HCV-Induced Cryoglobulinemic Vasculitis: Pathogenesis and Therapeutic Implications
Leucocytoclastic vasculitis is the dominant lesion of mixed cryoglobulinemia (MC). The high prevalence of antibodies to hepatitis C virus (HCV) in association with the higher concentration of HCV RNA genomic sequences in the cryoglobulins and analysis of the composition of immune complexes (ICs) suggest a close relation between MC and HCV infection and strongly supports the view that this virus plays a key role in causing vascular damage. Our data indicate that endothelial cells are fully susceptible to infection of HCV, and support the contention that they serve as sufficient targets for the binding of HCV proteins expressed on the cell surface to serum immunoglobulins. The in situ demonstration of IgM RF WA cross-idiotype (XId) adds further evidence that RF of the WA group participates in the development of vasculitis, and probably stabilizes the binding of ICs. Lymphomonocytes may be crucial in the infection of endothelial cells by acting as a circulating viral reservoir. The efficacy of interferon in the treatment of MC, has been shown in more than 50% of patients and includes improvement of cutaneous vasculitis and renal function. However, almost 80% of responders have a clinical and biochemical relapse after treatment withdrawal.
KeywordsMixed Cryoglobulinemia Membranoproliferative Glomerulonephritis Cutaneous Vasculitis Endothelial Cell Circ Essential Mixed Cryoglobulinemia
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- 2.Jennette, J.C., Falk, R.J., Andrassy, K., Bacon, P.A., Churg, J., Gross, W.L., Hagen, E.C., Hoffman, G.S., Hunder, G.G., Kallenberg, C.G.M., McCluskey, R.T., Sinoco, R.A., Rees, A.J., van Es, L.A., Waldherr, R. and Wiik, A. (1994) Nomenclature of systemic vasculitides, Arthritis Rheum.37, 187–192.PubMedCrossRefGoogle Scholar
- 14.Sansonno D., Cornacchiulo, V., Iacobelli, A.R. and Dammacco F. (1993) New clinical and molecular features of essential mixed cryoglobulinemia, in A.G. Dalgleish, A. Albertini and R. Paoletti (eds.), The Impact of Biotechnology on Autoimmunity, Kluwer Academic Publishers, Dordrecht, pp. 27–36.Google Scholar
- 16.Andrews, D.W., and Capra, J.D. (1981) Complete aminoacid sequence of variable domains from two human monoclonal anti-gamma globulins of the WA cross-idiotypic group: suggestion that the J segments are involved in the structural correlate of the idiotype, Proc. Natl. Acad. Sci. USA 78,3799–3803.CrossRefGoogle Scholar
- 17.Sansonno, D., Iacobelli, A.R., Cornacchiulo, V., Lauletta, G., Di Stasi, M.A., Gatti, P. and Dammacco, F. (In press) Immunochemical and biomolecular studies of circulating immunecomplexes isolated from patients with acute and chronic hepatitis C virus infection, Eur. J. Clin. Invest.Google Scholar
- 21.Sansonno, D., Cornacchiulo, V., Iacobelli, A.R. and Dammacco, F. (Submitted) In situ demonstration of HCV RNA and HCV-related proteins in skin and liver of patients with mixed cryoglobulinemia.Google Scholar
- 22.Theophilopoulos A.N. and Dixon, F.J. (1990) Immune Complexes in Human Diseases, Am. J. Pathol. 100, 531–594.Google Scholar
- 24.Sansonno, D., Iacobelli, A.R., Cornacchiulo, V., Iodice, G., and Dammacco, F. (1996) Detection of hepatitis C virus (HCV) proteins by immunofluorescence and HCV RNA genomic sequences by nonisotopic in situ hybridization in bone marrow and peripheral blood mononuclear cells of chronically HCV-infected patients, Clin Exp Immunol. 103, 414–421.PubMedCrossRefGoogle Scholar
- 28.Fornasieri, A., Li, M., Armelloni, S., Pinerolo De Septis, C, Schiaffino, E., Sinico, R.A., Schmid, C. and D’Amico, G. (1993) Glomerulonephritis induced by human IgMK-IgG cryoglobulins in mice, Lab. Invest. 5, 531–540.Google Scholar
- 29.Oppenheimer-Marks, N. and Lipsky, P.E. (1994) Transendothelial migration of T-cells in chronic inflammation, The Immunologist 2, 58–64.Google Scholar
- 32.Ferri, C, Marzo, E., Longombardo, G., Lombardini, F., La Civita, L., Vanacore, R., Liberati, A.M., Gerli, R., Greco, F., Moretti, A., Monti, M., Gentilini, P., Bombardieri, S. and Zignego, A.L. (1993) Interferon-a in mixed cryoglobulinemia patients: a randomized crossover-controlled trial, Blood 81, 1132–1136.Google Scholar
- 33.Misiani, R., Bellavita, P., Fenili, D., Vicari, O., Marchesi, D., Sironi, P.L., Zilio, P., Vernocchi, A., Massazza, M., Vendramin, G., Tanzi, E. and Zanetti, A. (1994) Interferon alpha-2a therapy in cryoglobulinemia associated with hepatitis C virus, N. Engl. J. Med. 330, 751–756.PubMedCrossRefGoogle Scholar
- 34.Dammacco, F., Sansonno, D., Han, J.H., Shyamala, V., Cornacchiulo, V., Iacobelli, A.R., Lauletta, G. and Rizzi, R. (1994) Natural interferon alpha vs its combination with 6-methyl-prednisolone in the therapy of type II Mixed cryoglobulinemia. A long-term, randomized, controlled study, Blood 84, 3336–3343.PubMedGoogle Scholar