ImmunologyTier 1Medical Sciences concept

Immunoglobulin classes - complement activation, function, structure

Core concept

Structure

Two heavy + two light chains, disulphide-linked; light chain is kappa or lambda (kappa:lambda ~2:1 in normal serum - the basis of clonality assessment)
Fab (x2) = variable region = antigen binding
- Neutralises toxins and blocks pathogen-host interaction; agglutinates and precipitates antigen
- F(ab')2 from pepsin digestion (bivalent, no Fc); Fab from papain digestion
Fc = constant region = effector function
- Complement fixation (C1q binding)
- Fc receptor binding on phagocytes and NK cells -> opsonisation, ADCC
- Placental transfer (FcRn) and IgG recycling - why IgG has a long half-life
Diversity: V(D)J recombination (RAG1/2), junctional diversity (TdT), somatic hypermutation and class switching (AID) in the germinal centre

Key detail

	IgG	IgM	IgA	IgE	IgD
Serum share	~75-80%	~10%	~15%	Trace	Trace
Form	Monomer	Pentamer (J chain)	Monomer in serum, dimer in secretions (J chain + secretory component)	Monomer	Monomer
Complement (classical)	Yes - IgG1 and IgG3 best; IgG2 weak; IgG4 NOT	*Most efficient - one pentamer engages C1q*	No (activates alternative pathway)	No	No
Crosses placenta	Yes - the only one	No	No	No	No
Half-life	~21 days	~5 days	~6 days	~2 days (tissue-bound much longer)	-
Role	Secondary response, opsonisation, neutralisation, ADCC	Primary response, first made, agglutination	Mucosal defence, neutralises without inflammation	Mast cell/basophil FcepsilonRI - allergy and helminths	Naive B-cell receptor

IgM is the most efficient complement activator: complement fixation needs two adjacent Fc regions, and a single pentameric IgM in its "staple" configuration provides them; IgG requires two molecules bound close together on the surface
IgG subclasses
- IgG1 - protein antigens, most abundant
- IgG2 - polysaccharide (encapsulated bacteria); selective IgG2 deficiency -> pneumococcal disease
- IgG3 - most potent complement activator, shortest half-life (~7 d)
- IgG4 - does not fix complement; undergoes Fab-arm exchange -> functionally monovalent, "blocking" antibody
  - Rises with chronic antigen exposure and after immunotherapy; IgG4-related disease; the isotype of the pemphigus, MuSK myasthenia and thrombotic anti-ADAMTS13 antibodies
Secretory IgA resists proteolysis because of the secretory component; IgA deficiency is the commonest primary immunodeficiency and causes anaphylaxis to IgA-containing blood products

Clinical relevance

IgM vs IgG determines the type of haemolysis
- IgM (cold agglutinins, ABO-incompatible transfusion) -> complement fixation -> INTRAVASCULAR haemolysis, haemoglobinaemia/uria
- IgG (warm autoimmune haemolysis, Rh) -> Fc receptor-mediated splenic clearance -> EXTRAVASCULAR haemolysis, spherocytes
- Direct antiglobulin test distinguishes IgG from C3d coating
Maternal IgG transfer protects the newborn for ~6 months and explains haemolytic disease of the newborn, neonatal lupus/congenital heart block (anti-Ro), neonatal Graves and neonatal myasthenia - IgM-mediated maternal disease does not cross
- -> the timing of presentation of a primary antibody deficiency is after 6 months, when maternal IgG has waned
Therapeutic antibody engineering follows the isotype rules
- IgG1 chosen where killing is wanted (rituximab, trastuzumab, daratumumab - ADCC + CDC)
- IgG4 or Fc-silenced IgG1 chosen where blockade only is wanted (pembrolizumab, nivolumab, natalizumab, dupilumab) - no complement fixation, no ADCC
- FcRn blockade (efgartigimod, rozanolixizumab) accelerates IgG catabolism -> myasthenia gravis, ITP
- Suffixes: -ximab chimeric, -zumab humanised, -umab fully human
Interpreting immunoglobulins
- Paraprotein - serum electrophoresis + immunofixation + serum free light chain ratio; IgG or IgA in myeloma; IgM in Waldenstrom
- Polyclonal rise - chronic infection, liver disease, autoimmune disease, IgG4-RD
- Low IgG with low IgA/IgM - CVID; isolated low IgA - selective deficiency
Serology: IgM = acute/recent; IgG = past or immune; false-positive IgM from rheumatoid factor and polyclonal activation is common - always interpret with the clinical picture

Correlations

Complement activation pathways
B-cell affinity maturation, somatic hypermutation and class switching
Autoimmune haemolytic anaemia - warm vs cold
Primary immunodeficiency - CVID, XLA, hyper-IgM, IgA deficiency
Multiple myeloma and MGUS; Waldenstrom
IgG4-related disease
Monoclonal antibody therapeutics; hypersensitivity reactions

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.

Get premium access