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Semin Liver Dis 2000; 20(2): 143-158
DOI: 10.1055/s-2000-9613
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

The Lymphoid System in Hepatitis C Virus Infection: Autoimmunity, Mixed Cryoglobulinemia, and Overt B-Cell Malignancy

Franco Dammacco1 , Domenico Sansonno2 , Claudia Piccoli1 , Vito Racanelli1 , Francesca Paola D'amore1 , Gianfranco Lauletta1
  • 1Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
  • 2Chair of Internal Medicine, University of Foggia Medical School, Foggia, Italy. Reprint requests: Franco Dammacco, M.D., Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Policlinico, Piazza G. Cesare 11, 70124 Bari, Italy. E-mail: dimoclin@cimedoc.uniba.it
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Publication Date:
31 December 2000 (online)

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ABSTRACT

Like other hepatotropic viruses, hepatitis C virus (HCV) shares the property of inducing hepatocellular damage, possibly through induction of immune mechanisms that lead to hepatocellular necrosis. After infection of hepatocytes, and possibly other cells, humoral and cellular responses occur aimed at prevention of virus dissemination and elimination of infected cells. The early activated mechanisms include production of nonspecific and specific antibodies that represent the first-line of defense against invading foreign pathogens. As a consequence, circulating immune complexes are promptly formed, and antigen uptake and processing by specialized cells are enhanced. A major fraction of circulating immunoglobulins (Igs) are part of the spectrum of the so-called natural antibodies, which include anti-idiotypic antibodies and molecules with rheumatoid factor (RF) activity. They mainly belong to the IgM class, are polyclonal, and have no intrinsic pathogenetic potential. In 20-30% of HCV-infected patients, RFs share characteristics of high affinity molecules, are monoclonal in nature, and result in the production of cold-precipitating immune complexes and mixed cryoglobulinemia. It has been shown that anti-idiotypic antibodies and polyclonal and monoclonal RF molecules have the same cross-reactive idiotype, called WA, suggesting that their production is highly restricted. This strongly indicates that they arise from stimulation with the same antigen, likely HCV. It has also been speculated that B-1 (CD5+) and B-2 (CD5-) B-cell subsets, which use a limited number of VH germline genes, underlie the production of low-affinity polyclonal and high-affinity monoclonal antibodies, respectively. The persistent production of monoclonal RF molecules implies the existence of a further mechanism capable of restricting the reactivity and reflects a distinct selection of a cell population that can be maintained throughout life because they are continuously exposed to antigen pressure. Either polyclonal or monoclonal profiles of B-cell expansion are demonstrable in the liver of most HCV-infected patients. The occurrence of B-cell clonal expansion is strictly related to intrahepatic production of RF molecules, and this suggests that liver is a microenvironment, other than lymphoid tissue, in which a germinal centerlike reaction is induced. The frequent detection of oligoclonal B-cell expansion may, indeed, represent a key pathobiologic feature that sustains nonmalignant B-cell lymphoproliferation. The preferential expansion of one clone would in turn lead to a monoclonal pattern that could favor stochastic oncogenic events. It can be postulated that HCV is the stimulus not only for the apparent benign lymphoproliferative process underlying a wide spectrum of clinical features, but also for the progression to frank lymphoid malignancy in a subgroup of patients. Current data indicate a higher prevalence of overt B-cell non-Hodgkin's lymphoma in HCV-infected patients, especially in some geographic areas.

