Biased IGH VDJ gene repertoire and clonal expansions in B cells of chronically hepatitis C virus–infected individuals

Abstract

Patients chronically infected with hepatitis C virus (HCV) frequently develop mixed cryoglobulinemia (MC), a monoclonal expansion of immunoglobulin M (IgM) autoreactive B cells, and also have an increased B-cell lymphoma risk. Whether HCV infection also impacts the B-cell compartment and the B-cell receptor repertoire in patients not affected by MC or lymphomas is poorly understood. Flow cytometric analysis of peripheral blood B cells of 30 MC-negative HCV-infected patients and 15 healthy controls revealed that frequencies of class-switched memory B cells were increased in the patients, whereas frequencies of transitional and naive B cells were decreased. For 22 HCV patients and 7 healthy controls, we performed high-throughput sequencing of immunoglobulin heavy chain VDJ rearrangements of naive, mature CD5, IgM memory, and class-switched memory B cells. An increased usage of several IGHV genes, including IGHV1-69 and IGHV4-59, which are closely linked to MC and HCV-associated lymphomas, was specifically seen among IgM memory B cells of the patients. Moreover, many, and partly very large, expanded clones were seen predominantly among IgM memory B cells of all HCV-infected patients analyzed. Thus, chronic HCV infection massively disturbs the B-cell compartment even in patients without clinically detectable B-cell lymphoproliferation and generates many large B-cell clones, especially among non-class-switched memory B cells. Because B-cell clones in MC and lymphomas derive from this B-cell subset, this establishes IgM memory B cells as a general target of lymphoproliferation in HCV patients, affecting apparently all patients.

T‐cell receptor and B‐cell receptor repertoire profiling in adaptive immunity

“…Blum et al [102] identified preferential usage of certain IGHV segments in the plasmablast repertoires of Lyme disease patients. Tucci et al [103] reported disrupted B-cell repertoires in a cohort of chronic HCV patients due to preferential usage of several IGHV segments in IGM memory B-cells. While CDR3 may be conserved within a subset of antigen-specific sequences, even withinTCRs recognizing one epitope, there are frequently many distinct motifs, each successfully solving the task of antigen recognition [47,104].…”

Management of post‐transplant lymphoproliferative disorders

“…A major risk factor specific to SOT is the use of multivisceral or intestinal transplants due to a high volume of donor lymphoid tissue contained in the graft, which is subject to expansion when exposed to EBV and in an immunodeficient environment (Kinch et al , ). Although an intact immune system is essential for chronic viral hepatitis to directly cause a lymphoproliferative disorder, untreated infection with the hepatitis C virus can contribute to PTLD pathogenesis by inducing alterations in the B‐cell receptor immunoglobulin gene and through chronic antigenic stimulation (Morton et al , ; Tucci et al , ). Recipient HLA‐A26 and HLA‐B38 status has also been associated with a higher risk, probably due to altered antigen presentation or immune tolerance (Reshef et al , ).…”

Signatures of B Cell Receptor Repertoire Following Pneumocystis Infection

“…The B cell receptor (BCR), a B cell surface membrane immunoglobulin, possesses the ability to specifically recognize and bind antigens, with the complementarity-determining region 3 (CDR3) of the heavy chain as the major determinant of antibody specificity (Xu and Davis, 2000). The diversity of BCR repertoires in several infectious diseases has been explored, such as in coronavirus disease 2019 (Wen et al, 2020), dengue (Parameswaran et al, 2013), and chronic hepatitis C virus infection (Tucci et al, 2018). These results show that encountering a specific antigen could elicit clonal B-cell proliferation, thus altering the selective distribution of the BCR spectrum.…”