Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by elevated serum anti-mitochondrial Ab and lymphocyte-mediated bile duct damage. This study was designed to reveal the clonal characteristics of B lymphocyte repertoire in patients with PBC to facilitate better understanding of its pathogenesis and better management of these patients. Using high-throughput sequencing of Ig genes, we analyzed the repertoire of circulating B lymphocytes in 43 patients with PBC, and 34 age- and gender-matched healthy controls. Compared with healthy controls, PBC patients showed 1) a gain of 14 new clones and a loss of 8 clones; 2) a significant clonal expansion and increased relative IgM abundance, which corresponded with the elevated serum IgM level; 3) a significant reduction of clonal diversity and somatic hypermutations in class-switched sequences, which suggested a general immunocompromised status; 4) the reduction of clonal diversity and enhancement of clonal expansion were more obvious at the cirrhotic stage; and 5) treatment with ursodeoxycholic acid could increase the clonal diversity and reduce clonal expansion of the IgM repertoire, with no obvious effect on the somatic hypermutation level. Our data suggest that PBC is a complex autoimmune disease process with evidence of B lymphocyte clonal gains and losses, Ag-dependent ogligoclonal expansion, and a generally compromised immune reserve. This new insight into the pathogenesis of PBC opens up the prospect of studying disease-relevant B cells to better diagnose and treat this devastating disease.
Highlights
Using High-throughput sequencing (HTS) technology and advanced bioinformatics analysis, we observed a higher degree of clonal overlap among Primary biliary cholangitis (PBC) patients than healthy control (HC)
These overlapping unique CDR3s only accounted for a small proportion of the total unique CDR3s (PBC, 1.8164%; HCs, 1.5883%), from the perspective of clonal expression, their corresponding relative abundances were much higher (PBC, 34.531%; HCs, 27.147%)
It is reasonable to speculate that some of the gained clones could be the culprit for the development of PBC and that some of the missing B lymphocyte clones could guard against the development of PBC
Summary
Fewer class-switched lineages in PBC patients overall, UDCA-untreated patients, and cirrhotic PBC patients and an insignificant reduction in noncirrhotic PBC patients (p = 0.064) than HCs were observed (Fig. 4E), suggesting a reduced class-switching efficiency, which could have contributed to the accumulated relative abundance of IgM and decreased abundance of IgG (16). UDCA-untreated noncirrhotic PBC patients, who represent an early stage of the natural disease course, showed significantly decreased clonal diversity and increased clonal expansion and expression level, as measured by lineage numbers, unique CDR3 numbers, and HEC-lineage and HEC–unique CDR3 number rate of both IgM and IgG
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