Intrahepatic B‐cell follicles of chronically hepatitis C virus‐infected individuals lack signs of an ectopic germinal center reaction

Abstract

Chronic infection with hepatitis C virus (HCV) often affects the B-cell compartment, leading to the occurrence of autoimmunity and B-cell lymphoproliferation, in particular mixed cryoglobulinemia and B-cell lymphomas. HCV presumably causes these lymphoproliferations by chronic antigenic stimulation and/or direct mutagenic effects on B cells. It has been speculated that the interaction of HCV with B cells and the expansion of antigen-triggered B cells happens in germinal center-like structures in the livers of HCV carriers. We studied rearranged immunoglobulin V H genes from seven B-cell folli-cles microdissected from the livers of three unselected chronic HCV patients. The follicles consisted of polyclonal naive and memory B-cell populations with only rare indication of minor clonal expansions and no evidence for active somatic hypermutation. Frequent detection of V H rearrangements using the VH1-69 gene segment nevertheless indicated that at least a fraction of the B cells is HCV-specific and/or autoreactive. Thus, the typical intrahepatic B-cell follicles in chronic HCV carriers do not function as ectopic germinal centers for clonal expansion and affinity maturation of B cells. Hence, autoreactive and HCV-specific B-cell clones might either develop in secondary lymphoid organs or in intrahepatic follicles only under particular, yet undefined, circumstances.Keywords: B-cell clonal expansion r Germinal centers r HCV r IgV H genes r Somatic hypermutation Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionChronic infection by hepatitis C virus (HCV) not only causes liver cirrhosis and hepatocellular carcinoma [1] but, in a subgroup of patients is also associated with the development of B-cell lymphoproliferative diseases [2]. These diseases include the autoimmune disease mixed cryoglobulinemia (MC) type II, characterized by Correspondence: Prof. Ralf Küppers e-mail: ralf.kueppers@uk-essen.de a monoclonal population of rheumatoid factor-producing B cells, and a subgroup of B-cell non-Hodgkin lymphomas [3]. There are currently two main -not mutually exclusive -models of HCVassociated lymphomagenesis [4]. The observation that some lymphomas in HCV-infected patients show regression upon successful anti-viral therapies [5] suggests chronic antigenic stimulation as a driving force in lymphoma development. This is further supported by the specificity of the B-cell receptor of HCV-associated lymphomas for viral antigens, in particular the HCV protein E2 [6,7] 1843HCV-associated B-cell lymphomas use the immunoglobulin variable (IgV) gene segment VH1-69, which is known to be used both by rheumatoid factors and by some E2-specific antibodies, further supporting a role of antigenic drive in HCV-associated B-cell expansion [8][9][10][11][12]. A second pathogenetic mechanism of HCV on B cells may be a direct mutagenic effect of the virus, including induction of reactive oxygen species [13,14], and of activation-induced cytidine deaminase [15], which is t...

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

“…To date, the characterization of B-cell clonality in HCV infection has been based on analyses of bulk peripheral and/or intrahepatic B cells using conventional IGH VDJ gene polymerase chain reaction (PCR) approaches. 34,35 Here, we analyzed the B-cell compartment in MC-negative HCV-infected patients for potential disturbances. In particular, we searched for (1) alterations in the B-cell subset composition, (2) potential biases in the BCR immunoglobulin gene repertoire of the main mature B-cell subsets, and (3) B-cell clonal expansions in specific B-cell subsets by high-throughput sequencing (HTSeq).…”

Human antiviral B cell responses: Emerging lessons from hepatitis B and COVID‐19

“…Intrahepatic lymphoid follicles (ILFs) with features of ectopic GCs (including Bcl‐6 and Ki67) are well‐documented in Hepatitis C virus (HCV) infection 104 and are postulated to facilitate expansion of both HCV‐specific and autoreactive clones 105,106 . In comparison, B and T cell aggregates in patients with CHB have been shown to lack a well‐formed GC, 105 suggesting that an absence of mature tissue‐based responses may contribute to overall impaired humoral immunity in CHB.…”

Evidence of B‐cell follicles with germinal centers in chronic hepatitis C patients

“…With great interest we read the article published in the June 2014 issue by Tucci et al. , where they describe the lack of signs of an ectopic GC reaction in intrahepatic B‐cell follicles of individuals chronically infected with HCV.…”

“…The authors investigated the clonality of the B‐cell populations in seven B‐cell follicles in the livers of three HCV‐infected patients, by studying the rearrangement of Ig V H genes . They found that all follicles consisted of polyclonal naïve and memory B cells with only rare indication of minor clonal expansions and no evidence for active somatic hypermutation.…”

“…Therefore, the authors conclude that B‐cell follicles in the liver of chronic HCV patients are not functional GCs. They state that, although in individuals chronically infected with HCV, B‐cell lymphoproliferative disorders frequently occur, the process of B‐cell proliferation and diversification in response to HCV likely takes place in secondary lymphoid organs . Although Tucci et al.…”