KEYWORD

autoimmunity - hepatitis C virus - lymphoproliferation

REFERENCES

  • 1 Gumber S C, Chopra S. Hepatitis C. A multifaced disease.  Review of extrahepatic manifestations. Ann Intern Med . 1995;  123 615-620
    PubMedGoogle Scholar
  • 2 Agnello V, Chung R T, Kaplan L M. A role for hepatitis C virus infection in type II cryoglobulinemia.  N Engl J Med . 1992;  327 1490-1495
    CrossrefPubMedGoogle Scholar
  • 3 Ferri C, La Civita L, Longombardo G. Mixed cryoglobulinaemia: A cross-road between autoimmune and lymphoproliferative disorders.  Lupus . 1998;  7 275-279
    CrossrefPubMedGoogle Scholar
  • 4 Krawitt E L. Autoimmune hepatitis.  N Engl J Med . 1996;  334 897-903
    CrossrefPubMedGoogle Scholar
  • 5 Bianchi F B. Autoimmune hepatitis: The lesson of the discovery of hepatitis C virus.  J Hepatol . 1993;  18 273-275
    CrossrefPubMedGoogle Scholar
  • 6 Clifford B D, Donahue D, Smith L. High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C.  Hepatology . 1995;  21 613-619
    CrossrefPubMedGoogle Scholar
  • 7 Lunel F. Hepatitis C virus and autoimmunity: Fortuitous association or reality?.  Gastroenterology . 1994;  107 1550-1555
    PubMedGoogle Scholar
  • 8 Dupin N, Chosidow O, Lunel F. Essential mixed cryoglobulinemia. A comparative study of dermatologic manifestations in patients infected or noninfected with hepatitis C virus.  Arch Dermatol . 1995;  131 1124-1127
    CrossrefPubMedGoogle Scholar
  • 9 Dammacco F, Sansonno D. Mixed Cryoglobulinemia as a model of systemic vasculitis.  Clin Rev Allergy Immunol . 1997;  15 97-119
    PubMedGoogle Scholar
  • 10 Sansonno D, Iacobelli A R, Cornacchiulo V. Immunochemical and biomolecular studies of circulating immune complexes isolated from patients with acute and chronic hepatitis C virus infection.  Eur J Clin Invest . 1996;  26 465-475
    CrossrefPubMedGoogle Scholar
  • 11 Stott D I, Hiepe F, Hummel M. Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease.  J Clin Invest . 1998;  102 938-946
    PubMedGoogle Scholar
  • 12 Lam K P, Kuhn R, Rajewsky K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death.  Cell . 1997;  90 1073-1083
    CrossrefPubMedGoogle Scholar
  • 13 Neuberger M S. Antigen receptor signaling gives lymphocytes a long life.  Cell . 1997;  90 971-973
    CrossrefPubMedGoogle Scholar
  • 14 Zouali M. B-cell superantigens: Implications for selection of the human antibody repertoire.  Immunol Today . 1995;  16 399-405
    CrossrefPubMedGoogle Scholar
  • 15 Silverman G J. B-cell superantigens.  Immunol Today . 1997;  18 379-386
    CrossrefPubMedGoogle Scholar
  • 16 Pospisil R, Fitts M G, Mage R G. CD5 is a potential selecting ligand for B cell surface immunoglobulin framework region sequences.  J Exp Med . 1996;  184 1279-1284
    CrossrefPubMedGoogle Scholar
  • 17 Pospisil R, Mage R G. Rabbit appendix: A site of the development and selection of the B cell repertoire.  Curr Top Microbiol Immunol . 1998;  229 59-70
    PubMedGoogle Scholar
  • 18 Schroeder Jr W H, Dighiero G. The pathogenesis of chronic lymphocytic leukemia: Analysis of the antibody repertoire.  Immunol Today . 1994;  15 288-294
    CrossrefPubMedGoogle Scholar
  • 19 Pospisil R, Mage R G. CD5 and other superantigens as ``ticklers'' of the B-cell receptor.  Immunol Today . 1998;  19 106-108
    CrossrefPubMedGoogle Scholar
  • 20 Dighiero G. CD5+ B cells and autoimmunity.  Semin Clin Immunol . 1998;  2 5-13
    PubMedGoogle Scholar
  • 21 Stall A M, Wells S M, Lam K-P. B-1 cells: Unique origins and functions.  Semin Immunol . 1996;  8 45-59
    CrossrefPubMedGoogle Scholar
  • 22 Tsiagbe V K, Inghirami G, Thorbecke G J. The physiology of germinal centers.  Crit Rev Immunol . 1996;  16 381-421
    PubMedGoogle Scholar
