- Clinical science
Adaptive (acquired) immunity is a part of the immune system that provides an antigen-specific response following exposure to a microbial pathogen or foreign substance (e.g., antigen). The adaptive immune system primarily involves B cells, T cells, and circulating antibodies, all of which mount a targeted immune response to a particular antigen/invading pathogen. An important component of adaptive immunity is immunologic memory, a mechanism by which the immune system forms memory B cells and memory T cells. These cells are able to trigger a more rapid and extensive response following subsequent antigen exposure. Adaptive immunity can be conferred via vaccination, which induces immunity through selective exposure to antigens that have been rendered innocuous. Autoimmunity is a disorder of the adaptive immune system and is characterized by immune responses to the body's own tissue. Immunodeficiency conditions, in which a compromised immune system leaves the body highly susceptible to infections, can be either congenital (see the learning card on for more information) or acquired (e.g., HIV infection, iatrogenic immunosuppression).
- T cells (T lymphocytes) are a major component of the adaptive immune system and play an important role 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 bind to the 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 (i.e., macrophages, dendritic cells, B cells).
T cell development 
T cells 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)
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
- Additionally, T cells bind with their cluster of differentiation (CD).
- Immunocompetent (but still naive) 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 macrophages, monocytes, B cells, and dendritic cells). These cells present antigens (peptide fragments) via MHC molecules. T cell activation (“priming”) mainly occurs in secondary lymphoid organs, such as lymph nodes.(i.e.,
- Antigen-presentation by a dendritic cell
- Co-stimulatory signal: Interaction of a second set of molecules mediates survival and proliferation of T cell.
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||Associated conditions|
|CD4+|| || |
| || |
| || |
| || || |
|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.
- 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)
- Activation of mature B cells: occurs in response to an antigen
- 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
- Mechanisms that lead to increased affinity
- Somatic hypermutation: Point mutations that create random alterations in the variable region of the antibody gene.
- Clonal selection: B cells that possess antibodies with higher affinity for the antigen have a survival advantage through positive selection → proliferate and predominate within the follicle.
Within the germinal centers of lymph nodes, 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 → Released cytokines determine immunoglobulin class switching.
- The resulting antibody has the same affinity for the antigen but a different function.
- Isotype switching is irreversible.
- Contains the constant region
- Formed by heavy (H) chains
- Determines the antibody isotype (e.g., IgA, IgG, IgM)
- Binds complement (IgG, IgM)
- Binds various immunological cells, such as macrophages, to stimulate phagocytic or cytotoxic activity
- Contains the carboxy terminal
- Has many carbohydrate side chains
- 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
- Requires antigens
Occurs by somatic hypermutation and affinity maturation
- Alterations take place in the variable region.
- Normal response to antigenic stimulation: B lymphocytes with varying immunoglobulin alleles (i.e., polyclonal proliferation)
- Malignant lymphocyte proliferation: predominance of B lymphocytes with a single immunoglobulin variable domain (i.e., monoclonal proliferation)
Class switching (e.g., IgA, IgM, IgG)
- Alterations take place in the sequence of the heavy chain constant domain.
|Type||Structure||Characteristics||Examples and clinical relevance|
|IgA||Monomer or dimer|| || |
|IgD||Monomer|| || |
To memorize the timing of IgM formation, think of IgM as forming iMmediately!
- Definition: The ability of the immune system to recognize antigens from previous encounters and quickly and efficiently initiate an immune response to subsequent exposure to the antigen.
- Initial exposure to a potentially dangerous agent (antigen)
- Primary immune response: activation of B cells and T cells (see the sections on and above)
- Formation of memory B cells and memory T cells
- Memory B cells: Specialized plasma cells that have the ability to persist for decades following the elimination of an antigen and produce high-affinity antibodies throughout their lifespan. 
Memory T cells: Specialized T cells that persist following a primary immune response to an antigen and have the ability to elicit an immediate immune response to subsequent exposure to the same antigen. 
- Following a primary immune response, ∼ 90% of effector T cells die via apoptosis; a small fraction of the effector T cells survive to become memory T cells.
- Effector memory T cells (TEM cells, CCR7 negative cells): or that persist in the circulation and peripheral tissue.
- Central memory T cells ( positive cells): Persist in secondary lymphoid tissue and are able to differentiate into effector memory T cells upon activation.
- Subsequent immune response: Re-exposure to the antigen activates the memory cells.
Memory cells are a large pool of antigen-specific lymphocytes that can respond faster and more efficiently than naive lymphocytes when re-exposed to the antigen! These cells form the basis for the immunologic response to vaccinations!
- 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 undergo apoptosis 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., molecular mimicry. , ). The underlying pathomechanism is
- Examples of a genetic predisposition
- HLA-B8, e.g., myasthenia gravis, Graves disease, Addison disease
- HLA‑B27, e.g., , , ,
- HLA‑DR4, e.g., Addison disease , , ,
- HLD-DR3, e.g., , , Hashimoto thyroiditis,
- HLA-D2, e.g., , , multiple sclerosis
- HLA‑DQ2/DQ8, e.g., gluten‑sensitive enteropathy
- HLA-DR5, e.g., Hashimoto thyroiditis
- HLA-A3, e.g.,
- 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).
|Name||Target of the autoantibody||Possible detection in|
|ANA) (||Nuclear antigens|| |
|ANCA) (||Cytoplasmic antigens|
|TPO Ab) (||Thyroid peroxidase|
|Tissue transglutaminase in the bowel|| |
|Acetylcholine receptor|| |
|Type IV collagen on glomerular basement membrane|| |
|Cell membrane phospholipids|| |
|Islet cell cytoplasm|| |
|( )||tRNA synthetase|
|Signal recognition particle|
|helicase antibodies) (anti-||Helicase|
|Liver cells mitochondria|| |
|Parietal cells|| |
|Phospholipase A2 receptor|
|DNA topoisomerase I|| |
|Smooth muscle|| |
|Intracellular autoantigens|| |
|Anti-presynaptic calcium channel antibodies||Voltage-gated calcium channel|| |
|Neutrophil myeloperoxidase|| |
|Neutrophil proteinase|| |
- 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.
|Cause||Disease example|| |
Increased susceptibility to:
| || |
Defective cellular immunity