Springer Seminars in Immunopathology

, Volume 19, Issue 1, pp 111–129

The etiology and pathophysiology of mixed cryoglobulinemia secondary to hepatitis C virus infection

  • Vincent Agnello


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  1. 1.
    Agnello V (1995) Hypothesis: the etiology of mixed cryoglobulinemia associated with hepatitis C virus infection. Scand J Immunol 421:179Google Scholar
  2. 2.
    Agnello V, Abel G (1997) Localization of hepatitis C virus in cutaneous vasculitic lesions in patients with type II mixed cryoglobulinemia using in situ hybridization. Arthritis Rheum. 1997 (in press)Google Scholar
  3. 3.
    Agnello V, Barnes JL (1986) Human rheumatoid factor cross-idiotype. I. WA and BLA are heat labile conformational antigens requiring both heavy and light chains. J Exp Med 164:1809Google Scholar
  4. 4.
    Agnello V, Romain PL (1996) Mixed cryoglobulinemia associated with hepatitis C virus infection. Rheum Dis Clin North Am 22:2Google Scholar
  5. 5.
    Agnello V, Joslin FG, Kunkel HG (1972) Crossidiotypic specificity among monoclonal IgM antiglobulins. Scand J Immunol 1:283Google Scholar
  6. 6.
    Agnello V, Arbetter A, Ibanez de Kasep G, Powell R, Tan EM, Joslin F (1980) Evidence for a subset of rheumatoid factors which cross react with DNA-histone and have a distinct cross idiotype. J Exp Med 151:1514Google Scholar
  7. 7.
    Agnello V, Chung RT, Kaplan LM (1992) A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 327:1490Google Scholar
  8. 8.
    Agnello V, Ábel G, Knight GB, Monteverde A, Ballare M, Bertoncelli MC, Pileri SA (1995) Detection of hepatitis C virus (HCV) in liver, bone marrow, and lymph nodes in type II mixed cryoglobulinemia using in situ hybridization. Abstracts of the 3rd International Meeting on Hepatitis C Virus and Related Virus, Gold Coast, Australia. Abstr. no.C163Google Scholar
  9. 9.
    Agnello V, Ábel G, Knight GB, Zhang QX, Elfahal M, Confalonieri R, Montoli A, Muchmore E (1995) The role of hepatitis C virus in the pathogenesis of type II cryoglobulinemia. Keystone Symposia on Hepatitis C and Beyond, Burlington, Vermont. Keystone Symposia, Silverthome, CO, abstr. no.007Google Scholar
  10. 10.
    Agnello V, Zhang QX, Abel G, Knight GB (1995) The association of hepatitis C virus infection with monoclonal rheumatoid factors bearing the WA crossidiotype: implications for the etiopathogenesis and therapy of mixed cryoglobulinemia. Clin Exp Rheum 13:5101Google Scholar
  11. 11.
    Agnello V, Zhang QX, Elfahal M, Abel G, Knight GB (1995) Association of hepatitis C virus with VLDL in type II cryoglobulinemia. Abstracts of the 3rd International meeting on hepatitis C virus and related viruses, Gold Coast, Australia. Abstr. no. C86Google Scholar
  12. 12.
    Reference deletedGoogle Scholar
  13. 13.
    Agnello V, Ábel G, Zhang QX, Elfahal M, Knight GB (1997) The etiology of mixed cryoglobulinemia: the role of the LDL receptor and apolipoprotein E2. Arthritis Rheum 39:5315Google Scholar
  14. 14.
    Ballare M, De Vita S, Bertoncelli MC, Pivetta B, Biocchi M, Pileri S (1997) Clinical, pathological and molecular differences between the bone marrow lymphoproliferation and the overt B-cell lymphomas in patients with type II mixed cryoglobulinemia and HCV infection. Abstracts of the 4th International Meeting HCV and Related Virus. Kyoto, Japan, p 222Google Scholar
  15. 15.
