Fab region

**Structure** - Generated by papain cleavage of IgG above the hinge region: yields 2 Fab fragments + 1 Fc fragment. (Pepsin cleaves below the hinge to yield one F(ab')2 fragment, which remains bivalent, plus degraded Fc.) - Composition of each Fab: light chain (VL + CL) + heavy chain portion (VH + CH1), held together by a disulfide bond between CL and CH1. - Variable domains (VL and VH) contain 3 hypervariable regions each, called complementarity-determining regions (CDR1-3). CDR3 is the most variable. Together they form the antigen-binding site (paratope), which recognizes the epitope. - Constant domains (CL, CH1) are the same for a given isotype and light chain type (kappa or lambda).

**Generation of diversity (antigen specificity)** - V(D)J recombination (heavy chain: V, D, J; light chain: V, J), mediated by RAG1/RAG2 and TdT (adds N-nucleotides), in the bone marrow. - Random heavy and light chain pairing. - Somatic hypermutation and affinity maturation in germinal centers of lymph nodes (AID-dependent; occurs after antigen exposure), which change Fab affinity. - Class switching alters the Fc (constant heavy chain) region, NOT the Fab/antigen specificity. The variable region stays the same. - Allelic exclusion: each B cell expresses one heavy and one light chain allele, so each B cell has a single antigen specificity.

**Fab vs. Fc** - Fab: antigen binding (variable). Functions include neutralization of toxins and viruses, blocking pathogen adhesion, and agglutination. - Fc (CH2-CH3, constant): effector functions. These include complement activation (C1q binds IgG/IgM), opsonization via Fc receptors on phagocytes, and ADCC (NK cells via CD16), mast cell binding (IgE), and placental transfer (IgG via neonatal FcRn).

**Clinical significance (high-yield)** - **Digoxin Fab (DigiFab):** ovine Fab fragments used for digoxin toxicity (hyperkalemia, arrhythmias). Fab lacks Fc, so it is less immunogenic and has good tissue penetration and renal clearance. - **CroFab / Anavip:** Fab (or F(ab')2) antivenom for North American pit viper (rattlesnake) envenomation. - **Monoclonal antibody fragments:** abciximab (Fab against GPIIb/IIIa), ranibizumab (anti-VEGF Fab for wet AMD), certolizumab pegol (PEGylated Fab against TNF-alpha), idarucizumab (Fab reversing dabigatran). Absence of Fc means no complement activation or ADCC. - **Immunoglobulin structure in disease:** - Multiple myeloma: monoclonal Ig production. Free light chains (Bence Jones proteins) are found in urine and cause cast nephropathy. Serum protein electrophoresis shows an M-spike. - Waldenström macroglobulinemia: IgM paraprotein. - AL amyloidosis: deposits of light chains (variable region). - **Type II/III hypersensitivity and autoimmunity:** pathogenic autoantibodies bind self-antigen via Fab (e.g., anti-AChR receptor in myasthenia gravis, anti-dsDNA in SLE). - **Idiotype:** the unique antigenic determinants in the Fab variable region. Anti-idiotype antibodies are a concept in immune regulation. - **Rheumatoid factor:** IgM that binds the Fc portion of IgG (not Fab). - **Blood-type incompatibility/immunodeficiency:** X-linked (Bruton) agammaglobulinemia (BTK mutation) results in absent mature B cells and little or no antibody production, so recurrent bacterial infections after maternal IgG wanes (~6 months).

**Memory aids** - Fab = "Fragment, antigen-binding" (A for antigen, "arms"); Fc = "Fragment, crystallizable" (constant, "crystallizes", "stem"). - Papain: "Pa" = "Pieces": 2 Fab + 1 Fc. Pepsin: F(ab')2 "bivalent."