Age‑associated IgG accumulation in senescence‑sensitive tissues engages inhibitory FcγRIIB receptors on B cells, triggering a phosphatase cascade that elevates PP2A activity and suppresses AID‑driven somatic hypermutation. This creates a permissive environment for low‑affinity, autoreactive clones to expand, contributing to the observed repertoire contraction and frailty in older individuals.

Mechanistic link Elevated tissue IgG forms immune complexes that cross‑link FcγRIIB. The receptor’s immunoreceptor tyrosine‑based inhibitory motif recruits SHIP‑1 and SHP‑1 phosphatases, which de‑phosphorylate SYK and downstream MAPK pathways. Recent work shows PP2A activity rises when MAPK/p38 signaling is dampened, leading to reduced E47 and Pax5 transcription PP2A suppresses MAPK/p38 signaling. Lower E47/Pax5 diminishes AID expression, curbing class‑switch recombination and somatic hypermutation in both heavy and light chains SHM declines with age. Consequently, aged B cells produce more IgM and fewer high‑affinity IgG antibodies, yet the persistent IgG complexes maintain the inhibitory loop.

Clonal expansion driver When SHM is blunted, selection pressure on affinity drops. Autoreactive B‑cell receptors that would normally be culled in germinal centers survive because they receive insufficient negative selection signals. These cells receive strong BAFF/TNF‑α survival cues in the inflamed, senescence‑rich milieu, allowing them to proliferate as dominant clones Clonal expansions and frailty. The expanded clones secrete additional IgG, reinforcing the FcγRIIB‑PP2A axis—a positive feedback loop that accelerates repertoire narrowing.

Testable predictions

1. Blocking FcγRIIB in aged mice will lower PP2A activity in B cells, restore AID expression, and increase SHM frequency, especially replacement mutations in CDRs.
2. Administering a PP2A inhibitor (e.g., low‑dose LB‑100) to aged animals should rescue class‑switch recombination, raise IgG titers, and reduce the size of dominant clones without increasing autoimmunity.
3. Depleting tissue IgG with Fc‑engineered anti‑IgG antibodies will break the feedback loop, diminish clonal expansions, and improve frailty scores in longitudinal cohorts.
4. In humans, high serum IgG levels will correlate with elevated PP2A phosphorylation in peripheral B cells and with reduced CDR3 replacement mutation rates, even after adjusting for age and vaccine response.

Experimental approach

• Use aged (20‑month) C57BL/6 mice ± FcγRIIB‑blocking antibody; isolate splenic B cells, measure PP2A catalytic activity (immunoprecipitated phosphatase assay), AID mRNA (qPCR), and SHM depth (IgG‑seq) Bone marrow dysfunction in aging, Aged B cells retain SHM.
• Treat parallel cohorts with LB‑100; assess IgG subclasses, ELISpot for antigen‑specific cells, and clonal diversity (Shannon entropy) Clonal expansions and frailty.
• Perform passive transfer of purified IgG from old mice into young recipients; monitor PP2A activation and early clonal expansion over 4 weeks.
• In human blood samples from frailty‑stratified donors, quantify surface FcγRIIB, phospho‑PP2A (Western blot), and AID (intracellular flow) while sequencing the Ig repertoire for CDR3 replacement/frequency ratios SHM declines with age, B cells drive T cell immunosenescence.

If FcγRIIB or PP2A inhibition restores SHM and contracts pathogenic clones, the hypothesis gains support; failure to observe these changes would falsify the proposed feedback model.