  • 23 Crouzier R, Martin T, Pasquali J L. Monoclonal IgM rheumatoid factor secreted by CD5-negative B cells during mixed cryoglobulinemia. Evidence for somatic mutations and intraclonal diversity of the expresses VH region gene.  J Immunol . 1995;  154 413-421
    PubMedGoogle Scholar
  • 24 Soto-Gil R W, Olee T, Klink B K. A systematic approach to defining the germline gene counterparts of a mutated autoantibody from a patient with rheumatoid arthritis.  Arthritis Rheum . 1992;  35 356-363
    PubMedGoogle Scholar
  • 25 Tran A, Benzaken S, Braun H B. Anti-GOR and anti-thyroid auto-antibodies in patients with chronic hepatitis C.  Clin Immunol Immunopathol . 1995;  77 127-130
    CrossrefPubMedGoogle Scholar
  • 26 Quiroga J A, Pardo M, Navas S. Patterns of immune responses to the host-encoded GOR and hepatitis C virus core-derived epitopes with relation to hepatitis C viremia, geno-types and liver disease severity.  J Infect Dis . 1996;  173 300-305
    PubMedGoogle Scholar
  • 27 Michel G, Ritter A, Gerken G. Anti-GOR and hepatitis C virus in autoimmune liver diseases.  Lancet . 1992;  339 267-269
    CrossrefPubMedGoogle Scholar
  • 28 Andersen P, Small J V, Andersen H K, Sobieszek A. Reactivity of smooth-muscle antibodies with F- and G-actin.  Immunology . 1979;  37 705-709
    PubMedGoogle Scholar
  • 29 Johnson P J, McFarlane I G. Meeting report. International autoimmune hepatitis group.  Hepatology . 1993;  18 998-1005
    CrossrefPubMedGoogle Scholar
  • 30 Fried M W, Draguesku J O, Shindo M. Clinical and serological differentiation of autoimmune and hepatitis C virus-related chronic hepatitis.  Dig Dis Sci . 1993;  38 631-636
    CrossrefPubMedGoogle Scholar
  • 31 Reichlin M. ANAs and antibodies to DNA: Their use in clinical diagnosis.  Bull Rheum Dis . 1993;  42 3-5
    PubMedGoogle Scholar
  • 32 Van Venroij W J, Maini R N. Manual of Biological Markers of Disease. The Netherlands: Kluwer Academic Publishers 1994: 1-28
    Google Scholar
  • 33 Rizzetto M, Swana G, Doniach D. Microsomal antibodies in active chronic hepatitis and other disorders.  Clin Exp Immunol . 1973;  15 331-334
    PubMedGoogle Scholar
  • 34 Homberg J-C, Abuaf N, Bernard O. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: A second type of ``autoimmune'' hepatitis.  Hepatology . 1987;  7 1333-1339
    PubMedGoogle Scholar
  • 35 Homberg J-C, Andre C, Abuaf N. A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis.  Clin Exp Immunol . 1984;  55 561-570
    PubMedGoogle Scholar
  • 36 Crivelli O, Lavarini C, Chiaberge E. Microsomal autoantibodies in chronic infection with HBsAg associated δ (delta) agent.  Clin Exp Immunol . 1983;  54 232-238
    PubMedGoogle Scholar
  • 37 Bortolotti F, Vairo P, Balli F. Non-organ specific autoantibodies in children with chronic hepatitis C.  J Hepatol . 1996;  25 614-620
    CrossrefPubMedGoogle Scholar
  • 38 Klein R, Zanger U M, Berg T. Overlapping but distinct specificities of anti-liver-kidney microsome antibodies in autoimmune hepatitis type II and hepatitis C revealed by recombinant native CYP2D6 and novel peptide epitopes.  Clin Exp Immunol . 1999;  118 290-297
    CrossrefPubMedGoogle Scholar
  • 39 Lunel F, Abuaf N, Frangeul L. Liver/kidney microsome antibody type 1 and hepatitis C virus infection.  Hepatology . 1992;  16 630-636
    PubMedGoogle Scholar
  • 40 Koskinas J, McFarlane M, Kayhan T. Cellular and humoral immune reactions against autoantigens and hepatitis C viral antigens in chronic hepatitis C.  Gastroenterology . 1994;  107 1436-1442
    PubMedGoogle Scholar
  • 41 Takase S, Tsutsumi M, Kawahara H. The alcohol-altered liver membrane antibody and hepatitis C virus infection in the progression of alcoholic liver disease.  Hepatology . 1993;  17 9-13
    CrossrefPubMedGoogle Scholar
