Summary
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 article on congenital immunodeficiency disorders for more information) or acquired (e.g., HIV infection, iatrogenic immunosuppression).
T cells (T lymphocytes)
Overview [1][2][3]
- A major component of the adaptive immune response
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Essential for cell-mediated immunity
- Directly involves cytotoxic T cells and other phagocytes, but not B cells or antibodies
- Important in the recognition and destruction of intracellular pathogens (e.g., viruses, intracellular bacteria)
- All mature T cells express specific surface proteins that distinguish them from other lymphocytes and allow them to recognize antigens presented by MHC molecules of antigen-presenting cells.
T-cell receptors (TCRs)
- Complex of proteins of the immunoglobulin superfamily
- Each T cell expresses a TCR variant that binds to one specific antigen.
- Important for positive and negative selection during T-cell development
The cells of the acquired immune system (B cells, T cells) are activated upon antigen recognition.
T-cell development [4]
T cells originate from lymphoid progenitor cells in the bone marrow and mature in the thymus.
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Positive selection of T cells: ensures that the thymus produces functional T cells
- Location: thymic cortex
- Thymic cortical cells express MHC class I and MHC class II antigens.
- Tests if T-cell receptors can bind to MHC appropriately (not too strongly or too weakly)
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Negative selection of T cells: ensures that the thymus does not produce self-reacting T cells
- Location: thymic medulla
- Tests if T cells bind to tissue-restricted self-antigens presented on MHC by thymic medullary cells
- Self-antigen presentation is mediated by the autoimmune regulator protein (AIRE protein), dysfunction of which can lead to:
- In addition, 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).
“Life is ACHe without AIRE”: Autoimmune regulator protein (AIRE) dysfunction can lead to Adrenal insufficiency, chronic mucocutaneous Candidiasis, and Hypoparathyroidism.
T-cell activation
Overview
- Antigens are processed by antigen-presenting cells (i.e., macrophages, monocytes, B cells, Langerhans cells, and dendritic cells).
- Dendritic cells travel through different tissues, phagocytize and process antigens and then migrate through afferent lymphatic vessels to a lymph node to present these antigens via MHC I and II.
- T cell activation (“priming”) mainly occurs in secondary lymphoid organs, such as lymph nodes.
- Activation requires an initial signal, followed by a second, costimulatory signal.
Mechanism
- Antigen presentation
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Costimulatory signal: mediates survival and proliferation of T cells
- B7 protein (CD80 or CD86) on the dendritic cell: interacts with CD28 on the naive T cell.
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Antigen presentation without this co-stimulatory signal will lead to T-cell anergy:
- Important self-tolerance mechanism
- The cell will not be activated even though it is exposed to its antigen
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Effect
- T-helper cell: activation of NFAT (nuclear factor of activated T cells) → cytokine production → activation of other cells, e.g., B cells, macrophages, and cytotoxic T cells
- Cytotoxic T cell: recognizes and destroys cells that possess antigens (signals malignancy or viral infection)
T cell effects
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T cells (CD8+): direct cell lysis or induction of apoptosis via perforin and proteases
- Activated via antigen presentation by MHC class I receptors
- Induce apoptosis of virus-infected or malignant cellsusing mechanisms as those used by NK cells: release of granules that contain perforin, granzyme B, granulysin
- Release cytokines (including IFN‑γ, TNF, and lymphotoxin-α) → macrophage activation
- Clinical relevance: involved in organ rejection (acute and chronic), induce apoptosis of donor graft cells
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Th1 cell (CD4+): cell‑mediated response
- Activated via antigen presentation by MHC class II receptors
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Immune response to intracellular pathogens (viruses, intracellular bacteria)
- Release cytokines (including IFN‑γ, IL‑2, and TNF) → stimulation of macrophages (positive feedback) and CD8+ cytotoxic T cells; ; effect is amplified by binding of T-cell CD40L to CD40 receptors on macrophages
- IFN‑γ, IL-2, and TNF‑α induce granuloma formation against foreign bodies that cannot be eliminated by the immune cells.
- Clinical significance:
- Tuberculosis in HIV infection
- Delayed cell-mediated type IV hypersensitivity reactions (see the corresponding section in ”Hypersensitivity reactions”)
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Th2 cell (CD4+): cell‑mediated response
- Activated via antigen presentation by MHC class II receptors
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Immune response to extracellular pathogens (bacteria, parasites)
- Release cytokines (including IL-4, IL-5, IL-13) which stimulate eosinophils, basophils, and mast cells
T cell subtypes
- T cells are largely divided into cytotoxic T cells (CD8+), T helper cells (CD4+), and regulatory T cells.
