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Aberrant zonal recycling of germinal center B cells impairs appropriate selection in lupus

ABSTRACT: Systemic autoimmunity is driven by the production of pathogenic autoantibodies that can arise from germinal centers (GCs). Typically, B cells that acquire autoreactivity following somatic hypermutation in the GC die of neglect, but in autoimmunity these autoreactive clones still receive T cell help, driving aberrant selection. GC B cells cycle between the dark zone (DZ), where proliferation and mutation occur, and the light zone (LZ) where selection occurs. Temporal assessment comparing GCs from mice with chronic infection or lupus revealed a shared accumulation of LZ B cells while lupus GC B cells had a unique reduction in proliferation and a progressive loss of MYC and FOXO1 in lupus. This loss in proliferative capacity coincided with a reduction in B cell receptor repertoire diversity and mutational burden. Furthermore, we identified persistent dominant GC B cell clones associated with an expansion in plasma cell differentiation throughout disease. Together, our findings suggest that lupus disease progression is characterized by an inability for proper LZ selection, preventing zonal recycling, thereby driving the permissive selection and differentiation of autoreactive B cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE252246 | GEO | 2024/11/18

REPOSITORIES: GEO

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