  • 42 Abuaf N, Johanet C, Chretien P. Characterization of the liver cytosol antigen type 1 reacting with autoantibodies in chronic active hepatitis.  Hepatology . 1992;  16 892-898
    PubMedGoogle Scholar
  • 43 Swanson N R, Reed W D, Yarred L J. Autoantibodies to isolated human hepatocyte plasma membranes in chronic active hepatitis. II. Specificity of antibodies.  Hepatology . 1990;  11 613-621
    PubMedGoogle Scholar
  • 44 Tran A, Quaranta J-F, Benzaken S. High prevalence of thyroid autoantibodies in a prospective series of patients with chronic hepatitis C before interferon therapy.  Hepatology . 1993;  18 253-257
    CrossrefPubMedGoogle Scholar
  • 45 Prieto J, Yuste J R, Beloqui O. Anticardiolipin antibodies in chronic hepatitis C: Implication of hepatitis C virus as the cause of the antiphospholipid syndrome.  Hepatology . 1996;  23 199-204
    CrossrefPubMedGoogle Scholar
  • 46 Mulder L, Horst G, Haagsma E. Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases.  Hepatology . 1993;  17 411-417
    CrossrefPubMedGoogle Scholar
  • 47 Sansonno D, Cornacchiulo V, Iacobelli A R. Localization of hepatitis C virus antigens in liver and skin tissues of chronic hepatitis C virus-infected patients with mixed cryoglobulinemia.  Hepatology . 1995;  21 305-312
    CrossrefPubMedGoogle Scholar
  • 48 Khella S L, Frost S, Hermann G A. Hepatitis C infection, cryoglobulinemia, and vasculitic neuropathy. Treatment with interferon alfa: Case report and literature review.  Neurology . 1995;  45 407-411
    PubMedGoogle Scholar
  • 49 Mosnier J F, Degott C, Marcellin P. The intraportal lymphoid nodule and its environment in chronic hepatitis C: An immunohistochemical study.  Hepatology . 1993;  17 366-371
    CrossrefPubMedGoogle Scholar
  • 50 Young C L, Adamson T C, Vaughan J H, Fox R I. Immunohistologic characterization of synovial membrane lymphocytes in rheumatoid arthritis.  Arthritis Rheum . 1984;  27 32-39
    PubMedGoogle Scholar
  • 51 Knecht H, Saremaslani P, Hedinger C. Immunohistological findings in Hashimoto's thyroiditis, focal lymphocytic thyroiditis and thyroiditis de Quervain. Comparative study.  Virchows Arch Abteil Pathol Anat . 1981;  393 215-231
    PubMedGoogle Scholar
  • 52 Liversidge J, Dick A, Cheng Y-F. Retinal antigen specific lymphocytes, TCR-gamma delta T cells and CD5+ B cells cultured from the vitreous in acute sympathetic ophthalmitis.  Autoimmunity . 1993;  15 257-266
    PubMedGoogle Scholar
  • 53 Wallace W AH, Howie S EM, Krajewski A S, Lamb D. The immunological architecture of B-lymphocyte aggregates in cryptogenic fibrosing alveolitis.  J Pathol . 1996;  178 323-329
    PubMedGoogle Scholar
  • 54 De Vita S, De Re V, Sansonno D. Gastric mucosa as an additional extrahepatic localization of hepatitis C virus: Viral detection in gastric low-grade lymphoma associated with autoimmune disease and in chronic gastritis.  Hepatology . 2000;  31 182-189
    CrossrefPubMedGoogle Scholar
  • 55 Sansonno D, De Vita S, Dammacco F. Molecular analysis of intraportal lymphoid nodules isolated by microsection technique from liver biopsies of HCV chronically-infected patients (Submitted). 
    PubMedGoogle Scholar
  • 56 De Vita S, De Re V, Sansonno D. Latent infection of neoplastic B cells by HCV in a patient with low-grade non-Hodgkin's lymphoma and mixed cryoglobulinemia (Submitted). 
    PubMedGoogle Scholar
  • 57 Ikematsu W, Kobarg J, Ikematsu H. Clonal analysis of a human antibody response. III. Nucleotide sequences of monoclonal IgM, IgG, and IgA to rabies virus reveal restricted Vκ gene utilization, junctional VκJκ and VλJλ diversity, and somatic hypermutation.  J Immunol . 1998;  161 2895-2905
    PubMedGoogle Scholar
  • 58 Murakami J, Shimizu Y, Kashii Y. Functional B-cell response in intrahepatic lymphoid follicles in chronic hepatitis C.  Hepatology . 1999;  30 143-150
    CrossrefPubMedGoogle Scholar
