Gut and Liver B Cells of Common Clonal Origin in Primary Sclerosing Cholangitis–Inflammatory Bowel Disease

Abstract

B cells express an antigen‐specific B‐cell receptor (BCR) and may contribute to liver inflammation by recognizing shared antigens in the gut and liver. Herein, we used high‐throughput BCR sequencing of the immunoglobulin heavy chain, specifically the complementarity‐determining region 3 (CDR3), to characterize the B‐cell repertoire of freshly‐frozen paired gut and liver tissue samples from patients with primary sclerosing cholangitis (PSC) and concurrent inflammatory bowel disease (IBD) (PSC‐IBD, n = 10) and paired formalin‐fixed paraffin‐embedded (FFPE) tumor‐adjacent normal colon and liver tissue from patients with colorectal liver metastases (controls, n = 10). We observed significantly greater numbers of B cells (P < 0.01) and unique B‐cell clonotypes (P < 0.05) in gut samples compared to liver samples of patients with PSC‐IBD, whereas BCR sequences in FFPE normal gut and liver samples were nearly absent (14 ± 5 clonotypes; mean ± SD; n = 20). In PSC‐IBD, an average of 8.3% (range, 1.6%‐18.0%) of B‐cell clonotypes were found to overlap paired gut and liver samples following the exclusion of memory clonotypes reported in the blood of healthy controls. Overlapping gut and liver clonotypes showed stronger evidence of antigen‐driven activation compared to non‐overlapping clonotypes, including shorter CDR3 lengths and higher counts of somatic hypermutation (P < 0.0001). Conclusion: A proportion of gut and liver B cells originate from a common clonal origin (i.e., likely to recognize the same antigen) in patients with PSC which suggests B‐cell antigens are shared across the gut–liver axis. (Hepatology Communications 2018; 00:000‐000)

The Role of B Cells and B Cell Therapies in Immune-Mediated Liver Diseases

“…B cell clonality studies also point to the involvement of as yet unidentified auto-antigens, with individuals with PSC exhibiting increased B cell clonality in the liver and gut compared to healthy tissue (123). This study also found significant overlap in expanded B cell clones shared between the gut and liver (123), further supporting the hypothesis that loss of tolerance in the gut is important.…”

“…Supernatants from liver infiltrating B cells isolated from PSC patients and cultured ex-vivo have been shown to react to several proteins in an array assays, including nucleolar protein 3 (NOD3), expressed by cholangiocytes (82). B cell clonality studies also point to the involvement of as yet unidentified auto-antigens, with individuals with PSC exhibiting increased B cell clonality in the liver and gut compared to healthy tissue (123). This study also found significant overlap in expanded B cell clones shared between the gut and liver (123), further supporting the hypothesis that loss of tolerance in the gut is important.…”

The Contribution of B Cells in Autoimmune Liver Diseases

“…63,64 An important clue to the “gut–liver axis” hypothesis of PSC pathogenesis lies in the discovery of B cell clones within the liver and colonic tissue of PSC patients. 65 BCR sequencing revealed that 8.3% of B cell clones overlapped with paired colon and liver samples, suggesting that the same Ag(s) was driving B cell activation in both organs.…”

Waiting in the wings: RUNX3 reveals hidden depths of immune regulation with potential implications for inflammatory bowel disease

“…Although BAFF controls B cell maturation and survival, its high levels accompany chronic inflammation in the gut 80 . Antigen‐presenting cells that express B cell receptors (BCRs) constitute a major humoral component of the adaptive immune system 81 . A large number of B cells may infiltrate intestinal inflammatory sites, where they provide a response to recognized antigens through a broad spectrum of non‐specific antibodies 81 .…”

“…Antigen‐presenting cells that express B cell receptors (BCRs) constitute a major humoral component of the adaptive immune system 81 . A large number of B cells may infiltrate intestinal inflammatory sites, where they provide a response to recognized antigens through a broad spectrum of non‐specific antibodies 81 . Both the BAFF pathway and TGF‐β–induced IgA class switching are mediated by RUNX3/RUNX1 cross‐regulation 12,82 .…”