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Abstract

B cells mount specific antibody responses to protect our body from infection. At the same time, their antibody responses can be directed to local self or alloantigens to drive tissue inflammation. Although similarity is obvious between these two responses, a direct comparison remains to be made. Renal allograft rejection is one of diseases which involve pathogenic antibody responses and tissue-local B cell activation. Serum alloreactivity and intrarenal B cell infiltrates both predict a poor prognosis. However, it is unknown how or whether intrarenal B cells contribute to alloreactive antibody production and allograft rejection. In this study, we performed single cell RNA-sequencing (scRNA-seq) on activated B cells sorted from eight renal allograft rejection biopsies. Their transcriptome was compared with tonsil germinal center (GC) B cells, in order to elucidate a signature specific to intrarenal B cell activation. Our analyses revealed their unique transcriptional state that resembled peritoneal B1 cells including the upregulation of specific innate signaling pathways. Furthermore, comparison to transcriptome of whole rejected renal allografts discovered autocrine and paracrine interactions surrounding intrarenal B cells. Finally, we characterized their antibody reactivity. Although intrarenal B cells expressed highly mutated antibodies, none of them reacted to human leukocyte antigens (HLAs). Autoreactivity was not generally enriched either, leaving their reactivity elusive. However, infiltrating plasma cells showed robust clonal expansion, expressing antibodies that strongly and specifically bound to nucleolar self-antigens including Ki-67. Overall, this study uncovers two unique B cell states in renal allograft rejection: an innate peritoneal B1-like phenotype and plasma cells expressing antibodies to ubiquitous nucleolar self-antigens.

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