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Delineation of autoantibody repertoire through differential proteogenomics in hepatitis C virus-induced cryoglobulinemia.

ABSTRACT: Antibodies cross-reactive to pathogens and autoantigens are considered pivotal in both infection control and accompanying autoimmunity. However, the pathogenic roles of autoantibodies largely remain elusive without a priori knowledge of disease-specific autoantigens. Here, through a novel quantitative proteogenomics approach, we demonstrated a successful identification of immunoglobulin variable heavy chain (VH) sequences highly enriched in pathological immune complex from clinical specimens obtained from a patient with hepatitis C virus-induced cryoglobulinemia (HCV-CG). Reconstructed single-domain antibodies were reactive to both HCV antigens and potentially liver-derived human proteins. Moreover, over the course of antiviral therapy, a substantial "de-evolution" of a distinct sub-repertoire was discovered, to which proteomically identified cryoprecipitation-prone autoantibodies belonged. This sub-repertoire was characterized by IGHJ6*03-derived, long, hydrophobic complementarity determining region (CDR-H3). This study provides a proof-of-concept of de novo mining of autoantibodies and corresponding autoantigen candidates in a disease-specific context in human, thus facilitating future reverse-translational research for the discovery of novel biomarkers and the development of antigen-specific immunotherapy against various autoantibody-related disorders.

SUBMITTER: Ogishi M

PROVIDER: S-EPMC4941579 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Delineation of autoantibody repertoire through differential proteogenomics in hepatitis C virus-induced cryoglobulinemia.

Ogishi Masato M Yotsuyanagi Hiroshi H Moriya Kyoji K Koike Kazuhiko K

Scientific reports 20160712

Antibodies cross-reactive to pathogens and autoantigens are considered pivotal in both infection control and accompanying autoimmunity. However, the pathogenic roles of autoantibodies largely remain elusive without a priori knowledge of disease-specific autoantigens. Here, through a novel quantitative proteogenomics approach, we demonstrated a successful identification of immunoglobulin variable heavy chain (VH) sequences highly enriched in pathological immune complex from clinical specimens obt ...[more]

PMID: 27403724

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Project description:UnlabelledHepatitis 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.ConclusionSVR12 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.

Dataset Information

Delineation of autoantibody repertoire through differential proteogenomics in hepatitis C virus-induced cryoglobulinemia.

Publications

Delineation of autoantibody repertoire through differential proteogenomics in hepatitis C virus-induced cryoglobulinemia.

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