Increased serum levels of the chemokine CXCL13 and up-regulation of its gene expression are distinctive features of HCV-related cryoglobulinemia and correlate with active cutaneous vasculitis

Abstract

Chemokine CXCL13, also known as BCA-1 (B cell-attracting chemokine-1) or BLC (B-lymphocyte chemoattractant), is a major regulator of B-cell trafficking. Hepatitis C virus (HCV) infection may be associated with B-cell dysfunction and lymphoproliferative disorders, including mixed cryoglobulinemia (MC). This study evaluates circulating levels of CXCL13 protein and specific mRNA expression in chronically HCV-infected patients with and without MC. Compared with healthy controls and HCV-infected patients without MC, CXCL13 serum levels were significantly higher in MC patients. The highest CXCL13 levels strongly correlated with active cutaneous vasculitis. CXCL13 gene expression in portal tracts, isolated from liver biopsy tissues with laser capture microdissection, showed enhanced levels of specific mRNA in MC patients with active cutaneous vasculitis. Specific CXCL13 gene mRNA expression was also up-regulated in skin tissue of these patients. These findings paralleled specific deposits of CXCL13 protein both in the liver and in the skin. Our results indicate that up-regulation of CXCL13 gene expression is a distinctive feature of HCVinfected patients. Higher levels of this chemokine in the liver as well as in the skin of patients with active MC vasculitis suggest a possible interrelation between these biologic compartments. (Blood. 2008;112:1620-1627) IntroductionChronic active liver disease (CALD) is an inflammatory disorder recognizing several etiologies and different pathogenetic mechanisms. 1 Within inflamed liver, there is an accumulation of lymphoid and myeloid cells, including T and B cells. 2 Local activation of these cells is thought to be essential in perpetuating the chronic inflammatory process and accelerating liver damage. 3 T and B cells in CALD frequently accumulate in the portal tracts and organize follicle-like structures, with features of germinal centers (GCs). 4 In these sites, local differentiation of follicular dendritic cells, plasma cells, and antibody production may occur. 5 In hepatitis C virus (HCV) infection, distinct B-cell expansions contribute to the formation of intraportal follicle-like structures. 6,7 Circulating B-cell clonotypes have been suggested to be of hepatic origin, indicating that IgH VDJ mutational activity is up-regulated in the hepatic microenvironment. 8 Sequence analyses of IgH CDR-3 gene segments of intraportal B-cell clonalities have revealed a wide range of variations, possibly implying that they are the result of an antigen-driven response. 9 The occurrence of B-cell clonal expansions in the liver of HCV-infected patients has been found to deeply influence the clinical picture, which appears to be strictly related to mixed cryoglobulinemia (MC) and, in general, to lymphoproliferative stigmata, including high serum levels of rheumatoid factor (RF) and monoclonal gammopathy of undetermined significance. 8 The relationship between emergence and persistence of intrahepatic or circulating B-cell clonotypes and HCV infection is still unknown. Accumulating evidence indi...

Clinical Relevance of Cytokines, Chemokines and Adhesion Molecules in Systemic Vasculitis

“…Similar to the increased levels of CXCL10, significantly increased levels of CXCL13 were observed in HCV-related MC patients; these levels correlated with vasculitis disease activity (Sansonno et al 2008). In this report, the mRNA expression of CXCL13 was detected in the portal tract of biopsied liver tissues and also in the skin tissues from MC patients with active cutaneous vasculitis.…”

CXCL13 is a plasma biomarker of germinal center activity

“…B-and Tfh-cell expressions of CXCR5, the receptor for CXCL13, are necessary for migration to the B-cell follicle. Although CXCL13 acts locally, it can also be detected in human plasma in the steady state, and perturbations in plasma CXCL13 have been associated with immune activity (17)(18)(19)(20)(21). Because GC Tfh cells regulate the size of the GC response and can be major producers of CXCL13, we explored whether plasma CXCL13 changes may reflect lymphoid tissue GC activity.…”

Activation-induced cytidine deaminase in B cells of hepatits C virus-related cryoglobulinaemic vasculitis

“…Molecular analyses of the B cellcontaining microdissected lymphoid structures of liver tissue demonstrated that they are hypermutated and clonally restricted, suggesting that an antigen-driven B cell response is ongoing in the liver microenvironment [4][5][6][7]. The persistence of ectopic lymphoid structures in the liver from chronically HCV-infected patients with or without CV probably reflects the sustained over-expression of genes regulating ectopic lymphoneogenesis [32,33].…”