Postdoc, University of Chicago
発表演題: In situ antibody selection in lupus nephritis.
B cells normally become activated in germinal centers in secondary lymphoid organs. They affinity-mature their B cell receptors for target antigens to neutralize pathogens. However, in tissue inflammation, B cells infiltrate afflicted tissues and become activated in situ. Although their tissue infiltration is associated with poor clinical outcomes in lupus nephritis (LN), their phenotype and mode of antibody selection and affinity maturation remain largely unknown.
To understand the mechanism of in situ antibody selection in LN, we cloned and recombinantly expressed 25 antibodies from tissue-infiltrating B cells in renal biopsies of 8 LN patients. 10 antibodies cloned from 6 patients directly bound to a cytoskeletal antigen vimentin. On the other hand, none of the cloned antibodies reacted to double-stranded DNA, a frequently targeted antigen in serum. Furthermore, those anti-vimentin antibodies were highly somatically mutated. The vimentin reactivity was diminished by reverting the mutations to their germline sequences. Finally, tissue expression of vimentin is robustly upregulated upon inflammation. These results indicate that antibody repertoire of tissue-infiltrating B cells is shaped in a mechanism distinct from that of circulating B cells: B cells are selected to locally abundant antigens in the inflammatory milieu of LN.