🫀 Humoral immunity & antibody isotypes

First responder IgM is the first immunoglobulin secreted during a primary immune response. Its heavy chain is the μ chain, and the constant-region genes for IgM lie closest to the V(D)J recombination sites, making it the default isotype.

• Membrane form: monomeric IgM acts as the B-cell antigen receptor (BCR).
• Secreted form: a pentamer (five monomers) linked by a J chain. This structure gives 10 antigen-binding sites (valence 10) → high avidity (functional binding strength) despite lower affinity early in the response.
• Key effector functions:
  • Excellent at neutralising and aggregating free antigen (sponging effect).
  • Most potent activator of the classical complement pathway among all isotypes.
  • No opsonisation (cannot bind Fc receptors) and no ADCC.

IgG is the dominant isotype in the secondary response and in the circulation (adult serum levels ~620–1400 mg/dL). It is a monomer with a γ heavy chain.

• Induction: driven by IFN-γ from Th1 cells; class-switch recombination (CSR) replaces μ with γ constant genes.
• Subclasses: IgG1, IgG2, IgG3, IgG4 (differ in hinge flexibility and effector potency).
• Effector functions:
  • ✅ Activates complement (classical pathway) — IgG3 > IgG1.
  • ✅ Potent opsonin — binds Fcγ receptors on phagocytes.
  • ✅ Mediates ADCC (antibody-dependent cell-mediated cytotoxicity) via NK cells.
  • ✅ Crosses the placenta via neonatal Fc receptor (FcRn) → provides passive immunity to the fetus.

IgA is the predominant antibody at mucosal surfaces. It exists as a dimer (two monomers joined by a J chain) and is produced by plasma cells in the mucosa-associated lymphoid tissue (MALT) — including Peyer’s patches, tonsils, and lamina propria.

• Two subclasses: IgA1 (predominant in serum) and IgA2 (more resistant to bacterial proteases, enriched in secretions).
• Secretory IgA (sIgA): the dimer binds the poly-Ig receptor on the basolateral surface of epithelial cells, is transcytosed, and is released into the lumen attached to a secretory component (a proteolytic fragment of the receptor). This secretory piece protects IgA from enzymatic degradation.
• Functions:
  • Neutralises toxins and pathogens at mucosal surfaces (respiratory, GI, urogenital).
  • Does NOT activate complement, opsonise, or mediate ADCC.
• Induction: TGF-β (and IL-5) from epithelial cells and Th2 cells drives IgA class switching.

IgE has the ε heavy chain, is present in trace amounts in serum, and is chiefly produced in mucosal tissues.

• Effector functions: binds with high affinity to FcεRI on mast cells, basophils, and eosinophils. Cross-linking by allergen triggers degranulation → release of histamine, leukotrienes, and cytokines.
• Protective role: defence against helminths (parasitic worms).
• No complement activation, no opsonisation, no placental transfer.

Both IgM and IgG activate the classical complement pathway. IgM is the most efficient activator due to its pentameric structure.

• Classical pathway: C1q binds to the Fc regions of antigen-bound IgM or IgG (especially IgG3, IgG1) → triggers C4 and C2 cleavage → C3 convertase → opsonisation (C3b), inflammation (C3a, C5a), and membrane attack complex (MAC).
• Complement also concentrates antigen in secondary lymphoid organs and enhances B-cell responses.

X-linked hyper-IgM syndrome (XHIM) is a primary immunodeficiency caused by mutations in the CD40 ligand (CD40L, on X chromosome). Th cells cannot deliver the CD40–CD40L costimulatory signal to B cells.

• Lab findings: markedly elevated IgM (often >2000 mg/dL), very low or absent IgG, IgA, IgE.
• Clinical: recurrent respiratory infections (especially Pneumocystis jirovecii), failure to form germinal centres, autoantibodies (neutropenia, thrombocytopenia).
• Key concept: T-independent B-cell responses remain intact (IgM production), but T-dependent class switching fails.