- Other subtypes include memory T cells and natural killer T cells.
Overview of T cell subtypes | |||||
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Cell type | Important surface markers | Function | Stimulate/activate | Clinical significance | |
Cytotoxic T cells (killer T cells) |
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T-helper cells (Th cells) | Th1 cells |
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Th2 cells |
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Th17 cells |
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T follicular helper cells (TFH cells) |
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Regulatory T cells (Treg, suppressor T cells) |
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Surface markers
Surface protein expression determines the specific function of T cell subtypes.
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General T cell markers
- All T cells carry membrane-bound marker proteins that distinguish them from other lymphocytes.
- These general T-cell markers are CD3, CD28, and the T-cell receptor (TCR).
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Specific markers of T cell subtypes
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T cells are largely divided into CD8+ T cells (cytotoxic T cells) and CD4+ T cells (T helper cell subpopulations).
- Besides CD4, T helper cells express CD40L, CXCR4, and CCR5.
- See also “CD4/CD8 ratio.”
- Subtypes within the group of CD4+ T cells may be identified by the cytokines they secrete and/or by their specific surface markers (see table below; the list is not exhaustive).
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T cells are largely divided into CD8+ T cells (cytotoxic T cells) and CD4+ T cells (T helper cell subpopulations).
Differentiation of T helper cell subtypes | ||||
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Cell type | Surface marker | Stimulated by | Cytokines produced | Inhibited by |
Th1 cell | ||||
Th2 cell |
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Th17 cell |
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TFH cell |
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Treg cell |
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CD8 proteins on the surface of cytotoxic T cells interact with MHC I receptors, while CD4 proteins on the surface of T-helper cells interact with MHC II receptors.
Rule of 8: MHC I x CD 8 = 8. MHC II x CD 4 = 8.References:[4][5][6][7][8][9]
B cells (B lymphocytes)
Overview [1][2][3][10]
- Major component of the adaptive immune system: The humoral immune response of the adaptive immune system mainly consists of B cells and antibodies.
- Originate and mature in the bone marrow
- Naive B cell: a mature B cell that has not come in contact with antigens yet
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Express numerous surface proteins
- CD19, CD20 , CD21 (used by EBV), and CD40
- MHC II
- B7
- B cell receptor with immunoglobulin component (binds antigens)
- Mature B cells circulate between the blood and secondary lymphatic organs (e.g., lymph nodes, spleen, MALT).
- After activation, B cells differentiate into plasma cells that produce and secrete antibodies; (see “Immunoglobulins” below).
“Mr. Epstein, you have to be 21 to Be in this Barr!”: The Epstein-Barr virus uses the CD21 receptor to invade B cells.
B-cell receptors (BCRs)
- Type I; transmembrane proteins on the B cell surface that are composed of immunoglobulins and signal-transmitting subunits
- Necessary for B cell activation and maturation
- The immunoglobulin parts of mature BCRs are highly specific to certain antigens.
- Naive BCR: a BCR that has not interacted with an antigen yet
B cell activation
B cell activation and class switching require an initial signal, as well as a costimulatory signal. Activated B cells migrate to germinal centers of secondary lymphoid organs.
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T cell-dependent activation of B cells
- Requires activation of CD4+ T-helper cells, which, in turn, requires prior antigen presentation via MHC II by the B cell
- Initiated as a response to protein or peptide antigens (thymus-dependent antigens), e.g.:
- PCV13 Streptococcus pneumoniae vaccine
- Diphtheria toxin-like protein with conjugated polysaccharides
- B lymphocytes recognize 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 plus costimulation of B cell CD40 receptor by Th cell CD40L → T cell‑dependent activation of B cells (plasma cells) → immunoglobulin production
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T cell-independent activation of B cells
- Initiated as an immediate response to nonprotein antigens (thymus-independent antigens; e.g., gram-negative lipopolysaccharide)
- Leads to production of IgM antibodies
- No prior T-cell activation since MHC are unable to present nonprotein antigens to T cells
- Thymus independent antigens are considered to be only weakly immunogenic, which is why vaccines containing nonprotein antigens need adjuvants (like the PPSV23 Streptococcus pneumoniae vaccine, containing a capsular polysaccharide subunit) and boosters.
Affinity maturation
- Definition: : A process in which B cells interact with Th cells within the germinal center ; of secondary lymphoid tissue in order to secrete immunoglobulins with higher affinity for specific antigens.
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Mechanisms
- 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 a positive selection that allows them to proliferate and predominate within the follicle.
Isotype switching (class switching)
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).