  • 59 Williams Jr C R, Malone C C, Kao K-J. IgM rheumatoid factors react with human class I HLA molecules.  J Immunol . 1996;  156 1684-1694
    PubMedGoogle Scholar
  • 60 Dammacco F, Sansonno D. Antibodies to hepatitis C virus in essential mixed cryoglobulinemia.  Clin Exp Immunol . 1992;  87 352-356
    PubMedGoogle Scholar
  • 61 Agnello V. Hepatitis C virus infection and type II cryoglobulinemia: An immunological perspective.  Hepatology . 1997;  26 1375-1379
    PubMedGoogle Scholar
  • 62 Dammacco F, Sansonno D, Cornacchiulo V. Hepatitis C virus infection and mixed cryoglobulinemia: A striking association.  Int J Clin Lab Res . 1993;  23 45-49
    PubMedGoogle Scholar
  • 63 Pascual M, Perrin L, Giostra E, Schifferli J A. Hepatitis C virus in patients with cryoglobulinemia type II.  J Infect Dis . 1990;  162 569-570
    PubMedGoogle Scholar
  • 64 Ferri C, Greco F, Longombardo G. Association between hepatitis C virus and mixed cryoglobulinemia.  Clin Exp Rheumathol . 1991;  9 621-624
    PubMedGoogle Scholar
  • 65 Cacoub P, Lunel Fabiani F, Musset L. Mixed cryoglobulinemia and hepatitis C virus.  Am J Med . 1994;  96 124-132
    CrossrefPubMedGoogle Scholar
  • 66 Pawlotsky J M, Roudot-Thoraval F, Simmonds P. Extrahepatic immunologic manifestations in chronic hepatitis C and hepatitis C virus serotypes.  Ann Intern Med . 1995;  122 169-173
    PubMedGoogle Scholar
  • 67 Feiner H D. Relationship of tissue deposits of cryoglobulin to clinical features of mixed cryoglobulinemia.  Hum Pathol . 1983;  14 710-715
    PubMedGoogle Scholar
  • 68 Sansonno D, Gesualdo L, Manno C. Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-infected patients with cryoglobulinemic membranoproliferative glomerulonephritis.  Hepatology . 1997;  25 1237-1244
    CrossrefPubMedGoogle Scholar
  • 69 Gorevic P D, Frangione B. Mixed cryoglobulinemia cross-reactive idiotypes: Implications for the relationship of MC to rheumatic and lymphoproliferative diseases.  Semin Hematol . 1991;  28 79-94
    PubMedGoogle Scholar
  • 70 Geltner D, Franklin E C, Frangione B. Antiidiotypic activity in the IgM fractions of mixed cryoglobulins.  J Immunol . 1980;  125 1530-1535
    PubMedGoogle Scholar
  • 71 Bona C A, Victor-Kobrin C, Manheimer A J. Regulatory arms of the immune network.  Immunol Rev . 1984;  79 25-44
    PubMedGoogle Scholar
  • 72 Knight G B, Agnello V, Bonagura V. Human rheumatoid factor cross-idiotypes. IV. Studies on WA XId-positive IgM without rheumatoid factor activity provide evidence that the WA XId is not unique to rheumatoid factors and is distinct from the 17.109 and G6 XIds.  J Exp Med . 1993;  178 1903-1911
    CrossrefPubMedGoogle Scholar
  • 73 Stewart J J, Agosto H, Litwin S. A solution to the rheumatoid factor paradox. Pathologic rheumatoids factors can be tolerized by competition with natural rheumatoid factors.  J Immunol . 1997;  159 1728-1738
    PubMedGoogle Scholar
  • 74 Wykes M, Pombo A, Jenkins C, MacPherson G G. Dendritic cells interact directly with naive B lymphocytes to transfer antigen and initiate class switching in a primary T-dependent response.  J Immunol . 1998;  161 1313-1319
    PubMedGoogle Scholar
  • 75 Carson D A, Chen P P, Kipps T J. New roles for rheumatoid factor.  J Clin Invest . 1991;  87 379-383
    PubMedGoogle Scholar
  • 76 Sansonno D, De Vita S, Cornacchiulo V. Detection and distribution of hepatitis C virus-related proteins in lymph nodes of patients with type II mixed cryoglobulinemia and neoplastic or non-neoplastic lymphoproliferation.  Blood . 1996;  88 4638-4645
    PubMedGoogle Scholar
  • 77 Newkirk M M, Mageed R A, Jefferis R. Complete amino acid sequences of variable regions of two human IgM rheumatoid factors, BOR and KAS of the Wa idiotypic family, reveal restricted use of heavy and light chain variable and joining region gene segments.  J Exp Med . 1987;  166 550-564