    Bonagura VR, Kunkel HG, Pernis B (1982) Cellular localization of rheumatoid factor idiotypes. J Clin Invest 69:1356Google Scholar
  16. 16.
    Bonagura VR, Pernis B, Agostino N, Hatam L (1992) The major rheumatoid factor cross-reactive idiotype is dominantly expressed byStaphylococcus aureus Cowan strain 1-activated CD5+ control B Cells. Cell Immunol 140:381Google Scholar
  17. 17.
    Brouet J-C, Clauvel J-P, Danon F, Klein M, Seligmann M (1974) Biologic and clinical significance of cryoglobulins: a report of 86 cases. Am J Med 57:775Google Scholar
  18. 18.
    Bukh J, Miller RH, Purcell RH (1995) Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes. Semin Liver Dis 15:41Google Scholar
  19. 19.
    Cacoub P, Fabian FL, Musset L, Perrini M, Franguel L, Leger JM, Huraux JM, Piette JC, Godeau P (1994) Mixed cryoglobulinemia and hepatitis C virus. Am J Med 96:124Google Scholar
  20. 20.
    Casato M, Lagana B, Antonelli G, Dianzani F, Bonomo F (1991) Long-term results of therapy with interferon-α for type II essential mixed cryoglobulinemia. Blood 78:3142Google Scholar
  21. 21.
    Cattaneo R, Fenini MG, Facchetti F (1986) Cryoglobulinemic vasculitis. Ric Clin Lab 16:327Google Scholar
  22. 22.
    Chemello L, Cavalletto D, Pontisso P, Bortolotti F, Donada C, Donadon V, Frezza M, Cesarin P, Alberti A (1993) Patterns of antibodies to hepatitis C virus in patients with chronic non-A, non-B hepatitis and their relationship to viral replication and liver disease. Hepatology 17:179Google Scholar
  23. 23.
    Circolo A, Barnes JL, Agnello V (1988) Inhibition of complement activation by anti-crossidiotype antibodies. FASEB J 2:A1647Google Scholar
  24. 24.
    Cordonnier D, Martin H, Groslambert P, Micouin C. Chenais F, Stoebner P (1975) Mixed IgG-IgM cryoglobulinemia with glomerulonephritis: immunochemical, fluorescent and ultrastructural study of kidney and in vitro cryoprecipitate. Am J Med 59:867Google Scholar
  25. 25.
    Crouzier R, Martin T, Pasquali JL (1995) Monoclonal IgM rheumatoid factor secreted by CD5-negative B cells during mixed cryoglobulinemia: evidence for somatic mutations and intraclonal diversity of the expressed Vh region gene. J Immunol 143:413Google Scholar
  26. 26.
    Crovatto M, Ceselli S, Mazzaro C, Modolo ML, Martelli P, Mazzi G, Pozzato G, Giannini F, Barbisin M, Chiarotta B (1995) HCV genotypes and cryoglobulinemia. Clin Exp Rheumatol 13:S79Google Scholar
  27. 27.
    D'Amico G, Colasanti G, Ferrario F Sinico RA (1989) Renal involvement in essential mixed cryoglobulinemia. Kidney Int 35:1004Google Scholar
  28. 28.
    Ferri C, Lacivita L, Cirafis C, Siciliano G, Longombardo G, Bombardieri S, Rossi B (1992) Peripheral neuropathy in mixed cryoglobulinemia: clinical and electrophysiologic investigations. J Rheumatol 19:889Google Scholar
  29. 29.
    Galli M, Zehender G, Monti G, Ballare M, Saccardo F, Piconi S, De Maddelena C, Bertoncelli MC, Rinaldi G, Invernizzi F, Monteverde A (1995) Hepatitis C virus RNA in the bone marrow of patients with mixed cryoglobulinemia and in subjects with noncryoglobulinemic chronic hepatitis type C. Infect Dis 171:672Google Scholar
  30. 30.
