vessel

There also are blood vessels to supply the lymph node with oxygen → there is an incoming artery and an outgoing vein.

Spleen:

Macrophages present antigens to B- and T-cells. Macrophages in the spleen are specialized in filtering free pathogens and immune complexes carried by erythrocytes:

• Red pulp macrophages: very efficient in filtering erythrocytes from the blood
• White pulp macrophages: filter the blood and present pathogens to the B-cells
  • Line the area between the lymphoid system and the red pulp
  • Have the exact same function as the marginal sinus in the lymph node

Langerhans cells:

Langerhans cells are innate cells in the epidermis and dermis of the skin which belong to the antigen-presenting cells or dendritic cells. They have lots of dendrites, with which they form a tight network → they are "senitel" cells controlling T-cell priming. When there is a wound in the skin and bacteria intrudes, the following happens:

1. A Langerhans cell is a dendritic cell, which adopts an antigen of the intruder
2. The Langerhans cell takes the antigen to the T-cell zone of a lymph node
3. The antigen is offered to a T-cell

Langerhans cells play a key-role in presenting antigens to trigger the immune response to skin-invading pathogens.

Activated T- and B-cells:

T- and B-cells are the only cells that are able to migrate to lymph nodes via the blood. Activated T- and B-cells follow a specific route:

1. The T- and B-cells leave the lymph nodes and Peyer's patches
2. The T- and B-cells go to the mesenteric lymph node
3. The T- and B-cells enter the circulation via the thoracic duct
4. The T- and B-cells recognize the endothelial cells of the vessels where the pathogens have entered
5. Endothelial cells have selectine and integrin as receptors → leukocytes can bind to the wall → the movement slows down, the bond is strong, a transmembrane process is activated
6. Endothelial cells start to produce cytokines
7. Cytokines destroy the pathogen

Immune surveillance:

Innate and adaptive immune cells are highly dynamic. They are not static → they constantly are in a state of movement. They move from lymph node to veins to heart to arteries to lymph node. This way, they have the highest chance of encountering an antigen. Most lymphocytes are hidden in tissues:

• 150 x 10⁹ in lymph nodes
• 31 x 10⁹ in the spleen
• 25 x 10⁹ in the bone marrow
• 95 x 10⁹ in extra-lymphoid organs