Background: Dysregulation of cutaneous lymphocyte antigen–positive regulatory T cells (CLA ⁺ Tregs) contributes to immune imbalance and heightened disease activity in autoimmune disorders, yet the mechanisms underlying their depletion in rheumatoid arthritis (RA) remain poorly understood.

Objectives: The objective is to explore why CLA ⁺ Tregs are decreased in RA.

Methods: Peripheral blood samples were obtained from patients with RA and healthy controls.CLA ⁺ Tregs and GFO-specific B cells were characterized by multiparameter flow cytometry. The effects of purified anti-GFO IgG on CLA ⁺ Tregs were examined using ADCC and CDC assays.

Results: Here, we showed that CLA ⁺ Tregs were significantly reduced in RA patients compared with healthy controls. Notably, the immunogenic region of CLA shared a conserved six–amino-acid motif with GFO peptides derived from Bacteroides sp. A1C1, a bacterium enriched in the tonsillar microbiota of RA patients. Anti-GFO antibodies were elevated in RA sera and inversely correlated with CLA ⁺ Treg frequencies. Mechanistically, GFO peptides activated B cells and expanded GFO-specific B-cell populations. Purified anti-GFO IgG induced CLA ⁺ Treg apoptosis via antibody- and complement-dependent pathways and promoted osteoclast differentiation and bone resorption.

Conclusions: Together, these findings reveal that GFO-derived peptides impair CLA ⁺ Treg homeostasis through molecular mimicry, thereby exacerbating RA progression and establishing a mechanistic link between tonsillar microbiota dysbiosis and immune dysregulation in RA.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.