10.2 Immunoglobulins: Classes, Structure, and Properties

10.2 Immunoglobulins: Classes, Structure, and Properties

Quick Answer: An immunoglobulin monomer is two heavy + two light chains. Fab binds antigen; Fc binds complement, Fc receptors, and the placental FcRn. IgM is a J-chain pentamer with 10 binding sites, cold- and saline-reactive, the best complement fixer, and the usual ABO isotype — it does not cross the placenta. IgG is a warm monomer, needs AHG to agglutinate, crosses the placenta (HDFN), and is the clinically significant unexpected antibody. IgG1 and IgG3 beat IgG2 and IgG4 at complement and placental transfer. DTT/2-ME destroy IgM. AHG detects IgG coating.

The June 9, 2026 BB outline lists immunoglobulins at III.A.2. If you cannot say which class is a saline agglutinin and which class needs AHG, antibody-ID items later in the outline are guesswork.

Four chains, Fab, Fc, hinge, valence

The monomer is a Y. Two identical heavy chains and two identical light chains are held by disulfide bonds. Light chains are kappa or lambda — one molecule uses one or the other, never both. Heavy-chain constant regions set the isotype: μ (IgM), γ (IgG), α (IgA), ε (IgE), δ (IgD).

• Variable domains (VH + VL) form the antigen-binding site. That specificity is the idiotype.
• Fab (fragment antigen-binding) is the arm: one light chain plus the VH/CH1 of the heavy chain. Papain cuts above the hinge and yields two Fab + one Fc. Pepsin cuts below the hinge and yields F(ab′)2.
• Fc (fragment crystallizable) is the stem. Complement C1q binds here. Fcγ receptors on macrophages and NK cells bind here. The neonatal Fc receptor (FcRn) on placenta and endothelium binds IgG Fc — that is placental transfer and the long IgG half-life (~21 days for most subclasses).
• The hinge (especially IgG) supplies flexibility so both Fabs can land on epitopes.
• Valence is the number of antigen-binding sites. IgG valence is 2. IgM theoretically 10. Secretory IgA 4.

Isotype = class. Allotype = inherited Gm/Km polymorphisms on constant regions. Idiotype = the binding-site fingerprint. A stem that asks “which fragment binds C1q” wants Fc, not Fab.

Classes that matter in the transfusion service

IgM is a ~900 kDa pentamer. It is a complete antibody: it agglutinates in saline at immediate spin because the pentamer spans the gap between red cells (Section 10.3). One IgM Fc cluster binds C1q, so IgM is the most efficient classical-pathway activator. It does not use FcRn and does not cause HDFN. ABO antibodies are the clinically deadly IgM (group O also makes IgG anti-A,B, which is why ABO HDFN is usually a group O mother). Most anti-I, anti-P1, anti-M, anti-N, and anti-Lea start as cold IgM and are insignificant unless they react at 37 °C.

IgG is a ~150 kDa monomer. It is an incomplete antibody in saline: valence 2 cannot overcome zeta potential, so the tube looks negative until AHG bridges Fc. Clinically significant unexpected antibodies are IgG until proven otherwise. Because IgG crosses the placenta, HDFN is an IgG disease. Because IgG is warm, a 37 °C / AHG panel is the clinically significant phase.

IgA in secretions is a dimer with J chain and secretory component. Blood bankers care because a patient with undetectable IgA can make class-specific anti-IgA and have anaphylaxis to plasma, platelets, or unwashed red cells. The product fix is washed red cells, IgA-deficient plasma, or an IgA-poor derivative — not “give diphenhydramine and proceed with FFP.”

IgE arms mast cells and basophils (type I hypersensitivity). It is the isotype behind some allergic transfusion reactions. It is not an alloantibody you identify on a panel. IgD sits with IgM on naive B cells. Do not invent an IgD blood-group antibody.

IgG subclasses

Human IgG is four subclasses. IgG1 (~65%) and IgG3 (~7%) are the dangerous ones for complement and for the fetus. IgG2 (~25%) is poorer at both and is over-represented among antibodies to carbohydrate antigens. IgG4 (~4%) does not bind C1q and is a weak placental crosser. IgG3 also has the short half-life (~7 days versus ~21 days for IgG1/2/4) because of its long hinge.

If a stem asks which subclasses are “better at complement and placenta,” the pair is IgG1 and IgG3, not IgG2/IgG4.

Reducing agents destroy IgM; AHG detects IgG

Dithiothreitol (DTT) and 2-mercaptoethanol (2-ME) reduce disulfide bonds. The IgM pentamer falls apart (J-chain / inter-subunit disulfides). IgG, a monomer, keeps its activity. Treat the serum, repeat the panel:

• Reactivity gone → the antibody was IgM — unless the antigen was DTT-sensitive. Kell antigens are destroyed by DTT. That is the classic trap. A disappearing anti-K after DTT is not proof it was IgM.
• Reactivity remains → IgG is present.

Use the trick to strip cold IgM so an underlying warm IgG can be seen, or to decide whether an anti-M is a harmless IgM or a 37 °C IgG. Thiol reagents in antibody workups return in Chapter 16; the immunology point here is pentamer versus monomer.

AHG (anti-human globulin, Coombs reagent) is antibody to human IgG Fc (and, if polyspecific, to C3). It is how the bench detects IgG coating that did not agglutinate in saline. Polyspecific AHG = anti-IgG + anti-C3b/C3d. Monospecific reagents split those activities. Check cells (IgG-coated red cells) must agglutinate after a negative AHG reading or the wash/AHG step is invalid. Complement details sit in Section 10.4; DAT versus IAT sit in Section 10.3.

Exam traps

• Giving IgM credit for HDFN. IgM does not cross the placenta.
• Calling ABO antibodies IgG-only. Group O often has IgG anti-A,B as well as IgM.
• Using DTT to “prove IgM” on a Kell antibody. DTT destroys Kell antigens.
• Saying IgG agglutinates at immediate spin in saline. IgG needs AHG.
• Treating anti-IgA anaphylaxis as a garden-variety urticarial reaction.
• Ranking IgG4 as the best complement fixer. It is the worst.