- Clinical science
The human body is host to innumerable microorganisms. While this normal flora helps to prevent infection, it also contains potential pathogens. Through contact or exchange with the environment (e.g., breathing, eating) the body is also exposed to millions of external microorganisms at all times. To protect the body from diseases caused by those microorganisms, humans possess a complex immune system that involves various cellular and non-cellular components. Mechanical barriers, i.e., the skin and mucous membranes, and chemical barriers, such as gastric acid, represent the body's first line of defense against pathogens. If these fail and pathogens manage to enter the tissue or bloodstream, they are attacked by the complement system and white blood cells. Leukocytes are categorized by their physical and functional characteristics as granulocytes (neutrophils, eosinophils, basophils, mast cells) and mononuclear cells, including lymphocytes (comprising B cells, various subtypes of T cells, and natural killer cells) and monocytes (which differentiate into macrophages or dendritic cells).
Immunity against pathogens can be innate or acquired. Innate immunity is immediate, but nonspecific, and operates based on inherited cellular receptors that respond to broad pathogen-related patterns and common threat signals (for more details see ). Acquired immunity (adaptive immunity), which involves mainly B cells, T cells and circulating antibodies, develops only after initial exposure to a pathogen and is highly specific to that pathogen. This specificity allows for a more effective immune response that can achieve clearance of the pathogen. Immunologic memory is a mechanism of the adaptive immune system that triggers a more rapid and extensive immune response to a pathogen upon subsequent exposure. Acquired immunity can be conferred via vaccination, which induces immunity through selective exposure to antigens that have been rendered innocuous. Disorders of the immune system include autoimmunity, which is caused by abnormal immune responses to the body's own tissue, and immunodeficiency conditions, in which a weakened immune system leaves the body vulnerable to pathogens and frequent infection.
- T cells (T lymphocytes) are a major component of the adaptive immune system and significantly involved in cell-mediated immunity
T-cell receptors (TCRs)
- Binding of a T-cell receptor to its specific antigen triggers activation of the T cell.
- This antigen fragment has to be complexed with major histocompatibility complex molecule on the surface of another cell in order to be recognized by the TCR.
- The adaptive immune response is initiated in secondary lymphoid organs, where antigens are presented on the surface of antigen-presenting cells (e.g., macrophages, dendritic cells).
T cell development  
They originate from lymphoid progenitor cells in the bone marrow and mature in the thymus (hence “T cells”)
- The thymus is a primary lymphatic organ that arises from the ventral wings of the third branchial pouches
Positive selection of T cells: ensures that the thymus produces functional T cells.
- Takes place in the thymic cortex:
- Thymic cortical cells express MHC class I and MHC class II antigens
- Tests if T cell receptors can bind MHC appropriately (not too strongly or too weakly) → these T cells (CD4+ / CD8+) receive survival signal → dysfunctional T cells undergo apoptosis
Negative selection of T cells: ensures that the thymus does not produce self-reacting T cells.
- Takes place in the thymic medulla:
Tests if T cells bind to tissue-restricted self-antigens presented on MHC by thymic medullary cells → T cells that do not bind receive survival signal → dysfunctional T cells undergo apoptosis
- Mediated by the autoimmune regulator protein (AIRE)
- Additionally, T cells bind with their cluster of differentiation (CD) → the type of CD that the T cell has the higher affinity for is kept, the other is downregulated → either (CD4+ / CD8-) or (CD4- / CD8+)
- Immunocompetent (but still naïve) T cells leave the thymus and migrate within and between peripheral tissues, blood vessels, and secondary lymphoid organs (e.g., lymph nodes, spleen, MALT)
Defective negative T-cell selection can cause autoimmune disorders (e.g., type 1 autoimmune polyendocrine syndrome).
T cell activation
Antigens are processed by antigen-presenting cells including macrophages, monocytes, and dendritic cells. They present antigens (peptide fragments) via MHC molecules. T cell activation (“priming”) mainly occurs in secondary lymphoid organs such as lymph nodes .
- Antigen-presentation by a dendritic cell:
Costimulatory signal: interaction of a second set of molecules → mediates survival and proliferation of T cell
- On the dendritic cell: B7 protein (CD80 or CD86)
- On the T cell: CD28
T cell effects
Direct cell lysis or induction of apoptosis via perforin and proteases from cytotoxic T cells (CD8+)
- Activated via antigen presentation by MHC class I receptors
- Induce apoptosis of virus-infected or malignant cells
- Release granules that contain perforin, granzyme B, granulysin
- Release cytokines (including IFN‑γ, TNF-β, and TNF‑α)
- Macrophage activation
- Clinical relevance: involved in organ rejection, induce apoptosis of donor graft cells
Cellular‑mediated response via Th1 cell (CD4+)
- Activated via antigen presentation by MHC class II receptors
- Immune response to intracellular pathogens (viruses, intracellular bacteria)
- Clinical relevance:
- Cellular‑mediated response via Th2 cell (CD4+)
- Differentiated T cells express specific T-cell receptors that allow them to recognize antigens presented by MHC molecules on the surface of antigen-presenting cells (e.g., macrophages).
