STEPTRACKERIMMUNOLOGY | ADAPTIVE IMMUNITY | HIGH-YIELD REVIEW

B-Cell Activation & Class Switching

B cells bind whole antigen; with T-cell help they form germinal centers, switch isotype and sharpen affinity — without help, they make short-lived IgM.

FOCUS ON
T-dependent (protein) antigens: B cell takes up antigen via BCR → presents peptide on MHC II → helper T cell gives CD40L–CD40 + cytokines → germinal center: class switching (AID; IL-4 → IgE/IgG4, IFN-γ → IgG, TGF-β/IL-5 → IgA) and somatic hypermutation → affinity maturation → plasma cells and memory B cells. T-independent (polysaccharide, LPS) antigens: cross-link many BCRs → mostly IgM, no memory, weak in children < 2 → conjugate vaccines. Marginal zone B cells (spleen) make fast IgM to encapsulated bacteria. Defects: CD40L (X-linked hyper-IgM), AID (AR hyper-IgM), BTK (XLA). Primary response: IgM first; secondary: faster, higher-affinity IgG.
STEP
WHAT HAPPENS
MOLECULES
DEFECT · CLINICAL LINK
Antigen capture
BCR (surface IgM/IgD) binds native antigen; coreceptor CD19–CD21–CD81 lowers threshold
C3d on antigen binds CD21
EBV enters via CD21
Presentation to T cell
Internalized antigen → peptide on MHC II
MHC II, B7
Hapten–carrier principle
T-cell help
Tfh cell binds peptide–MHC II; CD40L engages CD40; cytokines direct isotype
CD40L (CD154), IL-21, IL-4
CD40L defect → X-linked hyper-IgM (high IgM, no IgG/IgA/IgE, Pneumocystis, Cryptosporidium)
Germinal center
Rapid proliferation (dark zone), selection on follicular DCs (light zone)
BCL-6
Follicular lymphoma (BCL-2 overexpression t(14;18))
Class switch recombination
Constant region DNA deleted; variable region kept → same specificity, new isotype
Activation-induced cytidine deaminase (AID)
AID/UNG defect → AR hyper-IgM (lymphoid hyperplasia)
Isotype directed by cytokine
IL-4, IL-13 → IgE (and IgG4) · IFN-γ → IgG (opsonizing) · TGF-β, IL-5 → IgA
—
Allergy is Th2-driven IgE
Somatic hypermutation
Point mutations in variable regions; best binders survive
AID
Affinity maturation
Plasma cell
Antibody factory; CD38, CD138; loses surface Ig, MHC II
BLIMP-1, XBP-1
Multiple myeloma · daratumumab (CD38)
Memory B cell
Long-lived; fast secondary response
—
Booster doses rely on these
T-independent response
Repetitive polysaccharide or LPS cross-links BCRs; marginal zone and B1 cells
Little class switch, no memory
Poor in < 2 years and asplenia → conjugate vaccines (Hib, PCV, MenACWY)
Primary vs secondary response
Primary: lag, IgM peak ~1–2 weeks · secondary: rapid, high-titer, high-affinity IgG
—
IgM = recent infection in serology

Mechanism — why conjugate vaccines work

B cell binds polysaccharide
→
Internalizes attached protein
→
Presents protein peptide on MHC II
→
T-cell help → switch to IgG, memoryAntibody still targets the sugar

T-dependent vs T-independent

FEATURE
T-DEPENDENT
T-INDEPENDENT
Antigen
Protein
Polysaccharide, LPS
Isotype
IgG, IgA, IgE
Mostly IgM
Affinity maturation
Yes
No
Memory
Yes
Little
Works in infants
Yes
Poorly (< 2 y)

How it's tested

COMMON CONFUSIONClass switching changes the constant region (effector function) but keeps the variable region, so antigen specificity stays the same.
THE TRAPHyper-IgM syndrome is a switching failure, not overproduction — the patient lacks IgG, IgA and IgE and gets opportunistic infections from absent CD40L signaling to macrophages.
YOUR APPROACHAntigen type → T-dependent or not → help signals (CD40L, cytokines) → isotype produced → defect pattern.

If you see… think…

Enzyme required for class switching and hypermutation → AID
Boy with high IgM, absent IgG/IgA, Pneumocystis pneumonia → CD40L deficiency
Cytokine switching B cells to IgE → IL-4 (and IL-13)
Cytokine switching to IgA → TGF-β
Sharper antibodies after a booster → affinity maturation (somatic hypermutation)
Polysaccharide vaccine fails in infants → T-independent antigen
First antibody in a primary response → IgM
Plasma cell markers → CD38, CD138
Splenic B cells making fast IgM to encapsulated bacteria → marginal zone
Coreceptor that binds C3d → CD21