• Clinical science

Adaptive immune system

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 learning card on congenital immunodeficiency disorders for more information) or acquired (e.g., HIV infection, iatrogenic immunosuppression).

T cells

Overview

The cells of the acquired immune system (B cells, T cells) are activated upon antigen recognition!

T cell development [1][2]

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 (i.e., 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.

  1. Antigen-presentation by a dendritic cell
    • Exogenous antigens are presented via MHC II to TCR/CD4.
    • Endogenous antigens, cross-presentation of antigens are presented via MHC I to TCR/CD8.
  2. Co-stimulatory 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
    • Antigen presentation without this co-stimulatory signal will lead to T-cell anergy.
  3. Effect:

T cell effects

  1. Direct cell lysis or induction of apoptosis via perforin and proteases from cytotoxic T cells (CD8+)
  2. Cellular‑mediated response via Th1 cell (CD4+)
    • Activated via antigen presentation by MHC class II receptors
    • Immune response to intracellular pathogens (viruses, intracellular bacteria)
      • Release cytokines (including IFN‑γ, IL‑2, and TNF‑α)cytokines stimulate macrophages (positive feedback) and CD8+ cytotoxic T cells
      • IFN‑γ, IL-2, and TNF‑α induce granuloma formation against foreign bodies that cannot be eliminated by the immune cells.
    • Clinical relevance:
  3. Cellular‑mediated response via Th2 cell (CD4+)

T cell subtypes

CD marker Cell type Function Stimulate/activate Associated conditions
CD4+
  • Th1 cells
  • Fight intracellular pathogens
  • Th2 cells
  • Fight extracellular parasites
  • Th17 cells
  • Fight extracellular parasites
  • Follicular helper T (TFH) cells
  • Support B cells in lymphoid follicles
  • Autoimmune diseases
  • Effector T cells
CD8+
  • Recognize and kill virus-infected or neoplastic cells
Cell-type Marker Stimulation Secretion Inhibition
Th1 cell
  • CXCR3
  • CCR5
  • IFN‑γ, IL-12
  • IFN‑γ, IL-2
  • IL-4, IL-10 (from Th2 cells)
Th2 cell
  • CRTH2
  • CCR4
  • CCR3
  • IL-2, IL-4
  • IL-4
  • IL-5
  • IL-6
  • IL-10
  • IL-13
  • IFN‑γ (from Th1 cells)
Th17 cell
  • CCR6+
  • CCR4+
  • TGF-β, IL-1, IL-23, IL-6, IL-22
  • IL-17
  • IL-21
  • IL-22
  • IFN‑γ, IL-4
TFH cell
  • CXCR5
  • PD-1
  • IL- 6
  • IL-21
  • IL-4
  • IL-2
Treg cell
  • TGF-β, IL-2
  • TGF-ß
  • IL-10
  • IL-35
  • IL-6


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:[3][4][1][1][5][5][6][7][8]

B cells

Overview [2]

B cell activation

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.

  • Mechanisms that lead to increased affinity

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).

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.

  • 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
  • Fab 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

Fc Complement, Constant, Carboxy terminal, Carbohydrate side chains
FabAntigen binding

Immunoglobulin properties

Immunoglobulin types

Type Structure Characteristics Examples and clinical relevance
IgM Pentamer
  • Largest antibody , located on the surface of B cells as a monomer and circulating as pentamer (with J chain)
  • Formed early (evidence of recent infection)
  • Activates complement
IgG Monomer
  • Most abundant immunoglobulin in blood serum
  • Delayed formation during the course of infection (IgM-IgG switch); ensures long‑term immunity
  • Titer determination for follow‑up: high affinity and specificity
  • Can be free-floating in serum or bound to the surface of lymphocytes
  • The only immunoglobulin that can cross the placenta and thus convey passive immunity to the child
  • Activates complement
  • Opsonization of bacteria
  • Neutralization of viruses and toxins
IgA Monomer or dimer
  • Monomer in circulation and dimer when secreted
  • Most abundant immunoglobulin in the body but has a low serum concentration
  • Found especially on mucosal surfaces and in bodily fluids
  • Prevents binding of pathogens to host cells
  • Secretory component protects IgA from proteases (e.g., in the gastrointestinal tract)
IgE Monomer
IgD Monomer
  • Function is incompletely understood

