Douglas R S, Woo E Y, Capocasale R J, Tarshis A D, Nowell P C, Moore J S
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6082, USA.
Cell Immunol. 1997 Aug 1;179(2):126-37. doi: 10.1006/cimm.1997.1149.
New Zealand Black (NZB) mice spontaneously develop immune dysfunction manifested as autoimmune hemolytic anemia and systemic lupus erythematosus. In later life, a subset of these mice develop clonal CD5+ B cell tumors analogous to human chronic lymphocytic leukemia (CLL). NZB disease is marked by B cell hyperactivity characterized by spontaneous immunoglobulin secretion and proliferation. Elimination of autoreactive lymphocytes by apoptosis is a vital mechanism to prevent expansion of self-reactive lymphocyte population. TGF-beta appears to be an important factor in normal and abnormal immune regulation and this cytokine may play a role in the development of chronic human B cell tumors. We asked whether the response to or production of TGF-beta by NZB B cells was aberrant and could contribute to disease development. In this study, we demonstrated that the apoptotic response to TGF-beta was increased in B cells from NZB mice compared to B cells from normal BALB/c mice. The increased apoptosis was related to endogenous activation and was possibly mediated through increased expression of the TGF-beta Type II receptor. Despite functional differences between CD5-negative B cells and CD5-positive B cells, TGF-beta induced apoptosis in both populations to a similar extent. NZB B cells also secrete increased active TGF-beta compared to BALB/c B cells. We suggest that the aberrant secretion of active TGF-beta and the increased response to the apoptotic effects of TGF-beta by NZB B cells may play a role in the disease process of these mice, perhaps attempting to limit the autoimmune phenomena, but possibly also contributing to generalized immunosuppression. We also suggest that the CD5(+) tumors in the NZB mouse may not be a fully appropriate model of human CLL, since CLL B cells are abnormally resistant to the apoptotic effects of TGF-beta.
新西兰黑鼠（NZB）会自发出现免疫功能障碍，表现为自身免疫性溶血性贫血和系统性红斑狼疮。在其后期生活中，这些小鼠的一部分会发展出类似于人类慢性淋巴细胞白血病（CLL）的克隆性CD5 + B细胞肿瘤。NZB疾病的特征是B细胞过度活跃，表现为自发的免疫球蛋白分泌和增殖。通过凋亡消除自身反应性淋巴细胞是防止自身反应性淋巴细胞群体扩增的重要机制。转化生长因子-β（TGF-β）似乎是正常和异常免疫调节中的一个重要因素，这种细胞因子可能在人类慢性B细胞肿瘤的发展中起作用。我们研究了NZB B细胞对TGF-β的反应或产生是否异常，以及是否会促进疾病发展。在本研究中，我们证明，与正常BALB / c小鼠的B细胞相比，NZB小鼠的B细胞对TGF-β的凋亡反应增强。凋亡增加与内源性激活有关，可能是通过TGF-β II型受体表达增加介导的。尽管CD5阴性B细胞和CD5阳性B细胞之间存在功能差异，但TGF-β在两个群体中诱导凋亡的程度相似。与BALB / c B细胞相比，NZB B细胞还分泌更多的活性TGF-β。我们认为，NZB B细胞活性TGF-β的异常分泌以及对TGF-β凋亡作用的反应增强可能在这些小鼠的疾病过程中起作用，也许试图限制自身免疫现象，但也可能导致全身性免疫抑制。我们还认为，NZB小鼠中的CD5（+）肿瘤可能不是人类CLL的完全合适模型，因为CLL B细胞对TGF-β的凋亡作用异常抵抗。