    CrossrefPubMedGoogle Scholar
  • 78 Martin T, Duffy S F, Carson D A, Kipps T J. Evidence for somatic selection of natural autoantibodies.  J Exp Med . 1992;  175 983-991
    CrossrefPubMedGoogle Scholar
  • 79 Monteverde A, Sabattini E, Poggi S. Bone marrow findings further support the hypothesis that essential mixed cryoglobulinemia type II is characterized by a monoclonal B-cell proliferation.  Leuk Lymph . 1995;  20 119-124
    PubMedGoogle Scholar
  • 80 Sansonno D, De Vita S, Iacobelli A R. Clonal analysis of intrahepatic B cells from HCV-infected patients with and without mixed cryoglobulinemia.  J Immunol . 1998;  160 3594-3601
    PubMedGoogle Scholar
  • 81 Tighe H, Warnatz K, Brinson D. Peripheral deletion of rheumatoid factor B cells after abortive activation by IgG.  Proc Natl Acad Sci USA . 1997;  94 646-651
    CrossrefPubMedGoogle Scholar
  • 82 Schettino E W, Chai S K, Kasaian M T. VHDJH gene sequences and antigen reactivity of monoclonal antibodies produced by human B-1 cells. Evidence for somatic selection.  J Immunol . 1997;  158 2477-2489
    PubMedGoogle Scholar
  • 83 Zhang M, Majid A, Bardwell P. Rheumatoid factor specificity of a VH3-encoded antibody is dependent on the heavy chain CDR3 region and is independent of protein A binding.  J Immunol . 1998;  161 2284-2289
    PubMedGoogle Scholar
  • 84 Mannik M F, Nardella A, Sasso E H. Rheumatoid factors in immune complexes of patients with rheumatoid arthritis.  Springer Semin Immunopathol . 1988;  10 215-230
    CrossrefPubMedGoogle Scholar
  • 85 Youngblood K, Fruchter L, Ding G. Rheumatoid factors from the peripheral blood of two patients with rheumatoid arthritis are genetically heterogeneous and somatically mutated. J Clin Invest .  1994;  93 852-861
    PubMedGoogle Scholar
  • 86 De Vita S, Boiocchi M, Sorrentino D. Characterization of prelymphomatous stages of B cell lymphoproliferation in Sjögren's syndrome.  Arthritis Rheum . 1997;  40 318-331
    PubMedGoogle Scholar
  • 87 Kyburz D, Corr M, Brinson D C. Human rheumatoid factor production is dependent on CD40 signaling and autoantigen.  J Immunol . 1999;  163 3116-3122
    PubMedGoogle Scholar
  • 88 Ferri C, Caracciolo F, Zignego A L. Hepatitis C virus infection in patients with non-Hodgkin's lymphoma.  Br J Haematol . 1994;  88 392-394
    PubMedGoogle Scholar
  • 89 Pozzato G, Mazzaro C, Crovatto M. Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia.  Blood . 1994;  84 3047-3053
    PubMedGoogle Scholar
  • 90 Mazzaro C, Zagonel V, Monfardini S. Hepatitis C virus and non-Hodgkin's lymphomas.  Br J Haematol . 1996;  94 544-550
    CrossrefPubMedGoogle Scholar
  • 91 Silvestri F, Pipan C, Barillari G. Prevalence of hepatitis C virus infection in patients with lymphoproliferative disorders.  Blood . 1996;  87 4296-4301
    PubMedGoogle Scholar
  • 92 De Rosa G, Gobbo M L, De Renzo A. High prevalence of hepatitis C virus infection in patients with B-cell lymphoproliferative disorders in Italy.  Am J Hematol . 1997;  55 77-82
    CrossrefPubMedGoogle Scholar
  • 93 De Vita S, Sacco C, Sansonno D. Characterization of overt B-cell lymphomas in patients with hepatitis C virus infection.  Blood . 1997;  90 776-782
    PubMedGoogle Scholar
  • 94 Zuckerman E, Zuckerman T, Levine A M. Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma.  Ann Intern Med . 1997;  127 423-428
    PubMedGoogle Scholar
  • 95 Vallisa D, Bertè R, Rocca A. Association between hepatitis C virus and non-Hodgkin's lymphoma, and effects of viral infection on histologic subtype and clinical course.  Am J Med . 1999;  106 556-560
    CrossrefPubMedGoogle Scholar
  • 96 Ryan J, Wallace S, Jones P. Primary hepatic lymphoma in a patient with chronic hepatitis C.  J Gastroenterol Hepatol . 1994;  9 308-310
