Pappworth Isabel Y, Kulik Liudmila, Haluszczak Catherine, Reuter Jason W, Holers V Michael, Marchbank Kevin J
Institute of Human Genetics, Newcastle University, Central Parkway, Center for Life, Newcastle-upon-Tyne NE1 3BZ, UK.
Mol Immunol. 2009 Mar;46(6):1042-9. doi: 10.1016/j.molimm.2008.08.273. Epub 2009 Feb 1.
The involvement of complement receptor 2 (CR2) in B cell tolerance and autoimmune disease has been revealed over the past decade or so. Our previous studies have established that mice prematurely expressing human CR2 under the control of a lambda light chain promoter (in particular the hCR2(high) line) have a marked deficit in their immune response to various antigens and fail to develop collagen-induced arthritis. This phenotype appears to be the result of irreversible changes in B cell signalling pathways and suggested that hCR2 expressing mice are protected from developing autoimmune disease. To test this hypothesis, we examined the ability of the hCR2 to block the development of spontaneous autoimmune disease on the C57BL/6j-Fas(lpr/)Fas(lpr) (B6(lpr)) background. We found that expression of hCR2 on the B6(lpr) background resulted in a significant reduction in levels of anti-nuclear antibodies (ANA) generated as mice aged but the levels of ANA were still higher than those found in age matched C57BL/6j (B6) mice. B cells from hCR2(high) mice were found to display a higher baseline level of apoptosis, whether analysed ex vivo or after in vitro culture, than their B6 counterparts and this was apparently linked to both surface IgM expression by the B cells and C3 levels in the mice. Our data also provides evidence that B cell survival in the presence of hCR2 is heavily modified by the background strain of the mouse. Overall, we have demonstrated that mice expressing hCR2 on their B cells during bone marrow development display a higher degree of apoptosis which may lead to a deletion of autoreactive B cells and be protective against the development of autoimmune disease.
在过去十年左右的时间里，补体受体2（CR2）在B细胞耐受性和自身免疫性疾病中的作用已被揭示。我们之前的研究表明，在λ轻链启动子控制下过早表达人CR2的小鼠（特别是hCR2（高表达）品系）对各种抗原的免疫反应明显不足，且不会发生胶原诱导的关节炎。这种表型似乎是B细胞信号通路不可逆变化的结果，表明表达hCR2的小鼠受到保护，不会发生自身免疫性疾病。为了验证这一假设，我们研究了hCR2阻断C57BL/6j-Fas(lpr/)Fas(lpr)（B6(lpr)）背景下自发性自身免疫性疾病发展的能力。我们发现，在B6(lpr)背景下表达hCR2会导致随着小鼠年龄增长产生的抗核抗体（ANA）水平显著降低，但ANA水平仍高于年龄匹配的C57BL/6j（B6）小鼠。无论是体外分析还是体外培养后分析，发现hCR2（高表达）小鼠的B细胞比其B6对应物表现出更高的基线凋亡水平，这显然与B细胞表面IgM表达和小鼠体内C3水平有关。我们的数据还提供了证据，表明在存在hCR2的情况下，B细胞的存活受到小鼠背景品系的严重影响。总体而言，我们已经证明，在骨髓发育过程中B细胞表达hCR2的小鼠表现出更高程度的凋亡，这可能导致自身反应性B细胞的缺失，并对自身免疫性疾病的发展具有保护作用。
