ImmunologyTier 1Medical Sciences concept

B-cell affinity maturation - somatic hypermutation and class switching

Core concept

```

Antigen + T-cell help (CD40L on Tfh -> CD40 on B cell) + cytokines

-> germinal centre forms in the follicle
Dark zone: centroblasts proliferate, AID drives somatic hypermutation of V regions
Light zone: centrocytes compete for antigen on FDCs and for Tfh help
- high affinity -> survives, recycles or exits
- low affinity / self-reactive -> apoptosis
-> affinity maturation, plus class switch recombination
-> plasma cells + memory B cells

```

AID (activation-induced cytidine deaminase) does both jobs: deaminates C -> U
- in V regions -> point mutations -> SHM (affinity)
- in switch regions -> double-strand breaks -> CSR (isotype)
SHM changes the antigen-binding site; CSR changes the constant region and therefore the effector function. Specificity is preserved through class switching.

Cytokines that direct the switch

Cytokine	Isotype
IL-4 / IL-13	IgE, IgG4
IL-10 / IL-21	IgG1, IgG3
TGF-beta (+ IL-10, BAFF/APRIL, retinoic acid)	IgA1/IgA2 - mucosal
IL-21, IFN-gamma	IgG3
(unknown)	IgG2

IgG subclass function
- IgG1 and IgG3 fix complement well and bind FcgammaR - the effector antibodies
- IgG4 does not fix complement, and undergoes Fab-arm exchange -> functionally monovalent, "blocking" - the tolerance isotype
IgM - pentameric, low affinity, high avidity, best complement fixer - the primary response
Primary vs secondary response: primary is slow, IgM, low affinity; secondary is fast, IgG, high affinity, from memory B cells
T-independent antigens (polysaccharide) do NOT get germinal centres -> IgM-dominant, no memory, poor in children <2 yr
- Conjugating polysaccharide to a protein carrier recruits T-cell help -> class switching, affinity maturation and memory - the whole reason conjugate vaccines (Hib, pneumococcal 13/15/20-valent, meningococcal) exist

When it fails

Defect	Disease
CD40L (X-linked) or CD40	Hyper-IgM syndrome - high/normal IgM, absent IgG/IgA/IgE, no germinal centres, PJP and cryptosporidium (T-cell help is also lost)
AID or UNG (AR)	Hyper-IgM with giant germinal centres, bacterial infection, no opportunistic infection
Multiple, mostly polygenic	CVID - low IgG plus IgA or IgM, poor vaccine responses, bronchiectasis, autoimmunity, granulomas, lymphoma
Germinal centre origin	Follicular lymphoma, Burkitt, DLBCL and most B-cell malignancies arise here - AID-driven translocations (t(14;18) BCL2, t(8;14) MYC)

Somatic hypermutation status is prognostic in CLL: mutated IGHV = post-germinal-centre = better prognosis; unmutated IGHV = adverse
Vaccine response testing (tetanus, diphtheria, pneumococcal) assesses this whole pathway - the functional test for suspected antibody deficiency
- Do not vaccinate to test while the patient is on rituximab or high-dose steroid
Allergen immunotherapy works by inducing IgG4 blocking antibodies and Tregs - IL-4-driven IgE switching is redirected
Anti-CD20 (rituximab) spares plasma cells (CD20-negative) -> IgG falls slowly, and pre-existing immunity persists while new responses fail
Affinity maturation takes weeks - the argument for prime-boost intervals and for why a booster gives a qualitatively better antibody, not merely more

3 more sections, plus exam facts

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