Outlook Perspectives

Although the structure of Ro/SSA autoantigens and the antigenic targets (epitopes) for anti-Ro/SSA autoantibodies have been characterized in detail, two important challenges should be addressed in future research: (a) the function of the RoRNP particle is still unknown and (b) the molecular causes and mechanisms leading to systemic autoimmune responses against RoRNPs remain to be identified.

Since autoantibodies cannot penetrate into the cells, the central question is: How is an immune response against intracellular, nuclear proteins generated? Processing and presentation of antigens represents the prerequisite for every antigen-driven (auto)immune response. To date, little information exists on how nuclear autoanti-

gens are processed and where this processing takes place in the cell, in situ. Recent evidence suggests that nuclear autoantigens are subjected to proteasomal proteolysis (Desai et al. 1997, Everett et al. 1999) within the nucleus (Chen et al. 2002, Rockel and von Mikecz 2002). Since proteasomes constitute a major proteolytic system that delivers peptides to antigen presentation, these new findings are the basis for the following hypothesis on the generation of systemic autoimmune responses: alteration of nuclear structure and function may result in recruitment of autoantigens to antigen-processing proteases, for example, the proteasome system. Previously cryptic nuclear proteins may be efficiently processed into peptides and subjected to antigen presentation. Thus, new antigenic peptides might appear on the surface of antigen-presenting cells, which are mistakenly interpreted as "non self" or foreign by T lymphocytes, and an autoimmune response is initiated against components of the body's own cells.

Sensitivity to sun is a cardinal feature of SLE, and UV light may be involved in its pathogenesis (Chen et al. 2000). In this respect, it is intriguing that the presence of anti-Ro/SSA antibodies in patients suffering from rheumatic disease is highly correlated with photosensitive dermatitis (von Muhlen and Tan 1995). According to the above-mentioned hypothesis, UV irradiation might induce recruitment of Ro/SSA to proteasomal proteolysis. Thus, future investigations on processing and presentation of RoRNPs and their intracellular trafficking may permit more insight into the molecular mechanisms that cause the generation of autoimmune responses and the production of anti-Ro/SSA antibodies.

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