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

点击翻译按钮获取中文摘要

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.