IgM

STRUCTURE: Secreted as a pentamer (10 antigen-binding sites) joined by a J chain; monomeric form is the B-cell surface receptor (with IgD) on mature naive B cells. Heavy chain is mu (μ). Pentameric structure gives high avidity despite low affinity per binding site (little somatic hypermutation/affinity maturation early on).

FUNCTION: (1) First responder: the earliest antibody in a primary response (before class switching). (2) Best complement activator (classical pathway; C1q binding), so strong opsonization/agglutination and lysis. (3) Excellent at agglutination. (4) Does not cross the placenta (too large). (5) Can be transported across mucosa via the poly-Ig receptor (as can IgA), and is found in secretions in small amounts.

CLASS SWITCHING: Requires CD40 on B cell binding CD40L (CD154) on helper T cells, plus cytokines (e.g., IL-4 → IgE/IgG4; IFN-γ → IgG; IL-5, TGF-β → IgA). Occurs in germinal centers via AID (activation-induced cytidine deaminase). Defects: - Hyper-IgM syndrome: Defective CD40L (X-linked, most common) or CD40/AID. Elevated or normal IgM with low IgG, IgA, IgE. Presents with recurrent pyogenic sinopulmonary infections and opportunistic infections (e.g., Pneumocystis, Cryptosporidium) in the CD40L form; absent germinal centers.

CLINICAL SIGNIFICANCE: - Acute infection marker: Anti-HAV IgM (acute hepatitis A), anti-HBc IgM (acute hepatitis B, and the sole positive marker in the "window period"), anti-EBV VCA IgM, anti-CMV IgM, etc. IgG indicates past infection or immunity. - Congenital infection: Elevated neonatal IgM (e.g., TORCH) indicates fetal production. - Waldenström macroglobulinemia: Lymphoplasmacytic lymphoma secreting monoclonal IgM paraprotein; causes hyperviscosity syndrome (blurred vision, headache, Raynaud, bleeding, neurologic symptoms), no lytic bone lesions (unlike multiple myeloma), lymphadenopathy/hepatosplenomegaly; MYD88 L265P mutation. Treat with plasmapheresis (for hyperviscosity) and chemo/rituximab-based regimens or BTK inhibitors. - Hypersensitivity: Mediates type II (cytotoxic) reactions (with IgG), e.g., ABO incompatibility transfusion reactions (naturally occurring anti-A/anti-B are IgM, causing intravascular hemolysis via complement). Also type III (immune complexes, with IgG). - Cold agglutinin disease: IgM autoantibodies bind RBCs at cold temperatures (<4°C); associated with Mycoplasma pneumoniae and infectious mononucleosis (EBV); anti-I (Mycoplasma) and anti-i (EBV) specificity; causes extravascular and some intravascular hemolysis, acrocyanosis. Coombs positive for C3 only. - Rheumatoid factor: IgM autoantibody against the Fc portion of IgG (seen in RA, though not specific). - Syphilis: Nontreponemal tests (VDRL/RPR) detect antibodies (IgM and IgG) to cardiolipin; FTA-ABS IgM appears early. - Selective IgM deficiency is rare; Selective IgA deficiency is the most common primary immunodeficiency.

MNEMONIC: IgM = "Macro" (pentamer), "first Mover," "Mediates complement (classical)," "Monomer on B cell surface." IgG = Gold standard, crosses placenta, most abundant in serum; IgA = mucosal; IgE = allergies/helminths; IgD = B-cell surface receptor.

KEY TAKEAWAY: Think IgM when the question mentions acute/primary infection, pentamer, complement activation, newborn infection, Waldenström hyperviscosity, cold agglutinins, ABO incompatibility, or CD40L deficiency.