    Gigli I (1986) Complement activation in patients with mixed cryoglobulinemia. In: Ponticelli C, Minetti L, D'Amico G (eds) Antiglobulins, cryoglobulins and glomerulonephritis. Marfinus Nijhoff, Dordrecht, pp 135–146Google Scholar
  31. 31.
    Gorevic PD (1986) Mixed cryoglobulinemia: an update of recent clinical experience. In: Ponticelli C, Minetti L, D'Amico G (eds) Antiglobulins, cryoglobulins and glomerulonephritis. Martinus Nijhoff, Dordrecht, pp 179–192Google Scholar
  32. 32.
    Gorevic PD, Frangione B (1991) Mixed cryoglobulinemia cross-reactive idiotypes: implications for the relationship of MC to rheumatic and lymphoproliferative diseases. Semin Hematol 28:79Google Scholar
  33. 33.
    Gorevic PD, Kassab JH, Levo Y, Kohn R, Meltzer M, Prose P, Franklin EC (1980) Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients. Am J Med 69:287Google Scholar
  34. 34.
    Hardy RR, Hayakawa K, Shimizu M, Yamasaki K, Kishimoto T (1987) Rheumatoid factor secretion from human leu-1+ B cells. Science 236:81Google Scholar
  35. 35.
    Janeway C, Travers P (1994) Immunobiology The immune system in health and disease. Janeway CA, Travers P (eds) Garland Pub., New York, p.22Google Scholar
  36. 36.
    Johnson RJ, Gretch DR, Yamabe H, Hart J, Bacchi CE, Hartwell P, Couser WG, Corey L, Wener MH, Alpers C, Wilson R (1993) Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 328:465Google Scholar
  37. 37.
    Kipps TJ, Duffy SF (1991) Relationship of the CD5 B cell to human tonsillar lymphocytes that express autoantibody-associated cross-reactive idiotypes. J Clin Invest 87:2087Google Scholar
  38. 38.
    Knight GB, Agnello V, Bonagura V, Barnes JL, Panka DJ, Zhang QX (1993) 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 178:1903Google Scholar
  39. 39.
    Kunkel HG, Agnello V, Joslin FG, Winchester RJ, Capra JD (1973) Cross-idiotypec specificity among monoclonal IgM proteins with anti-7 globulin activity. J Exp Med 137:331Google Scholar
  40. 40.
    Lanford RE, Chavez D, Chisari FV, Sureau C (1995) Lack of detection of negative-strand hepatitis C virus RNA in peripheral blood mononuclear cells and other extrahepatic tissues by the highly strandspecific rTth reverse transcriptase PCR. J Virology 69:8079Google Scholar
  41. 41.
    Levinson AL, Tar L, Carafa C, Haidar M (1986)Staphylococcus aureus Cowan I. J Clin Invest 78:612Google Scholar
  42. 42.
    Levo Y, Gorevi PD, Kassab HJ, Zucker-Franklin D, Franklin EC (1977) Association between hepatitis B virus and essential mixed cryoglobulinemia. N Engl J Med 296:1501Google Scholar
  43. 43.
    Lunel F, Musset L, Cacoub P, Frangeul L, Cresta P, Perrin M, Grippon P, Hoang C, Valla D, Piette JC, Huraux J, Opolon P (1994) Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology 106:1291Google Scholar
  44. 44.
    Madi N, Steiger G, Estreicher J, Schifferli JA (1991) Defective immune adherence and elimination of hepatitis B surface antigen/antibody complexes in patients with mixed essential cryoglobulinemia type II. J Immunol 147:495Google Scholar
  45. 45.
    Maggiore Q, Bartolomeo F, L'Abbate A, Misefari V, Martorano C, Caccamo A, Behojoso GB di, Tarantino A, Colsanti G (1982) Glomerular localization of circulating antiglobulin activity in essential mixed cryoglobulinemia with glomerulonephritis. Kidney Int 21:387Google Scholar
  46. 46.
