Quantitative genetic variation in CD19 expression correlates with autoimmunity
Quantitative genetic variation in CD19 expression correlates with autoimmunity
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DOI：
10.4049/jimmunol.165.11.6635
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发表时间：
2000-12-01
影响因子：
4.4
通讯作者：
Takehara, K
中科院分区：
文献类型：
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作者：
Sato, S;Hasegawa, M;Takehara, K
信号传导阈值影响体液免疫和自身免疫之间的平衡。细胞表面CD 19调节内在和Ag受体诱导的B淋巴细胞信号传导阈值，并且过表达CD 19 3倍的转基因小鼠在与自身免疫无关的遗传背景中产生自发性自身抗体。为了量化单个细胞表面分子表达的遗传决定差异可以影响自身抗体产生的程度，我们评估了CD 19细胞表面表达轻微增加15-29%的C57 BL/6转基因小鼠系（CD 19转基因）的自身免疫性。在这些转基因小鼠中产生抗核抗体，特别是抗纺锤体极抗体，类风湿因子和ssDNA，dsDNA和组蛋白的自身抗体，但不是同窝对照。这表明CD 19表达的微小变化可诱导自身抗体产生。值得注意的是，在系统性硬化症（一种产生自身抗体的结缔组织多系统疾病）患者的B细胞上发现了CD 19表达的类似变化。系统性硬化症患者血B细胞上的CD 19密度显著高于正常人（接近20%），而CD 20、CD 22和CD 40表达正常。这些结果表明，调节分子如CD 19的表达或功能的适度变化可能会改变耐受性和免疫性之间的平衡，使其变为自身免疫性。因此，自身免疫性疾病可能是由一系列微妙的多基因改变引起的，这些改变可能包括细胞表面信号分子的密度变化。
Signaling thresholds influence the balance between humoral immunity and autoimmunity. Cell surface CD19 regulates intrinsic and Ag receptor-induced B lymphocyte signaling thresholds, and transgenic mice that overexpress CD19 by 3-fold generate spontaneous autoantibodies in a genetic background not associated with autoimmunity. To quantify the extent that genetically determined differences in expression of a single cell surface molecule can influence autoantibody production, we have assessed autoimmunity in a C57BL/6-transgenic mouse line with subtle 15-29% increases in CD19 cell surface expression (CD19 transgenic). Antinuclear Abs, especially anti-spindle pole Abs, rheumatoid factor, and autoantibodies for ssDNA, dsDNA, and histone were produced in these transgenic mice, but not littermate controls. This demonstrates that small changes in CD19 expression can induce autoantibody production. Remarkably, similar changes in CD19 expression were found on B cells from patients,vith systemic sclerosis, a multisystem disorder of connective tissue with autoantibody production. CD19 density on blood B cells from systemic sclerosis patients was significantly (similar to 20%) higher compared with normal individuals, whereas CD20, CD22, and CD40 expression were normal, These results suggest that modest changes in the expression or function of regulatory molecules such as CD19 may shift the balance between tolerance and immunity to autoimmunity. Thereby autoimmune disease may result from a collection of subtle multigenic alterations that could include incremental density changes in cell surface signaling molecules.