LYMPHOPROLIFERATION IN TYPE-II MIXED CRYOGLOBULINEMIA

Objective. The role of the hepatitis C virus (HCV) in the etiology of type II mired cryoglobulinemia (MC) has been well established, but the pathogenetical relationships among the virus, the immune system, the natural history of MC, and lymphoproliferation in the bone marrow and liver need to be further elucidated. Methods. Eighty-two patients with HCV positive type II MC and 20 subjects with chronic hepatitis C with out MC were studied: bone marrow and liver specimens were examined by routine histology and immunohistochemistry, particularly focusing on p arameters related to disease behaviour, such as the expression of the bcl-2 oncogene product and the proliferation-associated Ki67 antigen. Results. In most MC patients there were lymphoid infiltrates within th e bone marrow showing a monomorphic cytology, frequent immunoglobulin light chain monotypic restriction, expression of the anti-apoptotic bc l-2 oncogene product, and a low proliferative capacity (Ki-67<3%). On the other hand, in all non-cryoglobulinemic patients a bone marrow pic ture of reactive lymphoplasmacytosis was found. In both MC and chronic hepatitis patients, the liver biopsy showed portal infiltrates consis ting of T-cells, associated with a significant B-cell component; the l atter was particularly abundant in MC, where it was frequently arrange d in pseudo-follicles. The B-cell component expressed the bcl-2 oncoge ne product and CD5 antigen, thus suggesting that the immune system is actively involved in the production of liver damage both in MC and non -cryoglobulinemic patients. It is worth noting that in MC patients (bu t not in the non-cryoglobulinemic patients) these CD5+/bcl-2 + B-cells frequently also exhibited a monotypic restriction bearing an IgM kapp a. Conclusion. Our findings in these liver and bone marrow studies fur ther support the role of a lymphoproliferative disorder in the patholo gy of type II MC: the B cells involved accumulate due to the inhibitio n of apoptosis, and their low proliferative index justifies the indole nt course of the disease. HCV probably interacts with these B-cells, f acilitating their clonal expansion.