- General T cell markers: CD3, CD28, TCR
- Surface proteins determine T cell function.
|CD marker||Cell type||Function||Stimulate / Activate|
|CD4+|| || |
| || |
| || |
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|CD8+|| || |
- All T cells carry specific membrane-bound marker proteins that distinguish them from other lymphocytes. These general T cell markers are CD3, CD28 (which binds to B7 during T cell activation) and the T cell receptor (TCR). The two major T cell types are the cytotoxic T cells (CD8+) and T helper cells (CD4+, CD40L+, CXCR4/CCR5+). Subpopulations within the CD4+ subset have been identified by the cytokines they secrete or their surface markers (the following list is not exhaustive).
|Th1 cell|| || || || |
|Th2 cell|| || || || |
|Th17 cell|| || || || |
|TFH cell|| || || || |
|Treg cell|| || || |
B cells (B lymphocytes) are a major component of the adaptive immune system and significantly involved in the humoral immune response. They originate in the bone marrow, where they also develop to mature, naïve B cells. Mature B cells circulate in between the blood and secondary lymphatic organs (e.g., lymph nodes, spleen, MALT) until they are activated in response to an antigen. Each B cell responds to a specific antigen depending on; its unique B cell receptor. Response to protein or peptide antigens involves Ig class switching, which requires involvement of T-helper (Th) cells, whereas non-protein antigens activate B cells independently. After activation, B cells differentiate into plasma cells that produce and secrete antibodies (see ), e.g. to opsonize bacteria which facilitates phagocytosis.
- Th cell‑independent activation of B cells (1° response)
B cell activation via Th cells (2° response)
- Requires activation of CD4+ T-helper cells (see above)
- B lymphocytes recognize protein/peptide antigens via their B cell receptors (membrane‑bound immunoglobulins, IgD or IgM) → B cell receptor-mediated endocytosis of the BCR/antigen complex → breakdown of antigen into small fragments by lysosomal proteases → presentation of antigen fragment via MHC class II receptors on; B cell surface to Th cells → interaction between Th2 cells; and B lymphocytes →; T cell‑dependent activation of B cells (plasma cells) ; → immunoglobulin production
Interaction of B cells with Th cells takes place in secondary lymphoid tissue. This interaction is essential for affinity maturation, class switching of B cells, and immunoglobulin secretion. Activated B cells proliferate, forming germinal centers (dark zone) within the follicles.
- Processes that lead to increased affinity:
- Somatic hypermutation
- Clonal selection
Activated B cells change the antibody isotype in response to specific cytokines that are released by Th cells. IgM, the primary antibody on B cells before getting activated, is switched to IgA, IgE, or IgG. IgM is also secreted by plasma cells (stimulated by IL-6).
B cell class switching occurs via two signaling mechanisms:
- 1. signal = activation: Antigen bound to MHC II molecule binds to T cell receptor on the surface of T-helper cells
- 2. signal = membrane receptor on the B cell binds to (CD40L) on the surface of → cytokines released that determine immunoglobulin class switching
- The resulting antibody has the same affinity for the antigen, but a different function
- Isotype switching is irreversible
Overview: immunoglobulins (antibodies)
- Fc region
- Contains the variable/hypervariable region
- Formed by light (L) chains and heavy (H) chains
- Recognizes and binds to antigens
- Determines the idiotype, which is specific for one antigen only
|Structure||Characteristics||Examples and clinical relevance|
|IgA||Monomer or dimer|| |
|IgD||Monomer|| || |
- Definition: Autoimmunity refers to an immune reaction against the body's own cells that occurs as a result of a loss of immunological tolerance.
- Presumed pathogenesis: Autoreactive B lymphocytes are physiologically eliminated in the bone marrow, spleen, or lymph nodes. T lymphocytes that attack the body's own cells are either sorted out in the thymus or perish in peripheral lymphoid tissues (e.g, lymph nodes, adenoids, Peyer's patches) due to a lack of stimulation. If the selection mechanisms fail, this results in the immune cells attacking the body's own cells, which leads to autoimmune inflammation.
- Epidemiology: Women have a disproportionately higher incidence of autoimmune diseases.
- Mostly idiopathic
- Sometimes elicited by a previous infection (e.g., Guillain‑Barré syndrome, molecular mimicry. ). The underlying pathomechanism is
- Examples of a genetic predisposition
- The presence of autoreactive B lymphocytes causes the production of irregular antibodies, which can trigger various diseases. It can also be used as a diagnostic tool (see the table below). In T-cell‑mediated autoimmune reactions, there are usually no detectable specific antibodies (e.g., in multiple sclerosis).
|Autoantibodies||Target of the autoantibody||Possible detection in|
|ANA) (||Nuclear antigens|| |
|ANCA) (||Cytoplasmic antigens|
|TPO Ab) (||Thyroid peroxidase|
|Thyroid stimulating hormone receptor antibodies||TSH receptor|
|Tissue transglutaminase in the bowel|| |
|Acetylcholine receptor|| |
|Type IV collagen on glomerular basement membrane|| |
|Cell membrane phospholipids|| |
|Islet cell cytoplasm|| |
|Signal recognition particle|
|Liver cells mitochondria|| |
|Parietal cells|| |
|Phospholipase A2 receptor|
|DNA topoisomerase I|| |
|Smooth muscle|| |
|Intracellular autoantigens|| |
|Voltage-gated calcium channel|| |
|Neutrophil myeloperoxidase|| |
|Neutrophil proteinase|| |
Epidemiology: Primary immunodeficiency diseases are rare (an exception is )
- ∼ 1–2/1,000 patients are immunodeficient
- There are over 50 different forms of immunodeficiency, with the most frequent being:
- Clinical findings: The main symptom of a primary immunodeficiency is a pathological susceptibility to infection. The type of susceptibility is characterized by the invading pathogen, localization, course, severity, and number of infections. Not all immune defects are clinically apparent.
|Immune deficiency||Disease example|| |
Increased susceptibility to:
| || |
Defective cellular immunity