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B cell homeostasis in chronic hepatitis C virus-related mixed cryoglobulinemia is maintained through naive B cell apoptosis.

ABSTRACT: UNLABELLED:Mixed cryoglobulinemia (MC) is the most common extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. Although the formation of inflammation-triggering immune complexes is driven by clonal expansions of autoreactive B cells, we found total B cell numbers paradoxically reduced in HCV-infected patients with MC. HCV patients with MC (n = 17) also displayed a reduced number and a reduced frequency of naïve B cells compared with HCV-infected patients without MC (n = 19), hepatitis B virus-infected patients (n = 10), and uninfected controls (n = 50). This was due to an increased sensitivity of naïve B cells to apoptosis resulting in a reduction in the size of the naïve B cell subset. In addition, 4-fold expansion and skewing (lower T1/T2-ratio) of the immature B cell subset was noted in MC patients, suggesting that apoptosis of naïve B cells triggered the release of B cell precursors from bone marrow in an attempt to maintain normal B cell numbers. Following treatment of MC with the B cell-depleting antibody rituximab, the size of all B cell subsets, the T1/T2-ratio, and the cyroglobulin levels all normalized. Cryoglobulin levels correlated with in vivo proliferation of T2 B cells, suggesting a link between the skewing of the T1/T2 ratio and the formation of immune complexes. CONCLUSION:This study provides insight into the mechanisms maintaining B cell homeostasis in HCV-induced MC and the ability of rituximab therapy to restore normal B cell compartments. (HEPATOLOGY 2012;56:1602-1610).

SUBMITTER: Holz LE

PROVIDER: S-EPMC3421034 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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B cell homeostasis in chronic hepatitis C virus-related mixed cryoglobulinemia is maintained through naïve B cell apoptosis.

Holz Lauren E LE Yoon Joo Chun JC Raghuraman Sukanya S Moir Susan S Sneller Michael C MC Rehermann Barbara B

Hepatology (Baltimore, Md.) 20121014 5

<h4>Unlabelled</h4>Mixed cryoglobulinemia (MC) is the most common extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. Although the formation of inflammation-triggering immune complexes is driven by clonal expansions of autoreactive B cells, we found total B cell numbers paradoxically reduced in HCV-infected patients with MC. HCV patients with MC (n = 17) also displayed a reduced number and a reduced frequency of naïve B cells compared with HCV-infected patients without MC (n ...[more]

PMID: 22556016

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Project description:Hepatitis C virus (HCV) is the most common cause of mixed cryoglobulinemia syndrome (MCS). The efficacy and safety of all-oral direct-acting antiviral (DAA) therapy in HCV-associated MCS (HCV-MCS) is largely unknown. The authors studied case series of patients with HCV-MCS who were treated with sofosbuvir-based regimens and historical controls treated with pegylated interferon and ribavirin in a single health care network. HCV-MCS was defined by circulating cryoglobulin associated with systemic vasculitis symptoms. Renal involvement (n = 7) was established by kidney biopsy (n = 5) or by two or more of the following clinical findings: reduced kidney function, proteinuria, or hematuria with other causes excluded (n = 2). Twelve patients received DAA therapy between December 2013 and September 2014. Median age was 61 years, 58% were male, and 50% had cirrhosis. Median baseline serum creatinine was 0.97 mg/dL (range 0.7-2.47). Four patients received rituximab concurrent with DAA therapy. Sustained virological response rate at 12 weeks (SVR12) was 83% overall. Patients with glomerulonephritis who achieved SVR12 experienced an improvement in serum creatinine and a reduction in proteinuria. Cryoglobulin levels decreased in 89% of patients, with median percent decreasing from 1.5% to 0.5% and completely disappearing in four of nine cases who had cryoglobulins measured after treatment. Serious adverse events were infrequent (17%). In contrast, the historical cohort treated with pegylated interferon and ribavirin experienced only 10% SVR12, with 100% experiencing at least one adverse event and 50% experiencing premature discontinuation due to adverse events.SVR12 rates for sofosbuvir-based DAA regimens in HCV-MCS were 83%, significantly higher than historical controls treated with pegylated interferon and ribavirin; patients with glomerulonephritis experienced improvement in renal function, including those not concomitantly treated with immunosuppression.

Project description:Correlation of C-C chemokine receptor type 5 (CCR5) and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) gene polymorphisms with renal damage due to hepatitis C virus (HCV)-related cryoglobulinemia were investigated. The 1:1 matched case-control study design was adopted, 171 patients with renal damage due to HCV-related cryoglobulinemia were selected as the case group, and 171 patients without renal damage were selected as the control group. Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis was used to detect the polymorphisms of locus rs1799987A/G in CCR5 gene and locus rs35829419A/C in NLRP3 gene of 171 pairs of HCV patients. SPSS 20.0 software was used for logistic regression analysis, and genetics package of the R programming language for Hardy-Weinberg equilibrium test. The frequencies of locus rs1799987A/G in CCR5 gene in the case group were 48.0 and 52.0%, while those in the control group were 47.9 and 52.1%; the frequencies of locus rs35829419A/C in NLRP3 gene were 55.8 and 44.2%, while those in the control group were 55.3 and 44.7%. The results of logistic regression analysis showed that the distribution of CCR5 gene polymorphism in the case group was statistically different from that in the control group (P<0.05), which had a statistical correlation with the renal damage due to HCV-related cryoglobulinemia (P<0.05). At rs1799987, GG genotype was compared with AA genotype, and AG genotype was compared with AA genotype; the results showed that the renal damage due to HCV-related cryoglobulinemia was not decreased [odds ratio (OR) = 0.91, 95% confidence interval (95% CI): 0.47-1.54; OR = 0.89, 95% CI: 0.49-1.31]. The negative analysis model of the GG genotype reduced the risk of renal damage due to HCV-related cryoglobulinemia remarkably (OR = 0.62, 95% CI: 0.39-0.98). Rs1799987A/G and gene polymorphism of CCR5 may be associated with renal damage due to HCV-related cryoglobulinemia, and the carriage of G allele may lower the incidence rate of the disease, while rs35829419A/C in NLRP3 has no correlation with renal damage due to HCV-related cryoglobulinemia.

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B cell homeostasis in chronic hepatitis C virus-related mixed cryoglobulinemia is maintained through naive B cell apoptosis.

Publications

B cell homeostasis in chronic hepatitis C virus-related mixed cryoglobulinemia is maintained through naïve B cell apoptosis.

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