Dammacco F, Sansonno D
Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Policlinico, Italy.
Clin Rev Allergy Immunol. 1997 Spring;15(1):97-119. doi: 10.1007/BF02828280.
Leukocytoclastic 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 suggests a close relationship between MC and HCV infection and strongly supports the view that this virus plays a key role in causing vascular damage. Analysis of the composition of immune complexes (ICs) provides evidence that cryoglobulins include virions mostly bound to IgG that is specifically reactive with HCV-related proteins, which in turn are crosslinked by monoclonal IgM with rheumatoid factor (RF) activity, frequently bearing the WA crossidiotype (XId). This structure is similar (if not identical) to that of circulating ICs from HCV-infected patients without cryoglobulins, suggesting that the virus may be directly responsible for the production of WA RF. Evidence for the role of circulating cryoproteins in the pathogenesis of cutaneous and renal vasculitis stems from the demonstration of HCV-related proteins and/or HCV RNA genomic sequences in the vessel wall of patients with MC. Our data indicate that endothelial cells are fully susceptible to infection by and replication 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 XId adds further evidence that RF of the WA group participates in the development of vasculitis and probably stabilizes the binding of IgG antibodies. Lymphocytes may be crucial in the infection of endothelial cells by acting as a circulating viral reservoir. After encouraging initial results, controlled trials have defined the substantive efficacy of IFN-alpha in the treatment of MC. A response of IFN can be achieved in more than 50% of patients and includes improvement of cutaneous vasculitis and renal function. This clinical response is accompanied by a reduction in hepatitis C viremia, serum cryoglobulin concentration, and IgM RF synthesis. However, almost 80% of responders eventually have a clinical and biochemical relapse. Additional studies are required to improve the outcome and extension of this therapy, define the best candidates, and indicate the situations in which it is needed.
白细胞破碎性血管炎是混合性冷球蛋白血症（MC）的主要病变。丙型肝炎病毒（HCV）抗体的高流行率以及冷球蛋白中HCV RNA基因组序列的较高浓度表明MC与HCV感染之间存在密切关系，并有力地支持了这种病毒在导致血管损伤中起关键作用的观点。对免疫复合物（ICs）组成的分析提供了证据，表明冷球蛋白包括主要与IgG结合的病毒粒子，该IgG与HCV相关蛋白具有特异性反应性，而这些蛋白又被具有类风湿因子（RF）活性的单克隆IgM交联，这些单克隆IgM通常带有WA交叉同种异型（XId）。这种结构与来自无冷球蛋白的HCV感染患者的循环ICs的结构相似（如果不是相同的话），表明该病毒可能直接导致WA RF的产生。循环冷球蛋白在皮肤和肾血管炎发病机制中作用的证据源于在MC患者的血管壁中发现了HCV相关蛋白和/或HCV RNA基因组序列。我们的数据表明内皮细胞对HCV感染和复制完全敏感，并支持它们作为细胞表面表达的HCV蛋白与血清免疫球蛋白结合的充分靶点的观点。IgM RF WA XId的原位显示进一步证明WA组的RF参与血管炎的发展，并可能稳定IgG抗体的结合。淋巴细胞可能通过作为循环病毒库在内皮细胞感染中起关键作用。在取得令人鼓舞的初步结果后，对照试验确定了干扰素-α在治疗MC中的实际疗效。超过50%的患者对干扰素治疗有反应，包括皮肤血管炎和肾功能的改善。这种临床反应伴随着丙型肝炎病毒血症、血清冷球蛋白浓度和IgM RF合成的降低。然而，几乎80%的反应者最终会出现临床和生化复发。需要进一步的研究来改善这种治疗的结果和延长治疗时间，确定最佳候选者，并指明需要进行这种治疗的情况。