    Martin T, Duffy SF, Carson DA, Kipps TJ (1992) Evidence for somatic selection of natural autoantibodies. J Exp Med 175:983Google Scholar
  47. 47.
    Meltzer M, Franklin EC, Elias K, McCluskey RT, Cooper N (1966) Cryoglobulinemia: a clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity. Am J Med 40:837Google Scholar
  48. 48.
    Miescher PA, Huang YP, Izui S (1995) Type II cryoglobulinemia. Semin Hemat 32:80Google Scholar
  49. 49.
    Misani R, Bellavita P, Fenili D, Marchesi D, Massazza M, Borelli G, Comotti B, Tanzi E, Scudeller G, Zanetti A (1992) Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 117:573Google Scholar
  50. 50.
    Monteverde A, Rivano MT, Allegra GC, Monteverde AI, Zigrossi P, Baglioni P, Gobbi M, Falini B, Bordin G, Pileri S (1988) Essential mixed cryoglobulinemia, type II: a manifestation of a low-grade malignant lymphoma? Clinical-morphological study of 12 cases with special reference to immunohistochemical findings in liver frozen section. Acta Haemotol 79:20Google Scholar
  51. 51.
    Monteverde A, Sabattini E, Poggi S, Ballare M, Bertoncelli MC, De Vivo A, Briskomatis A, Roncador G, Falini B, Pileri SA (1995) Bone marrow findings further support the hypothesis that essential mixed cryoglobulinemia type II is characterized by a monoclonal B-cell proliferation. Leuk Lymphoma 2:1119Google Scholar
  52. 52.
    Monti G, Galli M, Invernizzi F, Pioltelli P, Saccardo F, Monteverde M, Pietrogrande M, Renoldi S, Bombardieri S, Bordin G, Candela M, Ferri C, Gabrielli A, Mazzaro C, Migliaresi S, Mussini C, Ossi E, Quintilani L, Tirri G, Vacca A, and the GISC (1995) Cryoglobulinemias: a multi-centre study of the early clinical and laboratory manifestations of primary and secondary disease. Q J Med 88:115Google Scholar
  53. 53.
    Muratori L, Gilbellini D, Lenzi M, Cataleta M, Muratori P, Morelli MC (1996) Quantification of hepatitis C virus-infected peripheral blood mononuclear cells by in situ reverse transcriptase-polymerase chain reaction. Blood 88:2768Google Scholar
  54. 54.
    Mussini C, Mascia MT, Zanni G, Curci G, Bonacorsi G, Artusi T (1991) A cytomorphological and immunohistochemical study of bone marrow in the diagnosis of essential mixed type II cryoglobulinemia. Haematologica 76:389Google Scholar
  55. 55.
    Pasquali JL, Waltziner C, Kuntz L, Knapp AM, Levallois H (1991) The majority of peripheral blood monoclonal 1gM rheumatoid factor secreting cells are CD5 negative in three patients with mixed cryoglobulinemia. Blood 77:1761Google Scholar
  56. 56.
    Pawlotsky JM, Yahia MB, Andre C, Voisin MC, Intrator L, Roudot-Thorval F, Deforges L, Duvoux C, Zafrani ES, Duval J (1994) Immunological disorders in C virus chronic active hepatitis: a prospective case-control study. Hepatology 19:841Google Scholar
  57. 57.
    Pawlotsky JM, Roudot-Thoraval F, Simmonds P, Mellor J, Ben Yahia MB, Andre C, Voisin MC, Intrator L, Zafrani ES, Duval J, Dhumeau D (1995) Extrahepatic immunologic manifestations in chronic hepatitis C and hepatitis C virus serotypes. Ann Intern Med 122:169Google Scholar
  58. 58.
    Pozzato G, Mazzaro C, Crovatto M, Modolo ML, Ceselli S, Mazzi G, Sulfaro S, Franzin F, Tulissi P, Moretti M, Santini GF (1994) Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia. Blood 84:3047Google Scholar
  59. 59.
