• Clinical science

Adaptive immune system

Abstract

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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 innate immune system). 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

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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 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 .

  1. Antigen-presentation by a dendritic cell:
    • Exogenous antigens → MHC II to TCR/CD4
    • Endogenous antigens, cross-presentation of antigens → MHC I to TCR/CD8
  2. 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
  3. Effect:

T cell effects

  1. 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)
    • Clinical relevance: involved in organ rejection, induce apoptosis of donor graft cells
  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)
    • Clinical relevance:
      • Tuberculosis in HIV infection
      • An exaggerated type 1 response can lead to autoimmune disease.
  3. Cellular‑mediated response via Th2 cell (CD4+)

T cell subtypes

CD marker Cell type Function Stimulate / Activate
CD4+
  • Th1 cells
  • Fight intracellular pathogens
  • Th2 cells
  • Fight extracellular parasites
  • Th17 cells
  • Fight extracellular parasites
  • TFHcells
  • Support B cells in lymphoid follicles
  • /
CD8+
  • Recognize and kill virus-infected or neoplastic cells
  • 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).
Cell-type Marker Stimulation Secretion Inhibition
Th1 cell
  • CXCR3
  • CCR5
  • IFN‑γ, IL-12
  • IFN‑γ
  • 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.

B cells

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Overview [2]

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 immunoglobulins), e.g. to opsonize bacteria which facilitates phagocytosis.

B cell activation

Affinity maturation

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.

Isotype switching (Class switching)

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

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Overview: immunoglobulins (antibodies)

Antibodies have two functional parts, the Fab region and the Fc 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 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

Immunoglobulin properties

Immunoglobulin types

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)
  • Activate complement
IgG Monomer
  • Most abundant immunoglobulin
  • Delayed formation during the course of infection (IgM-IgG switch); ensures long‑term immunity
  • Titer determination for follow‑up
  • 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
  • Activate complement
  • Neutralization of viruses
IgA Monomer or dimer
  • Monomer in circulation and dimer when secreted
  • Found especially on mucosal surfaces and in bodily fluids
  • Prevents binding of pathogens to host cells
IgE Monomer
IgD Monomer
  • Function is incompletely understood.

Autoimmunity

Content currently under development

Autoantibodies 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
Thyroid stimulating hormone receptor antibodies TSH receptor
Transglutaminase antibodies Tissue transglutaminase in the bowel
  • Gluten‑sensitive enteropathy
ACh receptor antibodies Acetylcholine receptor
Glomerular basement membrane antibodies Type IV collagen on glomerular basement membrane
Anti-β2 Glycoprotein Glycoprotein
Anti-cardiolipin Cardiolipin
Lupus anticoagulant Cell membrane phospholipids
Anticentromere Centromeres
Anti-desmoglein Desmosomes
Anti-glutamic acid decarboxylase Islet cell cytoplasm
Anti-hemidesmosome Hemidesmosomes
Anti-synthetase (anti-Jo-1) tRNA synthetase
Anti-SRP Signal recognition particle
Anti-helicase Helicase
Anti-mitochondrial antibodies Liver cells mitochondria
Anti-intrinsic factor Parietal cells
Anti-phospholipase A2 receptor Phospholipase A2 receptor
Anti-Scl-70 DNA topoisomerase I
Anti-smooth muscle Smooth muscle
Anti-SSA ; Anti-SSB (anti-Ro, anti-La) Intracellular autoantigens
Anti-presynaptic calcium channel Voltage-gated calcium channel
p-ANCA antibodies Neutrophil myeloperoxidase
c-ANCA antibodies Neutrophil proteinase
Anti-histone Histones
Anti-U1 RNP Ribonucleoprotein

Immune deficiency

Content currently under development

Immune deficiency Disease example

Increased susceptibility to:

Antibody deficiency

Complement defect

  • Bacterial infections: particularly Pneumococcus and Meningococcus

Defective cellular immunity

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last updated 11/14/2018
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