Ferri S, Dal Pero F, Bortoletto G, Bianchi F B, Lenzi M, Alberti A, Gerotto M
Venetian Institute of Molecular Medicine (VIMM), Padova, Italy.
J Viral Hepat. 2006 Mar;13(3):166-76. doi: 10.1111/j.1365-2893.2005.00675.x.
Hepatitis C virus (HCV) plays a major role in the induction of type II mixed cryoglobulinaemia (MCII). The role of HCV proteins and virus-host interaction in the pathogenesis of MC remains to be defined. To address this issue, we have characterized, in detail, the monoclonal IgM and the viral component of circulating immune complexes in eight patients with HCV-associated MCII. The proportion of HCV-RNA compartmentalized in the cryoprecipitate (CP) varied greatly (10-80% of total HCV-RNA). The complementary determining region (CDR)3 sequences of monoclonal immunoglobulin M (IgM) VH and VK genes were highly homologous to rheumatoid factor and to antibodies against HCV-E2. Furthermore, the CDR3 sequences in some of our MCII patients were highly similar to those described in HCV-positive patients with non-Hodgkin's lymphoma (NHL). From these results, it appears that, as in the case of NHL, the IgM-rheumatoid factor (RF) production in MCII patients is antigen driven, namely by E2. However, the limited number of mutations in VH and VK genes with respect to the germline and their distribution showed that the B-cell response in these cases was prevented from undergoing affinity maturation. Furthermore, in patients with monoclonal IgM and definite compartmentalization of HCV in either CP or supernatant, a highly homogeneous E2-hypervariable region (HVR)1 sequence distribution was found (90-100% identical clones), a feature of the quasispecies frequently associated with an impaired humoral immune response to HCV. These findings suggest that in patients with HCV-associated MCII, maturation of monoclonal B lymphocytes may be blocked in a primitive stage preventing serious damaging effects because of the auto-reactivity of their secreted immunoglobulins.
丙型肝炎病毒（HCV）在II型混合性冷球蛋白血症（MCII）的诱发中起主要作用。HCV蛋白和病毒-宿主相互作用在MC发病机制中的作用仍有待确定。为解决这一问题，我们详细分析了8例HCV相关MCII患者循环免疫复合物中的单克隆IgM和病毒成分。冷沉淀物（CP）中HCV-RNA的比例差异很大（占总HCV-RNA的10-80%）。单克隆免疫球蛋白M（IgM）VH和VK基因的互补决定区（CDR）3序列与类风湿因子及抗HCV-E2抗体高度同源。此外，我们部分MCII患者的CDR3序列与HCV阳性非霍奇金淋巴瘤（NHL）患者中描述的序列高度相似。从这些结果来看，似乎与NHL情况一样，MCII患者中IgM类风湿因子（RF）的产生是抗原驱动的，即由E2驱动。然而，VH和VK基因相对于种系的有限突变数量及其分布表明，这些病例中的B细胞反应无法进行亲和力成熟。此外，在单克隆IgM且HCV在CP或上清液中有明确分隔的患者中，发现了高度均匀的E2高变区（HVR）1序列分布（90-100%相同克隆），这是准种的一个特征，常与对HCV的体液免疫反应受损相关。这些发现表明，在HCV相关MCII患者中，单克隆B淋巴细胞的成熟可能在原始阶段受阻，由于其分泌的免疫球蛋白的自身反应性，从而防止了严重的损害作用。