    PubMedGoogle Scholar
  • 97 Borgonovo G, d'Oiron R, Amato A. Primary lymphoplasmacytic lymphoma of the liver associated with a serum monoclonal peak of IgG κ.  Am J Gastroenterol . 1995;  90 137-140
    PubMedGoogle Scholar
  • 98 De Vita S, Sansonno D, Dolcetti R. Hepatitis C virus within a malignant lymphoma lesion in the course of type II mixed cryoglobulinemia.  Blood . 1995;  86 1887-1892
    PubMedGoogle Scholar
  • 99 Satoh T, Yamada T, Nakano S. The relationship between primary splenic malignant lymphoma and chronic liver disease associated with hepatitis C virus infection.  Cancer . 1997;  80 1981-1988
    CrossrefPubMedGoogle Scholar
  • 100 De Vita S, Zagonel V, Russo A. Hepatitis C virus, non-Hodgkin's lymphomas and hepatocellular carcinoma.  Br J Cancer . 1998;  77 2032-2035
    PubMedGoogle Scholar
  • 101 Lombardo L, Rota Scalabrini D, Vineis P, De La Pierre M. Malignant lymphoproliferative disorders in liver cirrhosis.  Ann Oncol . 1993;  4 245-250
    PubMedGoogle Scholar
  • 102 Di Stasi M, Sbolli G, Fornari F. Hepatocellular carcinoma and B-cell tumors.  J Hepatol . 1994;  21 1146-1147
    CrossrefPubMedGoogle Scholar
  • 103 Clarke G, MacMathuna P, Fenlon H. Primary hepatic lymphoma in a man with chronic hepatitis C.  Eur J Gastroenterol Hepatol . 1997;  9 87-90
    PubMedGoogle Scholar
  • 104 Möhler M, Gutzler F, Kallinowsky B. Primary hepatic high-grade non-Hodgkin's lymphoma and chronic hepatitis C infection.  Dig Dis Sci . 1997;  42 2241-2245
    CrossrefPubMedGoogle Scholar
  • 105 Rasul I, Sheperd F A, Kamel-Reid S. Detection of occult low-grade B-cell non-Hodgkin's lymphoma in patients with chronic hepatitis C infection and mixed cryoglobulinemia.  Hepatology . 1999;  29 543-547
    CrossrefPubMedGoogle Scholar
  • 106 Viala J J, Trepo C, Creyssel R. Gammapathie monoclonale apparemment non myélomateuse associé à l'antigène de l'hépatite non-A non-B.  Nouv Presse Med . 1982;  11 52
    PubMedGoogle Scholar
  • 107 Heer M, Joller-Jemelka H, Fontana A. Monoclonal gammopathy in chronic active hepatitis.  Liver . 1984;  4 255-263
    PubMedGoogle Scholar
  • 108 Mussini C, Ghini M, Mascia M T. HCV and monoclonal gammopathies.  Clin Exp Rheumatol . 1995;  13(Suppl 13) S45-49
    PubMedGoogle Scholar
  • 109 Mangia A, Clemente R, Musto P. Hepatitis C virus infection and monoclonal gammopathies not associated with cryoglobulinemia.  Leukemia . 1996;  10 1209-1213
    PubMedGoogle Scholar
  • 110 Andreone P, Zignego A L, Cursaro C. Prevalence of monoclonal gammopathies in patients with hepatitis C virus infection.  Ann Intern Med . 1998;  129 294-298
    PubMedGoogle Scholar
  • 111 Misiani R, Bellavita P, Fenili D. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus.  N Engl J Med . 1994;  330 751-756
    CrossrefPubMedGoogle Scholar
  • 112 Mazzaro C, Franzin F, Tulissi P. Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to α-interferon therapy.  Cancer . 1996;  77 2604-2613
    CrossrefPubMedGoogle Scholar
  • 113 Zur Hausen H. Viruses in human cancers.  Science . 1991;  254 1167-1173
    PubMedGoogle Scholar
  • 114 Sansonno D, Cornacchiulo V, Racanelli V, Dammacco F. In situ simultaneous detection of hepatitis C virus RNA and hepatitis C virus-related antigens in hepatocellular carcinoma.  Cancer . 1997;  80 22-26
    CrossrefPubMedGoogle Scholar
  • 115 Dietrich C F, Lee J-H, Herrmann G. Enlargement of perihepatic lymph nodes in relation to liver histology and viremia in patients with chronic hepatitis C.  Hepatology . 1997;  26 467-472
    CrossrefPubMedGoogle Scholar
  • 116 Laskus T, Radkowski M, Wang L-F. Search for hepatitis C virus extrahepatic replication sites in patients with acquired immunodeficiency syndrome: Specific detection of negative-strand viral RNA in various tissues.  Hepatology . 1998;  28 1398-1401
