Rheumatoid arthritis (RA) represents a disease where we have recently acquired new knowledge on etiology and molecular pathogenesis, by combining data from studies on genetic end environmental determinants of disease with molecular and cellular immunology. This combined approach has provided insights into the heterogeneous nature of the clinical syndrome we call RA, and the subdivisions into different functional disease subsets now permit a better use of molecular immunology in contexts where genotypes and environmental triggers are defined. In this chapter, we discuss a series of different autoimmunities described in RA, with an initial emphasis on immunity to autoantigens that have been posttranslationally modified by citrullination. We then discuss a series of unresolved issues and challenges related both to the citrulline immunity and to other immune events in RA. Our perspective is that current studies on genes, environment, and immunity in this disease provides us with a great outlook to investigate interesting general aspects of autoimmunity and development of human autoimmune disease--in addition to the opportunity to better understand, prevent, and ultimately treat RA.
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