The COVID-19 Textbook

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SECTION 3 • Immunology

TABLE 8.1 Summary of major classes of antibodies in humans

IgM

IgG

IgA

IgE

IgD

μ

γ 1, γ 2, γ 3, γ 4

α 1, α 2

ε

δ

Heavy chain Light chain

κ , λ

κ , λ

κ , λ

κ , λ

κ , λ

Structure

Monomer, pentamer

Monomer

Monomer, dimer Monomer

Mono mer

Percentage of total antibody in serum Half-life (days) Fixes complement

10%

75%

15%

< 1%

< 1%

5

23

6-8 No

1-5 No

2-8 No

Yes

Yes

Fc γ RI/CD64, Fc γ RII/ CD32, Fc γ RIII/CD16 Secondary anti body responses; neutralization, opsonization, fixes complement

Fc α RI/CD89

Fc δ R

Fc receptor

FcμR

Fc e RI, Fc e RII

Major function Monomer form of IgM serves as

Predominant an tibody in mucosa and secretions

Allergy and antiparasitic activity

BCR

BCR; fixes comple ment; primary anti body responses

BCR, B-cell receptor; Ig, immunoglobulin. From Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell . 4th ed. Garland Science; 2002. ©1983, 1989, 1994. Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. Used by permission of W. W. Norton & Company, Inc.

F c -RECEPTORS The Fc-domain of an antibody plays two critical roles. First, it provides instructions to the im mune system on how the antigen to which the antibody is bound should be destroyed. Second, the Fc-domain dictates the half-life of the antibody. Interaction of the antibody Fc-domain with a range of FcRs, found across immune and nonimmune cells, dictates these two functions. Individual FcRs, expressed on a variety of innate immune cell types, exist for nearly all antibody isotypes and subclasses, allowing each to deploy specific immunologic functions (Table 8.2). For example, the Fcμ-receptor (FcµR) has been implicated in opsonophagocytosis and T-cell activation. 26,27 Fc α R expression is more restricted, but it can activate a large number of functions. For example, Fc α RI activation can result in phagocytosis, degranulation, superoxide generation, release of neutrophil extracellular traps (NETs), antibody-dependent cellular cytotoxicity (ADCC) , release of cytokines and chemokines, or antigen presentation. 28 A diverse set of activating and inhibitory Fc γ Rs, expressed across distinct immune cell types, can deploy a range of immunologic functions that may be essential to the elimi nation of pathogens or aberrant cells/materials in the body. All FcRs except Fc γ RIIIB possess or are associated with signaling receptors that provide activating or inhibitory signals. Fc γ RIIIB is a Glyco sylphosphatidylinositol (GPI)-anchored protein, which captures antibodies largely on neutrophils. Although FcRs for IgE and IgA exhibit high affinity for their antibodies, Fc γ RI is a high-affinity receptor and the remaining four Fc γ Rs—Fc γ RIIA, Fc γ RIIB, Fc γ RIIIA, and Fc γ RIIIB—are all low-affinity receptors, 29 requiring multimerization to activate cells. 30 This affinity threshold across the Fc γ Rs acts as a quality control and ensures the appropriate activation threshold is met on innate im mune cells prior to cellular activation, preventing pathologic activation of the innate immune system. Antibody half-life is dictated by the ability of the antibody Fc-domain to interact with the neonatal FcR (FcRn). 31,32 FcRn is expressed across both endothelial cells and a subset of immune cells. In nonimmune cells, antibody binding results in antibody capture and recycling back into the circulation. 33 FcRn is also involved in transferring antibodies across barriers, such as the placental or blood-brain barrier, to ensure the presence of antibodies across tissues and compartments. 34,35 IgG

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