Systemıc Vh4-34-Encoded Antıbody Responses Agaınst Commensal Bacterıa in Patıents Wıth Systemıc Lupus Erythematosus
Özet
The germline immunoglobulin variable heavy chain 4–34 encoding B lymphocytes (known as VH4–34 or 9G4 B cells) are endowed with inherent self-reactivity due to the presence of a germline AVY motif in their framework region 1 of the VH4–34 gene segment. Germline self-reactive VH4-34 undergoes negative selection in the memory and plasmablast compartments of healthy donors. However, the VH4-34 censorship is compromised in systemic lupus erythematosus (SLE) patients (1), resulting in higher proportions of VH4-34 expression among plasmablasts and memory B cells.(1-3) Given the fact that gut dysbiosis and disturbances to the gut barrier integrity can set off inflammatory immune responses, and also that the association between circulating 9G4 memory B lymphocytes isolated from individuals with SLE and the gut bacteria has not been investigated to date, we seek to determine the anti-commensal bacteria reactivity of VH4-34+ IgG antibodies in SLE subjects. VH4-34 CD27+IgG+ B lymphocytes from individuals with SLE exhibit aberrant VH4-34 gene usage and display a reduction in somatic hypermutation frequencies, often with an unmutated AVY site, suggesting that their antibodies continue to possess intrinsic self-reactivity unlike their healthy donor (HD) counterparts as well as a propensity for reactivity towards commensal microorganisms. Herein, we observed that SLE VH4-34+IgG+ B lymphocytes with an unmutated AVY site exhibited an elevated level of reactivity towards gut bacteria present in the fecal samples of control groups and SLE patients, but to a smaller extent in HD stools and to a greater extent in SLE stools. Since SLE VH4-34 clonal expansion is associated with disease flare, our discovery of the SLE VH4-34 clonal expansion of gut bacteria-reactive circulating 9G4+IgG+ B cells in one SLE patient suggests that commensal bacteria translocating from the gut to the bloodstream are therefore responsible for the VH4-34 expansion in SLE. Lastly, we identified bacteria strains recognized by circulating unmutated AVY motif-encoding VH4-34-encoded antibodies, which could be attributed to a compromised intestinal barrier function in SLE patients.
