Antibodies — Structure, Isotypes & Immunologic Memory — USMLE Step 1 Notes

Antibody structure

• A basic antibody is a Y-shaped molecule of two identical heavy chains and two identical light chains (kappa or lambda), joined by disulphide bonds.
• Fab region (fragment, antigen-binding): the two arms; each contains one light chain and part of a heavy chain. The tips hold the variable regions with hypervariable / complementarity-determining regions (CDRs) that actually bind antigen; determines specificity.
• Fc region (fragment, crystallisable): the stem, made of heavy-chain constant regions. It determines the isotype and effector function — it binds complement (C1q) and Fc receptors on phagocytes, NK cells and mast cells.
• The variable region gives antigen specificity; the constant region defines class (IgG, A, M, D, E) and what the antibody can recruit.

Antibody functions

• Neutralisation: antibody coats a toxin or virus so it cannot bind host cells (a function of all, especially IgG and secretory IgA).
• Opsonisation: antibody (especially IgG) coats a pathogen so phagocytes with Fc receptors engulf it.
• Complement activation: antigen-bound IgM and IgG fix complement via the classical pathway (C1q), driving lysis and inflammation.
• Antibody-dependent cellular cytotoxicity (ADCC): IgG-coated cells are killed by NK cells via CD16; IgE-coated parasites by eosinophils.
• Agglutination / precipitation: cross-linking clumps pathogens for clearance (IgM is especially good given its ten binding sites).

Affinity, avidity & affinity maturation

• Affinity is the strength of a single antigen-binding site; avidity is the total binding strength from all sites (IgM has low affinity but high avidity from 10 sites).
• Affinity maturation: in the germinal centre, somatic hypermutation plus selection produces B cells with higher-affinity antibody over the course of a response.

Immunoglobulin isotypes

• IgG (monomer): the most abundant serum antibody and the main antibody of the secondary response. Only isotype that crosses the placenta (neonatal passive immunity); opsonises, neutralises, fixes complement and does ADCC. Pathophysiology: type II/III hypersensitivity (e.g. autoimmune haemolysis, SLE immune complexes); maternal IgG causes haemolytic disease of the newborn.
• IgA (monomer in serum; dimer in secretions): the mucosal antibody in saliva, tears, breast milk and the gut; a dimer joined by a J chain with a secretory component that resists proteases. Prevents attachment of pathogens at mucosal surfaces. Pathophysiology: selective IgA deficiency (commonest primary immunodeficiency, anaphylaxis risk with blood products); IgA nephropathy; dermatitis herpetiformis.
• IgM (pentamer, with a J chain): the first antibody made in a primary response and by naive B cells (with IgD); the best complement fixer and agglutinator (10 binding sites). Too large to cross the placenta; its presence in a neonate implies intrauterine infection. Pathophysiology: cold agglutinin disease, Waldenstrom macroglobulinaemia (IgM paraprotein).
• IgD (monomer): found on the surface of naive B cells with IgM; its serum role is unclear (helps B-cell activation/maturation).
• IgE (monomer): lowest serum level; binds mast cells and basophils via high-affinity Fc receptors. Mediates type I hypersensitivity (allergy, atopy, anaphylaxis) and defence against helminths (arms eosinophils). Pathophysiology: asthma, atopy, anaphylaxis, hyper-IgE (Job) syndrome.

Antigen type & memory: thymus-dependent vs thymus-independent

• Thymus-dependent (T-dependent) antigens: protein antigens. The B cell presents peptide on MHC II to a helper T cell (CD40-CD40L + cytokines), producing class switching, affinity maturation and long-lived memory B cells and a strong secondary response. Protein/conjugate vaccines work this way.
• Thymus-independent (T-independent) antigens: polysaccharide antigens (e.g. bacterial capsules, LPS) with repeating epitopes that cross-link the B-cell receptor directly. They give a mostly IgM response with little class switching, weak/no memory, and are poorly immunogenic in children under 2 — which is why conjugate vaccines link the polysaccharide to a protein carrier to recruit T-cell help.

Primary vs secondary immune response

• Primary response: after first exposure — a lag of ~1-2 weeks, mostly IgM, lower magnitude and affinity.
• Secondary response: on re-exposure — faster, larger, higher-affinity and predominantly IgG (from memory B cells). This is the basis of vaccination and of the IgM→IgG serology shift used to date infections.

High-yield revision notes; verify against a primary source before clinical use.