Antibody Structure & Function

Antibody structure

Two heavy chains, two light chains. An antibody is built from two identical heavy chains and two identical light chains (either kappa or lambda), joined by disulfide bonds into a Y shape. The paired heavy- and light-chain variable regions at the tips of the arms form the two antigen-binding sites; within them, the hypervariable regions make direct contact with antigen.

Fab and Fc. Papain cleavage splits an antibody into two antigen-binding Fab fragments and one Fc stem. Fab (fragment, antigen-binding) contains the variable regions and sets antigen specificity and idiotype. Fc (fragment, crystallizable) is the constant heavy-chain stem: it determines isotype, fixes complement, and binds Fc receptors on phagocytes, NK cells, and mast cells.

Fc = Constant, Carboxy-terminal, Complement-binding, Carbohydrate side chains. Antigen binding at the Fab tips; effector functions at the Fc stem.

Diversity and class switching

Generating diversity. Before antigen is ever met, diversity arises from random V(D)J recombination (catalyzed by RAG1 and RAG2), junctional diversity (terminal deoxynucleotidyl transferase, TdT, adds random nucleotides at the joints), and combinatorial pairing of heavy and light chains. After antigen exposure, somatic hypermutation of the variable regions in germinal centers, with selection of the best binders, drives affinity maturation.

Class switching. Naive B cells express IgM and IgD. Switching to IgG, IgA, or IgE changes the heavy-chain constant region while keeping the same variable region, so specificity is preserved. It requires CD40L on the helper T cell engaging CD40 on the B cell, plus cytokines; the enzyme AID (activation-induced cytidine deaminase) mediates class-switch recombination (and somatic hypermutation).

• IL-4 → IgE and IgG.
• TGF-β (aided by IL-5) → IgA.

Hyper-IgM syndrome. A defect in the switch machinery — most commonly X-linked CD40L deficiency, also CD40 or AID defects — leaves high IgM with low IgG, IgA, and IgE. Boys present with recurrent pyogenic infections and opportunistic infections such as Pneumocystis.

The five isotypes

IgG. The most abundant serum antibody (~75–80%) and the dominant isotype of the secondary response. It is the ONLY isotype that crosses the placenta (via the neonatal Fc receptor, FcRn, which also gives IgG the longest half-life), providing passive neonatal immunity. It fixes complement, opsonizes, and neutralizes toxins and viruses.

IgM. Secreted as a pentamer joined by a J chain, giving 10 binding sites and high avidity that traps antigen early despite low per-site affinity. It is the FIRST antibody of the primary response and the best complement fixer. Monomeric surface IgM (with IgD) is the naive B-cell antigen receptor. It is too large to cross the placenta.

IgA. Guards mucosal surfaces. It is secreted as a dimer (J chain) and picks up a secretory component during transport across the epithelium, which shields it from proteases in the gut lumen. Found in saliva, tears, mucus, and breast milk/colostrum, it prevents pathogen attachment. It is the most-produced antibody by mass per day, although serum IgG is higher.

IgE. The lowest serum level. It binds mast cells and basophils through its Fc; allergen cross-linking of bound IgE triggers degranulation (type I hypersensitivity, anaphylaxis). IgE also mediates antiparasite/antihelminth immunity by activating eosinophils.

IgD. Found with IgM on the surface of naive B cells as an antigen receptor. Its serum level is very low and its precise function remains unclear.

Effector functions and passive immunity

• Neutralization — antibody blocks toxins and prevents microbial adherence and entry.
• Opsonization — IgG coats microbes so phagocytes engulf them via Fc receptors.
• Complement activation — IgM and IgG bind C1q to start the classical pathway.
• ADCC — NK cells kill IgG-coated cells through the Fc receptor CD16.

Passive immunity. Maternal IgG crosses the placenta, mostly in the third trimester, and secretory IgA passes in breast milk, protecting the newborn for months — which is why an infant is protected from measles without making any antibody of its own. Premature infants receive less maternal IgG. Preformed antibodies given therapeutically (antitoxins, RhoGAM, IVIG) provide rapid but temporary protection without memory.

T-dependent vs T-independent antigens

Thymus-dependent antigens. Protein antigens are processed by B cells and presented on MHC II to helper T cells, which provide CD40L–CD40 signals and cytokines. The result is class switching, affinity maturation, and memory.

Thymus-independent antigens. Polysaccharides and LPS cross-link B-cell receptors directly without T-cell help. They give mainly IgM, no memory, and respond poorly in children under 2.

Conjugate vaccines link a capsular polysaccharide to a protein carrier to recruit T-cell help, giving infants class-switched IgG and memory against encapsulated bacteria.