    CrossrefPubMedGoogle Scholar
  • 117 Stollar V, Schlesinger R W, Stevens T M. Studies on the nature of Dengue virus. III. RNA synthesis in cells infected with type 2 Dengue virus.  Virology . 1967;  33 650-658
    CrossrefPubMedGoogle Scholar
  • 118 Lerat H, Rumin S, Habersetzer F. In vivo tropism of hepatitis C virus genomic sequences in hematopoietic cells: Influence of viral load, viral genotype, and cell phenotype.  Blood . 1998;  91 3841-3849
    PubMedGoogle Scholar
  • 119 Shimizu Y K, Yoshikura H. Multicycle infection of hepatitis C virus in cell culture and inhibition by alpha and beta interferons.  J Virol . 1994;  68 8406-8408
    PubMedGoogle Scholar
  • 120 Nakajima N, Hijikata M, Yoshikura H, Shimizu Y K. Characterization of long-term cultures of hepatitis C virus.  J Virol . 1996;  70 3325-3329
    PubMedGoogle Scholar
  • 121 Bronowicki J-P, Loriot M-A, Thiers V. Hepatitis C virus persistence in human hematopoietic cells injected into SCID mice.  Hepatology . 1998;  28 211-218
    CrossrefPubMedGoogle Scholar
  • 122 Chang T-T, Young K-C, Yang Y-J. Hepatitis C virus RNA in peripheral blood mononuclear cells: Comparing acute and chronic hepatitis C virus infection.  Hepatology . 1996;  23 977-981
    PubMedGoogle Scholar
  • 123 Sansonno D, Lotesoriere C, Cornacchiulo V. Hepatitis C virus infection involves CD34+ hematopoietic progenitor cells in hepatitis C virus chronic carriers.  Blood . 1998;  92 3328-3337
    PubMedGoogle Scholar
  • 124 Krause D S, Fackler M J, Civin C I, Stratford May W. CD34: Structure, biology, and clinical utility.  Blood . 1996;  87 1-13
    PubMedGoogle Scholar
  • 125 Crosbie O M, Reynolds M, McEntee G. In vitro evidence for the presence of hematopoietic stem cells in the adult human liver.  Hepatology . 1999;  29 1193-1198
    CrossrefPubMedGoogle Scholar
  • 126 Taniguchi H, Toyoshima T, Fukao K, Nakauchi H. Presence of hematopoietic stem cells in the adult liver.  Nat Med . 1996;  2 198-203
    PubMedGoogle Scholar
  • 127 Satoh T, Yamada T, Nakano S. The relationship between primary splenic malignant lymphoma and chronic liver disease associated with hepatitis C virus infection.  Cancer . 1997;  80 1981-1988
    CrossrefPubMedGoogle Scholar
  • 128 Dammacco F, Gatti P, Sansonno D. Hepatitis C virus infection, mixed cryoglobulinemia, and non-Hodgkin's lymphoma: An emerging picture.  Leuk Lymph . 1998;  31 463-476
    PubMedGoogle Scholar
  • 129 Ascoli V, Lo Coco F, Artini M. Extranodal lymphomas associated with hepatitis C virus infection.  Am J Clin Pathol . 1998;  109 600-609
    PubMedGoogle Scholar
  • 130 Ohsawa M, Shingu N, Miwa H. Risk of non-Hodgkin's lymphoma in patients with hepatitis C virus infection.  Int J Cancer . 1999;  80 237-239
    CrossrefPubMedGoogle Scholar
  • 131 Rubbia-Brandt L, Bründler M-A, Kerl K. Primary hepatic diffuse large B-cell lymphoma in a patient with chronic hepatitis C.  Am J Surg Pathol . 1999;  23 1124-1130
    CrossrefPubMedGoogle Scholar
  • 132 McColl M D, Singer I O, Tait R C. The role of hepatitis C virus in the aetiology of non-Hodgkin's lymhoma. A regional association?.  Leuk Lymph . 1997;  26 127-130
    PubMedGoogle Scholar
  • 133 Germanidis G, Haioun C, Pourquier J. Hepatitis C virus infection in patients with overt B-cell non-Hodgkin's lymphoma in a French center.  Blood . 1999;  93 1778-1779
    PubMedGoogle Scholar
  • 134 Collier J D, Zanke B, Moore M. No association between hepatitis C and B-cell lymphoma.  Hepatology . 1999;  29 1259-1261
    CrossrefPubMedGoogle Scholar
  • 135 Ray R B, Martin Lagging L, Meyer K, Ray R. Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype.  J Virol . 1996;  70 4438-4443
    PubMedGoogle Scholar
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