    Prati D, Capelli C, Zanella A, Mozzi F, Bosoni P, Pappalettera M, Zanuso F, Vianello L, Locatelli E, de Fazio C, Ronchi G, del Ninno E, Colombo M, Sirchia G (1996) Influence of different hepatitis C virus genotypes on the course of asymptomatic hepatitis C virus infection. Gastroenterology 110:178Google Scholar
  60. 60.
    Realdi G, Alberti A, Rigoli A, Tremolada F (1974) Immune complexes and Australia antigen in cryoglobulinemic sera. Z Immunitätsforsch 147:114Google Scholar
  61. 61.
    Reininger L, Berney T, Shibata T, Spertini F, Merino R, Izui S (1990) Cryoglobulinemia induced by a routine IgG3 rheumatoid factor: skin vasculitis and glomerulonephritis arise from distinct pathogenic mechanisms Proc Natl Acad Sci USA 87:10038Google Scholar
  62. 62.
    Sansonno D, Cornacchiulo V, Lacobelli AR, Di Stefano R, Lospalluti M, Dammacco F (1995) Localization of hepatitis C virus antigens in liver and skin tissues of chronic hepatitis C virus-infected patients with mixed cryoglobulinemia. Hepatology 21:305Google Scholar
  63. 63.
    Sinico RA, Winearls CG, Sabadini E, Fornasieri A, Castiglione A, D'Amico G (1988) Identification of glomerular immune deposits in cryoglobulinemia glomerulonephritis. Kidney Int 34:109Google Scholar
  64. 64.
    Sinico RA, Ribero ML, Foruasieri A, Renoldi P, Zhou J, Fasola M, Portera G, Arrigo G, Gibelli A, D'Amico G, Tagger A (1995) Hepatitis C virus genotype in patients with essential mixed cryoglobulinemia. Q J Med 88:805Google Scholar
  65. 65.
    Stoebner P, Renversez JC, Groulade J, Vialtel P, Cordonner D (1978) Ultrastructural study of human IgG and IgG-IgM crystal cryoglobulins. Am Soc Clin Pathol 4:404Google Scholar
  66. 66.
    Tarantino A, Montagnino G, Baldassari A, Barbiano di'Belgiojoso G, Colasanti G, Montoli A, Bucci A, Ponticelli C (1986) Prognostic factors in essential mixed cryoglobulinemia nephropathy. In: Ponticelli C, Minetti L, D'Amico G (eds) Antiglobulins, Cryoglobulins and Glomerulonephritis. Martinus Nijhoff, Dordrecht, pp 219Google Scholar
  67. 67.
    Thomssen R, Monazahian M, Bonk S, Koch A, Bohme 1, Heerman K, Muller A, Scholz C, Uy A (1996) The binding of HCV to lipoproteins. Keystone symposium on Hepatitis C and Beyond, Burlington, Vermont. Keystone Symposia, Silver, abstr. no. 003Google Scholar
  68. 68.
    Willems M, Sheng L, Roskams T, Ramdani B, Doutrelepont JM, Nevens F, Durez P, Treille S, Adler M, Desmet V, Fevery J, Yap SH (1994) Hepatitis C virus and its genotypes in patients suffering from chronic hepatitis C with or without a cryoglobulinemia-related syndrome. J Med Virol 44:266Google Scholar
  69. 69.
    Zignego AL, Ferri C, Giannini C, Monti M, La Civita L, Careccia G, Longombardo G, Lombardini F, Bombardieri S, Gentilini P (1996) Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia. Ann Intern Med 124: 31Google Scholar

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© Springer-Verlag 1997

Authors and Affiliations

  • Vincent Agnello
    • 1
  1. 1.Lahey Hitchcock Clinic and the Edith Nourse Rogers Memorial Veterans Affairs HospitalBurlington and BedfordBurlingtonUSA

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