T cell receptor variable β gene repertoire in liver and peripheral blood lymphocytes of chronically hepatitis C virus‐infected patients with and without mixed cryoglobulinaemia

To characterize the repertoire of T lymphocytes in chronically hepatitis C virus (HCV)‐infected patients with and without mixed cryoglobulinaemia (MC). T cell receptor (TCR) variable (V) β clonalities in portal tracts isolated from liver biopsy sections with a laser capture microdissection technique in 30 HCV‐positive MC patients were studied by size spectratyping. Complementarity‐determining region 3 (CDR3) profiles of liver‐infiltrating lymphocytes (LIL) were also compared with those circulating in the blood. The representative results of TCR Vβ by CDR3 were also obtained from liver tissues and peripheral blood lymphocytes (PBL) of 21 chronically HCV‐infected patients without MC. LIL were highly restricted, with evidence of TCR Vβ clonotypic expansions in 23 of 30 (77%) and in 15 of 21 (71%) MC and non‐MC patients, respectively. The blood compartment contained TCR Vβ expanded clones in 19 (63%) MC and 12 (57%) non‐MC patients. The occurrence of LIL clonalities was detected irrespective of the degree of liver damage or circulating viral load, whereas it correlated positively with higher levels of intrahepatic HCV RNA. These results support the notion that TCR Vβ repertoire is clonally expanded in HCV‐related MC with features comparable to those found in chronically HCV‐infected patients without MC.

[1]  Bryan Lau,et al.  Exceeding the limits of liver histology markers. , 2009, Journal of hepatology.

[2]  B. Walker,et al.  Hepatitis C virus infection. , 2001, The New England journal of medicine.

[3]  A. Talal,et al.  The role of chemokines as inflammatory mediators in chronic hepatitis C virus infection , 2007, Journal of viral hepatitis.

[4]  Y. Liaw,et al.  Hepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity. , 1998, Gastroenterology.

[5]  J. Demengeot,et al.  Regulatory T Cells Accumulate in the Lung Allergic Inflammation and Efficiently Suppress T-Cell Proliferation but Not Th2 Cytokine Production , 2011, Clinical & developmental immunology.

[6]  B. Rehermann,et al.  Chronic HCV infection and the clonality of intrahepatic T cells. , 2003, Journal of hepatology.

[7]  Felicia A Tucci,et al.  Intrahepatic B cell clonal expansions and extrahepatic manifestations of chronic HCV infection , 2004, European journal of immunology.

[8]  T. Hodge,et al.  Human immunodeficiency virus type 1 RNA expression by four chronically infected cell lines indicates multiple mechanisms of latency , 1994, Journal of virology.

[9]  D. Sansonno,et al.  Immunochemical and biomolecular studies of circulating immune complexes isolated from patients with acute and chronic hepatitis C virus infection , 1996, European journal of clinical investigation.

[10]  V. Conteduca,et al.  Hepatitis C Virus Infection and Mixed Cryoglobulinemia , 2012, Clinical & developmental immunology.

[11]  C. Walker,et al.  Adaptive immune responses in acute and chronic hepatitis C virus infection , 2005, Nature.

[12]  C. Malone,et al.  IgM rheumatoid factors react with human class I HLA molecules. , 1996, Journal of immunology.

[13]  Zimmerman Hj,et al.  Morphologic spectrum of drug-induced hepatic disease. , 1995 .

[14]  M. Masucci,et al.  HLA-A11 epitope loss isolates of Epstein-Barr virus from a highly A11+ population. , 1993, Science.

[15]  É. Vivier,et al.  Features and distribution of CD8 T cells with human leukocyte antigen class I–specific receptor expression in chronic hepatitis C , 2007, Hepatology.

[16]  A. Tzakis,et al.  The Immune Reactivity Role of HCV-Induced Liver Infiltrating Lymphocytes in Hepatocellular Damage , 1997, Journal of Clinical Immunology.

[17]  D. Thorley-Lawson,et al.  A novel form of Epstein-Barr virus latency in normal B cells in vivo , 1995, Cell.

[18]  D. Sansonno,et al.  Clonal analysis of intrahepatic B cells from HCV-infected patients with and without mixed cryoglobulinemia. , 1998, Journal of immunology.

[19]  C. Katlama,et al.  Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy , 1998, Nature Medicine.

[20]  J. Rockstroh,et al.  Differential expansion of T‐cell receptor variable beta subsets after antigenic stimulation in patients with different outcomes of hepatitis C infection , 2002, Immunology.

