Autoimmune diseases are controlled by multiple genetic loci and usually modified by a multitude of unknown environmental factors. Insulin-dependent diabetes mellitus (IDDM), also called type 1 diabetes, is one example, others being multiple sclerosis (MS), myasthenia gravis (MG), rheumatoid arthritis (RA), systemiclupuserythematosus(SLE), andSjogrensyndrome(SS). Insys-temic autoimmunity such as SLE and MG, antibodies normally cause the main damage, with a role for T cells being less clear. In contrast, in organ-specific autoimmune diseases such as IDDM, MS, SS, and RA, organ-infiltrating T cells are believed to be of central importance.
Autoimmunity results from breakdown of immunological tolerance. Both faulty central and peripheral tolerance mechanisms have been implicated, in both cases resulting in escape of autoreactive T cells from normal control. The relative roles of insufficient central versus peripheral tolerance mechanisms in autoimmunity are unclear. Defects in central tolerance, for example, as demonstrated by mutations in the AIRE gene, lead to organ infiltration and functional impairments of organ function (Anderson et al. 2002; Ramsey et al. 2002). Conversely, exaggerated thymic deletion may also result in autoimmunity due to a disrupted balance between thymus-derived regulatory (CD4+CD25+) and nonregulatory T cells (Hori et al. 2003). Examples of other T cells with regulatory properties are NKT cells (Mars et al. 2004) and CD8+CD122+ T cells that may also play protective roles in autoimmune conditions (Rifa'i et al. 2004).
Additional players are also important in the induction and subsequent control of immune responses in the periphery. For example, naive T cells must encounter antigen presented as peptides by MHC molecules on specialized antigen-presenting cells (APC) in order to become activated. This occurs in secondary lymphoid organs such as the spleen and lymph nodes. Dendritic cells (DC) are critical players in this game. After activation, both MHC and costimulatory molecules are upregulated on DC and their stimulatory capacity thereby increases. Soluble factors present at the site of T cell activation also dictate the nature of the immune response and determines whether it should be of a Th1 or Th2 type (Dong and Flavell 2001). Many organ-specific autoimmune diseases are dominated by IFN-y, classifying them as Thl-dominated diseases (Trembleau et al. 1995).
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