ARTHRITOGENIC IGS--WHAT ARE THEY? WHY ARE THEY MADE?

类风湿性关节炎是一种常见的自身免疫性疾病，其病因和发病机制尚不清楚。类风湿性关节炎的小动物模型为剖析疾病机制提供了一种手段。最近描述了一种自发发展为具有人类类风湿性关节炎特征的关节紊乱的小鼠模型。K/BxN小鼠的疾病是关节特有的，但由全身T淋巴细胞自身反应引起，导致普遍的T细胞刺激和广泛的B细胞激活；T和B细胞都是必需的。B细胞的关键作用是产生关节炎免疫球蛋白：来自K/BxN小鼠的少量血清可以在几天内引发健康受者的关节炎，即使那些缺乏淋巴细胞的受者也是如此；血清活性存在于免疫球蛋白部分，既不是类风湿因子，也不是抗胶原抗体。这里提出的实验的两个主要目标是确定KBxN小鼠产生的关节炎IGs的靶点(S)，并确定在众多潜在的自身反应性IGs中，哪些因素导致它们的选择性产生。更具体地说，我们建议：(I)基于产生促进关节炎的单抗、组织蛋白的生化纯化或原核表达文库的筛选，鉴定致关节炎IGs识别的自身抗原(S)。(Ii)阐明导致关节炎的免疫球蛋白选择性分泌的因素，重点是该模型的压倒性T细胞刺激特性如何影响具有不同抗原特异性的B细胞的命运和活性。通过将KBxN菌株与各种现有的Ig或Ig/Ag转基因或敲入系杂交，将识别自我和非自身AGS的B细胞进行比较，并通过KBxN株与各种现有的Ig或Ig/Ag转基因或敲入系杂交，在不同位置、不同形式或不同浓度下看到它们的AGS。(Iii)通过设计适当的Ig基因敲入，并监测其B细胞在正常情况下和在KBxN小鼠中的行为，确定如何维持和打破表达关节特异性的B细胞的耐受性。我们预计，这些研究将为K/BxN模型中关节炎的发病机制提供重要线索，并有望通过外推，在人类患者中提供。

Rheumatoid arthritis is a common and debilitating autoimmune disease whose etiology and pathogenesis remain unknown. Small animal models of RA provide a means to dissect disease mechanisms. A mouse model that spontaneously develops a joint disorder with most of the characteristics of RA in humans was recently described. Disease in K/BxN mice is joint-specific, but is provoked by systemic T lymphocyte self-reactivity, resulting in pervasive T cell stimulation and broad B cell activation; both T and B cells are required. The critical role of B cells is to produce arthritogenic immunoglobulins: small amounts of serum from K/BxN mice can precipitate arthritis within days in healthy recipients, even those lacking lymphocytes; the serum activity resides in the IgG fraction and is neither rheumatoid factor nor anti-collagen antibodies. The two major goals of the experiments proposed here are to define the target(s) of the arthritogenic Igs generated in KBxN mice, and to determine what factors are responsible for their selective production, amongst the multitude of potentially autoreactive Igs. More specifically, we propose to: (i) Identify the self-antigen(s) recognized by the arthritogenic Igs following three strategies - based on production of arthritis-promoting monoclonal antibodies, biochemical purification of tissue proteins, or screening of prokaryotic cDNA expression libraries. (ii) Elucidate the factors dictating selective secretion of the arthritogenic Igs, focussing on how the overwhelming T cell stimulation characteristic of this model, with its potential for universal non-cognate "help" for B cells, influences the fate and activity of B cells with various Ag specificities. Comparisons will be made between B cells that recognize self versus non-self Ags, and that see their Ags at different sites, in different forms or at different concentrations by crossing the KBxN strain with various already existing Ig or Ig/Ag transgenic or knock-in lines. (iii) Determinate how tolerance of B cells expressing an arthritogenic specificity is maintained and broken by engineering the appropriate Ig gene knock-ins, and monitoring the behavior of their B cells in the normal context and in KBxN mice. We anticipate that these studies will provide important clues to the pathogenesis of arthritis in the K/BxN model and, hopefully, by extrapolation, in human patients.