Vallat Laurent, Benhamou Yves, Gutierrez Maya, Ghillani Pascale, Hercher Christel, Thibault Vincent, Charlotte Frédéric, Piette Jean-Charles, Poynard Thierry, Merle-Béral Hélène, Davi Frédéric, Cacoub Patrice
Department of Hematology, Assistance Publique Hopitaux, Hôpital La Pitié-Salpêtrière, 83 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France.
Arthritis Rheum. 2004 Nov;50(11):3668-78. doi: 10.1002/art.20594.
The association of hepatitis C virus (HCV) infection with type II mixed cryoglobulinemia is well established, but the role of HCV in B cell lymphoma remains controversial. The objective of this study was to determine the frequency of circulating and liver-infiltrating monoclonal B cells in patients with HCV infection.
One hundred sixty patients were studied prospectively, including 115 HCV-positive patients and 45 HCV-negative patients with other nonimmune chronic liver disease(s). B cell clonality was determined by DNA amplification of the IgH rearrangements, followed by polyacrylamide gel electrophoresis.
A clonal B cell population was detected in the blood of 21 (26%) of 81 HCV-positive patients whose cryoglobulin status was known, including 12 of 25 patients with type II cryoglobulinemia, 2 of 12 patients with type III cryoglobulinemia, and 7 of 44 patients without cryoglobulins. A clonal IgH rearrangement was detected in 26 (32%) of 81 liver biopsy specimens from HCV- infected patients, including 16 patients with a circulating clonal population. A clonal B cell population was not observed in the blood of 40 patients with non-HCV liver diseases and was present in only 1 (3%) of 30 liver biopsy specimens. Logistic regression analysis showed that HCV-infected patients with clonal B cell proliferation in both the blood and liver were older (P = 0.004) and had longer duration of HCV infection (P = 0.009), higher serum cryoglobulin levels (P = 0.001) that were more frequently symptomatic (P < 0.03), and liver disease that was more severe than that in patients without a clonal B cell population in the blood or liver (P = 0.05). In 4 of 16 patients with a clonal B cell population in both the blood and liver, a definite B cell malignancy was finally diagnosed.
Clonal B lymphocytes are frequently detected in the blood and liver of patients with chronic HCV infection, in the absence of overt B cell malignancy. These clones are usually, but not always, associated with the presence of type II cryoglobulins. A high percentage of patients with B cell clonality in both the blood and liver were finally diagnosed as having a definite B cell malignancy.
丙型肝炎病毒（HCV）感染与II型混合性冷球蛋白血症之间的关联已得到充分证实，但HCV在B细胞淋巴瘤中的作用仍存在争议。本研究的目的是确定HCV感染患者循环和肝脏浸润性单克隆B细胞的频率。
前瞻性研究了160例患者，包括115例HCV阳性患者和45例患有其他非免疫性慢性肝病的HCV阴性患者。通过对免疫球蛋白重链（IgH）重排进行DNA扩增，随后进行聚丙烯酰胺凝胶电泳来确定B细胞克隆性。
在81例已知冷球蛋白状态的HCV阳性患者的血液中检测到克隆性B细胞群体，其中21例（26%），包括25例II型冷球蛋白血症患者中的12例、12例III型冷球蛋白血症患者中的2例以及44例无冷球蛋白患者中的7例。在81例HCV感染患者的肝活检标本中，26例（32%）检测到克隆性IgH重排，其中16例患者血液中有克隆性细胞群体。在40例非HCV肝病患者的血液中未观察到克隆性B细胞群体，30例肝活检标本中仅1例（3%）存在克隆性B细胞群体。逻辑回归分析显示，血液和肝脏中均有克隆性B细胞增殖的HCV感染患者年龄较大（P = 0.004）、HCV感染持续时间较长（P = 0.009）、血清冷球蛋白水平较高（P = 0.001），且更常出现症状（P < 0.03），其肝病比血液或肝脏中无克隆性B细胞群体的患者更严重（P = 0.05）。在血液和肝脏中均有克隆性B细胞群体的16例患者中，最终有4例被确诊为明确的B细胞恶性肿瘤。
在慢性HCV感染患者的血液和肝脏中经常检测到克隆性B淋巴细胞，且无明显的B细胞恶性肿瘤。这些克隆通常但并非总是与II型冷球蛋白的存在相关。血液和肝脏中均有B细胞克隆性的患者中有很大比例最终被诊断为明确的B细胞恶性肿瘤。