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B cell class switching occurs via two signaling mechanisms:
- First signal = activation: Antigen bound to MHC II molecule binds to T-cell receptor on the surface of T-helper cells.
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Second signal = costimulation: CD40 membrane receptor on the B cell binds to CD40 ligand (CD40L) on the surface of CD4+ T cell (CD40L/CD40) → cytokine release → gene rearrangement, resulting in class switching
- IL-4, IL-13: stimulate class switching to IgE.
- IL-5, TGF-β: stimulate class switching to IgA.
- IFN-γ, IL-4, IL-21: stimulate class switching to IgG.
- The resulting antibody has the same affinity for the antigen but a different function.
- Isotype switching is irreversible.
Immunoglobulins
Overview
Immunoglobulins (antibodies) have two functional parts: the Fc region and the Fab region. The two enzymes papain and pepsin can be used to identify the different functional parts.
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Fc region
- 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
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Fab region
- Contains the variable/hypervariable region
- Formed bylight (L) chains and heavy chains (H)
- Recognizes and binds to antigens via epitope
- Determines the idiotype, which is specific for one antigen only
Fc → Complement, Constant, Carboxy terminal, Carbohydrate side chains
Fab → Antigen binding
Immunoglobulin properties
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Specificity
- Requires antigens
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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)
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Class switching (e.g., IgA, IgM, IgG)
- Alterations take place in the sequence of the heavy chain constant domain.
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Diversity
- Does not require antigens
- Random recombination of certain genes during B cell maturation in bone marrow
- Terminal deoxynucleotidyl transferase (TdT) randomly adds nucleotides to the DNA.
- Recombination of light chains with heavy chains occurs randomly.
Immunoglobulin types
Type | Structure | Characteristics | Examples and clinical relevance |
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IgM | Pentamer |
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IgG | Monomer |
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IgA | Monomer or dimer |
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IgE | Monomer |
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IgD | Monomer |
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To memorize the timing of IgM formation, think of IgM as forming iMmediately!
Immunologic memory
- 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.
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Process
- Initial exposure to a potentially dangerous agent (antigen)
- Primary immune response: activation of B cells and T cells (see the sections on B cells and T cells above)
- Formation of memory B cells and memory T cells
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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. [11][12]
- Undergo proliferation, somatic hypermutation, clonal selection, and antigen switching (see T cell‑dependent B cell activation)
- Arrested in their differentiation and persist in the marginal zone of follicles
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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. [12][13]
- 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): CD4+ T cells or CD8+ T cells that persist in the circulation and peripheral tissue.
- Central memory T cells (CCR7 positive cells): Persist in secondary lymphoid tissue and are able to differentiate into effector memory T cells upon activation.
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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. [11][12]
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Subsequent immune response: Re-exposure to the antigen activates the memory cells.
- Memory B cells secrete high-affinity antibodies and accelerate the secondary immune response to the antigen.
- Memory T cells mature to TEM cells and trigger an immediate release of cytokines or cytotoxicity.
- Repeated exposure to the antigen leads to more efficient immune responses.
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!
Autoimmunity
- 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.
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Causes
- Mostly idiopathic
- Sometimes elicited by a previous infection (e.g., Guillain-Barré syndrome, rheumatic fever). The underlying pathomechanism is molecular mimicry
- Examples of a genetic predisposition
- HLA-B8, e.g., myasthenia gravis, Graves disease, Addison disease
- HLA‑B27, e.g., ankylosing spondylitis, reactive arthritis, psoriatic arthritis, ulcerative colitis
- HLA-DR4, e.g., rheumatoid arthritis, type 1 diabetes, pemphigus vulgaris, Addison disease
- HLA-DR3, e.g., type 1 diabetes, SLE, Hashimoto thyroiditis, Graves disease
- HLA-D2, e.g., SLE, Goodpasture syndrome, multiple sclerosis
- HLA‑DQ2/HLA-DQ8, e.g., gluten‑sensitive enteropathy
- HLA-DR5, e.g., Hashimoto thyroiditis
- HLA-A3, e.g., hemochromatosis
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Consequences
- 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
Immune deficiency
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Epidemiology
- Primary immunodeficiency diseases are rare (an exception is selective IgA deficiency).
- ∼ 1–2/1,000 patients are immunodeficient.
- There are over 50 different forms of immunodeficiency, with the most frequent being:
- Innate (see the article on congenital immunodeficiency disorders for more information):
- Acquired
- HIV/AIDS
- Iatrogenic immune suppression
- 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: |
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Antibody deficiency |
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Defective cellular immunity |
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