Adaptive immune system

Last updated: June 30, 2022

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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 “Congenital immunodeficiency disorders” for more information) or acquired (e.g., HIV infection, iatrogenic immunosuppression).

Overview [1][2][3]

T-cell receptors (TCRs)

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.

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

Mechanism

  1. Antigen presentation
  2. Costimulatory signal: mediates survival and proliferation of T cells
  3. Effect

T cell effects

  1. T cells (CD8+): direct cell lysis or induction of apoptosis via perforin and proteases
  2. Th1 cell (CD4+): cell‑mediated response
  3. Th2 cell (CD4+): cell‑mediated response

T cell subtypes

Overview of T cell subtypes
Cell type Important surface markers Function Stimulate/activate Clinical significance

Cytotoxic T cells (killer T cells)

T-helper cells (Th cells) Th1 cells
Th2 cells
Th17 cells
  • Regulate tissue inflammation (both proinflammatory and antiinflammatory effects)
  • Fight extracellular pathogens
T follicular helper cells (TFH cells)
  • Support B cell activation and maturation in lymphoid follicles
  • Autoimmune diseases
Regulatory T cells (Treg, suppressor T cells)
  • Stimulate or suppress CD4+ and CD8+T effector cells
  • sIPEX syndrome

Surface markers

Surface protein expression determines the specific function of T cell subtypes.

Differentiation of T helper cell subtypes
Cell type Surface marker Stimulated by Cytokines produced Inhibited by
Th1 cell
Th2 cell
  • CRTH2
  • CCR4
  • CCR3
Th17 cell
  • CCR6+
  • CCR4+
TFH cell
Treg cell


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.

Overview [1][2][3][5]

B-cell development

“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)

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.

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
    • 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).

Class switching occurs with AGE: IgA, IgG, IgE.

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. Every immunoglobulin can have monomeric structure. In context of immunoglobulins, the term affinity refers to individual interaction of antibody and antigen, whereas avidity characterizes the accumulated binding strength of all antigen-binding sites combined.

  • Fc region
  • Fab region
    • Contains the variable/hypervariable region
    • Formed by light (L) chains and heavy (H) chains
    • Recognizes and binds to antigens via epitope
    • Determines the idiotype
      • Binding site with specificity for one particular kind of antigen
      • Every B cell expresses exactly one antigenic specificity

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

Immunoglobulin properties

Specificity

Diversity

Immunoglobulin types

Overview of immunoglobulins
Type Structure Characteristics Examples and clinical relevance
IgM
  • Pentamer
  • Largest antibody , located on the surface of mature B cells as a monomer and circulating as pentamer (with J chain)
  • Formed early (evidence of recent infection) as the first response to antigen contact
  • Binds and activates complement
  • Pentameric structure allows strong antigen binding while humoral immune response is initiated
IgG
  • Monomer
IgA
  • Monomer or dimer
IgE
  • Monomer
IgD
  • Monomer
  • Found in blood serum and on the surface of mature B lymphocytes
  • Function is not completely understood

To memorize the timing of IgM formation, think of IgM as forming iMmediately!

To remember that IgG can cross the placenta and conveys transient passive immunity, think of “IgG Grants immunity to the Growing fetus”

IgA is an Intra-gut Antibody (mainly found in the gastrointestinal mucosa).

Antibody-dependent cell-mediated cytotoxicity (ADCC) [6]

Anticancer monoclonal antibodies (e.g., trastuzumab, rituximab) act by neutralizing extracellular targets (e.g., membrane receptors, channels) or promoting immune system recognition via ADCC by NK 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.

Immune tolerance [4][10]

The unresponsiveness of an organism’s immune system to antigens in an effort to prevent harmful over-reactivity is called immune tolerance.

Central tolerance

Peripheral tolerance

Autoimmunity

Autoimmunity refers to an immune reaction against the body's own cells that occurs as a result of a loss of immune tolerance. Women have a disproportionately higher incidence of autoimmune diseases than men.

Presumed pathogenesis

Causes of autoimmune conditions

Consequences

  • The presence of autoreactive B cells results in the production of irregular antibodies, which can trigger various diseases.
  • Autoantibodies 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

Overview of autoantibodies
Name Target Potentially associated conditions
Antinuclear antibodies (ANAs)
Perinuclear antineutrophil cytoplasmic antibodies (p-ANCAs, MPO-ANCAs)
Cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCAs, PR3-ANCAs)
Antithyroglobulin antibodies
Thyroid peroxidase antibodies (TPO Abs)
TSH receptor antibodies
Antiendomysial antibodies (EMA; IgA)
Transglutaminase antibodies (IgA)

Antigliadin antibodies (DGP IgG, DGP IgA)

Acetylcholine receptor antibodies
Anti-glomerular basement membrane antibodies
Anti-β2 glycoprotein antibodies
  • Glycoprotein
Anticardiolipin antibodies
Rheumatoid factor
Anti-CCP antibodies
Lupus anticoagulant
Anticentromere antibodies
  • Centromeres
Antidesmoglein antibodies
Anti-glutamic acid decarboxylase antibodies

Islet cell cytoplasmic antibodies

Antihemidesmosome antibodies
Antisynthetase antibodies (anti-Jo-1 antibodies)
Anti-SRP antibodies
Anti-Mi-2 antibodies (antihelicase antibodies)
Antimitochondrial antibodies
Anti-intrinsic factor antibodies
Anti-parietal cell antibodies
Anti-phospholipase A2 receptor antibodies
  • Primary membranous nephropathy
Anti-Scl-70 antibodies
Anti-smooth muscle antibodies
Anti-liver-kidney-microsomal antibodies type 1

Anti-SSA (anti-Ro) antibodies

Anti-SSB (anti-La) antibodies

  • Intracellular autoantigens
Anti-presynaptic calcium channel antibodies
Antihistone antibodies
Anti-dsDNA antibodies
  • Double-stranded DNA
Anti-Smith antibodies
Anti-U1 RNP antibodies
  • Ribonucleoprotein
Overview of immune deficiency and infections
Defective immune system component Bacteria Viruses Fungi/parasites
T cells
B cells
  • ↑ Risk of enteroviral infection (may lead to encephalitis)
  • Affected individuals have an increased susceptibility to viral infections. Therefore, live vaccination against poliovirus is contraindicated.
  • IgA deficiency increases the risk of gastrointestinal giardiasis
↓ Complement
  • N/A
  • N/A
Granulocytes
  • Staphylococcus
  • Pseudomonas aeruginosa
  • Nocardia
  • Serratia
  • Burkholderia cepacia
  • N/A

Common pathogens of recurrent infections in granulocyte-deficient individuals (Staphyloccocus, Pseudomonas aeruginosa, Nocardia, Serratia, Burkholderia cepacia): Some Pathogens Need Strong anti-Biotics.

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