[21]  M Hummel,et al.  Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936 , 2003, Leukemia.

[22]  G. McFadden,et al.  How DNA viruses perturb functional MHC expression to alter immune recognition. , 1994, Advances in cancer research.

[23]  D. Geschwind,et al.  Longitudinal system-based analysis of transcriptional responses to type I interferons. , 2009, Physiological genomics.

[24]  R. Thimme,et al.  Success and Failure of Virus-Specific T Cell Responses in Hepatitis C Virus Infection , 2011, Digestive Diseases.

[25]  J. Borovička,et al.  Polyfunctional HCV‐specific T‐cell responses are associated with effective control of HCV replication , 2008, European journal of immunology.

[26]  P. Marche,et al.  Simultaneous evaluation of lymphocyte subpopulations in the liver and in peripheral blood mononuclear cells of HCV‐infected patients: relationship with histological lesions , 2002, Clinical and experimental immunology.

[27]  S. Hughes,et al.  Retroviral reverse transcription and integration: progress and problems. , 1992, Annual review of cell biology.

[28]  L. K. Ely,et al.  The molecular basis of TCR germline bias for MHC is surprisingly simple , 2009, Nature Immunology.

[29]  J. Piette,et al.  CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis. , 2004, Blood.

[30]  D. Sansonno,et al.  Hepatitis C virus infection, cryoglobulinaemia, and beyond. , 2006, Rheumatology.

[31]  Steven L Flamm,et al.  Chronic hepatitis C virus infection. , 2003, JAMA.

[32]  D. Sansonno,et al.  Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations. , 2005, The Lancet. Infectious diseases.

[33]  T. Macnaughton,et al.  A molecular comparison of T lymphocyte populations infiltrating the liver and circulating in the blood of patients with chronic hepatitis B: Evidence for antigen‐driven selection of a public complementarity‐determining region 3 (CDR3) motif , 2001, Hepatology.

[34]  Philippa Marrack,et al.  Many different Vβ CDR3s can reveal the inherent MHC reactivity of germline-encoded TCR V regions , 2009, Proceedings of the National Academy of Sciences.

[35]  Y. S. Hahn,et al.  Subversion of immune responses by hepatitis C virus: immunomodulatory strategies beyond evasion? , 2003, Current opinion in immunology.

[36]  Charles R. M. Bangham,et al.  Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition , 1991, Nature.

[37]  M. K. Spriggs.  Cytokine and cytokine receptor genes 'captured' by viruses. , 1994, Current opinion in immunology.

[38]  D. Sansonno,et al.  The lymphoid system in hepatitis C virus infection: autoimmunity, mixed cryoglobulinemia, and Overt B-cell malignancy. , 2000, Seminars in liver disease.

[39]  A. Vallejo,et al.  The Influence of Age on T Cell Generation and TCR Diversity1 , 2005, The Journal of Immunology.

[40]  K. Ishak,et al.  Morphologic spectrum of drug-induced hepatic disease. , 1995, Gastroenterology clinics of North America.

[41]  Felicia A Tucci,et al.  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. , 2008, Blood.

[42]  M. Hellard,et al.  Antigen-Driven Patterns of TCR Bias Are Shared across Diverse Outcomes of Human Hepatitis C Virus Infection , 2011, The Journal of Immunology.

[43]  B. Boehm,et al.  Oligoclonal CD8+ T-Cell Expansion in Patients with Chronic Hepatitis C Is Associated with Liver Pathology and Poor Response to Interferon-α Therapy , 2004, Journal of Clinical Immunology.

[44]  P. Marcellin,et al.  The intraportal lymphoid nodule and its environment in chronic active hepatitis C: An immunohistochemical study , 1993, Hepatology.

[45]  A. Rothman,et al.  Evolution of the intrahepatic T cell repertoire during chronic hepatitis C virus infection. , 2005, Viral immunology.

[46]  I. Warshawsky,et al.  A Comparison of Multiplex and Monoplex T-Cell Receptor Gamma PCR , 2004, Diagnostic molecular pathology : the American journal of surgical pathology, part B.

[47]  S. Kalams,et al.  Limited T Cell Receptor Diversity of HCV-specific T Cell Responses Is Associated with CTL Escape , 2004, The Journal of experimental medicine.

[48]  F. Chisari,et al.  Pathogenesis of chronic hepatitis C: Immunological features of hepatic injury and viral persistence , 1999, Hepatology.

[49]  C. Walker,et al.  Cell-mediated immunity and the outcome of hepatitis C virus infection. , 2004, Annual review of microbiology.