Ota Miyo, Duong Bao H, Torkamani Ali, Doyle Colleen M, Gavin Amanda L, Ota Takayuki, Nemazee David
Department of Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA.
J Immunol. 2010 Oct 1;185(7):4128-36. doi: 10.4049/jimmunol.1002176. Epub 2010 Sep 3.
The TNF-family cytokine BAFF (BLyS) promotes B lymphocyte survival and is overexpressed in individuals with systemic lupus erythematosus and Sjögren's Syndrome. BAFF can rescue anergic autoreactive B cells from death, but only when competition from nonautoreactive B cells is lacking. Yet, high BAFF levels promote autoantibody formation in individuals possessing diverse B cells. To better understand how excess BAFF promotes autoimmunity in a polyclonal immune system, Ig L chain usage was analyzed in 3H9 site-directed IgH chain transgenic mice, whose B cells recognize DNA and chromatin when they express certain endogenous L chains. BAFF levels were manipulated in 3H9 mice by introducing transgenes expressing either BAFF or its natural inhibitor ΔBAFF. B cells in BAFF/3H9 mice were elevated in number, used a broad L chain repertoire, including L chains generating high-affinity autoreactivity, and produced abundant autoantibodies. Comparison of spleen and lymph node B cells suggested that highly autoreactive B cells were expanded. By contrast, ΔBAFF/3H9 mice had reduced B cell numbers with a repertoire similar to that of 3H9 mice, but lacking usage of a subset of Vκ genes. The results show that limiting BAFF signaling only slightly selects against higher affinity autoreactive B cells, whereas its overexpression leads to broad tolerance escape and positive selection of autoreactive cells. The results have positive implications for the clinical use of BAFF-depleting therapy.
肿瘤坏死因子家族细胞因子BAFF（B淋巴细胞刺激因子）可促进B淋巴细胞存活，在系统性红斑狼疮和干燥综合征患者中过度表达。BAFF可挽救无反应性自身反应性B细胞免于死亡，但前提是缺乏来自非自身反应性B细胞的竞争。然而，高BAFF水平会促进拥有多种B细胞的个体中自身抗体的形成。为了更好地理解过量的BAFF如何在多克隆免疫系统中促进自身免疫，我们在3H9位点定向IgH链转基因小鼠中分析了Ig轻链的使用情况，这些小鼠的B细胞在表达某些内源性轻链时可识别DNA和染色质。通过导入表达BAFF或其天然抑制剂ΔBAFF的转基因来调控3H9小鼠中的BAFF水平。BAFF/3H9小鼠中的B细胞数量增加，使用广泛的轻链库，包括产生高亲和力自身反应性的轻链，并产生大量自身抗体。脾脏和淋巴结B细胞的比较表明，高度自身反应性的B细胞有所扩增。相比之下，ΔBAFF/3H9小鼠的B细胞数量减少，其轻链库与3H9小鼠相似，但缺乏一部分Vκ基因的使用。结果表明，限制BAFF信号传导只会略微筛选出亲和力较高的自身反应性B细胞，而其过度表达会导致广泛的耐受性逃逸和自身反应性细胞的阳性选择。这些结果对BAFF消耗疗法的临床应用具有积极意义。