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.
  • Process
    1. Initial exposure to a potentially dangerous agent (antigen)
    2. Primary immune response: activation of B cells and T cells (see the sections on B cells and T cells above)
    3. 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. [9][10]
      • 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. [10][11]
  • 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

Autoantibodies

Name Target of the autoantibody Possible detection in
Antinuclear antibodies (ANA) Nuclear antigens
Antineutrophil cytoplasmic antibodies (ANCA) Cytoplasmic antigens
Thyroid peroxidase antibodies (TPO Ab) Thyroid peroxidase
TSH receptor antibodies TSH receptor
Transglutaminase antibodies Tissue transglutaminase in the bowel
ACh receptor antibodies Acetylcholine receptor
Glomerular basement membrane antibodies Type IV collagen on glomerular basement membrane
Anti-β2 glycoprotein antibodies Glycoprotein
Anticardiolipin antibodies Cardiolipin
Rheumatoid factor IgM against Fc region of IgG
Anti-CCP antibody Citrullinated peptides
Lupus anticoagulant Cell membrane phospholipids
Anticentromere antibodies Centromeres
Anti-desmoglein antibodies Desmosomes
Anti-glutamic acid decarboxylase antibodies Islet cell cytoplasm
Anti-hemidesmosome antibodies Hemidesmosomes
Anti-synthetase antibodies (anti-Jo-1 antibodies) tRNA synthetase
Anti-SRP antibodies Signal recognition particle
Anti-Mi-2 antibodies (anti-helicase antibodies) Helicase
Anti-mitochondrial antibodies Liver cells mitochondria
Anti-intrinsic factor antibodies Parietal cells
Anti-phospholipase A2 receptor antibodies Phospholipase A2 receptor
Anti-Scl-70 DNA topoisomerase I
Anti-smooth muscle antibodies Smooth muscle
Anti-SSA; Anti-SSB (anti-Ro, anti-La) Intracellular autoantigens
Anti-presynaptic calcium channel antibodies Voltage-gated calcium channel

p-ANCA

Neutrophil myeloperoxidase
c-ANCA Neutrophil proteinase
Anti-histone antibodies Histones
Anti-dsDNA Double-stranded DNA
Anti-Smith antibodies Nonhistone nuclear proteins
Anti-U1 RNP antibodies Ribonucleoprotein

Immune deficiency

Cause Disease example

Increased susceptibility to:

Antibody deficiency

Complement defect

  • Bacterial infections: particularly Pneumococcus and Meningococcus

Defective cellular immunity

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  • 2. Le T, Bhushan V. First Aid for the USMLE Step 1 2015. McGraw-Hill Education; 2014.
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  • 7. Sanguine Biosciences Blog. Identification of CD4+ TH1, TH2, and TH17 Populations in Human PBMC. https://technical.sanguinebio.com/identification-of-cd4-th1-th2-and-th17-populations-in-human-pbmc/. Updated December 12, 2012. Accessed November 14, 2018.
  • 8. Baumjohann D, Ansel KM. Identification of T follicular helper (Tfh) cells by flow cytometry. Protocol Exchange. 2013. doi: 10.1038/protex.2013.060.
  • 9. Kurosaki et al. Memory B cells. Nature Reviews Immunology. 2015; 15: pp. 149–159. doi: 10.1038/nri3802.
  • 10. Zanetti. Immunological Memory. eLS. . doi: 10.1002/9780470015902.a0000951.pub3.
  • 11. Ademokun, Dunn-Walters. Immune Responses: Primary and Secondary. eLS. 2010. doi: 10.1002/9780470015902.a0000947.pub2 .
  • Mahnke et al. The who's who of T‐cell differentiation: Human memory T‐cell subsets. European Journal of Immunology. 2013; 43(11): pp. 2797–2809. doi: 10.1002/eji.201343751.
last updated 09/29/2019
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