Using three reference disease models--insulin-dependent diabetes mellitus (IDDM) as a prototype of T-cell mediated organ-specific autoimmune disease, myasthenia gravis (MG) as a prototype of autoantibody-mediated organ-specific autoimmune disease and systemic lupus erythematosus (SLE) as a prototype of non-organ-specific autoimmune disease--we have reached several conclusions: 1) All three diseases are associated with the presence of multiple autoantibodies and/or autoreactive T cells that recognize a large number of antigenic molecules. The apparent predominant role of certain antibodies in some diseases could relate to their functional properties such as acetylcholine receptor (AChR) blockade for anti-AChR autoantibodies in MG or anti-dsDNA in SLE. 2) Major target antigens are clustered in the target cell affected by organ-specific autoimmune diseases: beta cells in IDDM, striated-muscle cells in MG, or apoptotic cells in the case of SLE. 3) Antibodies and T cells recognize multiple epitopes in these molecules. 4) The most evident explanation for the observed clustering and diversity is autoantigen spreading. Spreading probably involves T cells secreting proinflammatory cytokines but also possibly antibodies as in the case of nucleosome autoantibodies in SLE. 5) The counterpart of antigen spreading is bystander suppression in which regulatory cytokines deviate the immune response towards a protective response. 6) The mechanisms underlying the initiation of the autoimmune response and antigen spreading are still undetermined. They could imply a direct abnormality of the target cell in the case of organ-specific autoimmune diseases (e.g. infection with a virus showing a selective tropism for the target cell in organ-specific autoimmune diseases, or loss of physiological regulation of major histocompatibility complex molecule expression) or could be consequence of a ubiquitous cell abnormality such as increased apoptosis in SLE. The respective roles of genetic and environmental factors in these triggering events remain to be determined.

Major histocompatibility complex class I (MHC I) molecules are glycoproteins that display peptide epitopes at the cell surface of nucleated cells for recognition by CD8+ T cells. Like other cell surface receptors, MHC class I molecules are continuously removed from the surface followed by intracellular degradation or recycling to the cell surface, in a process likely involving active quality control the mechanism of which remains unknown. The molecular players and pathways involved in internalization and recycling have previously been studied in model cell lines such as HeLa. However, dendritic cells (DCs), which rely on a specialized endocytic machinery that confers them the unique ability to “cross”-present antigens acquired by internalization, may use distinct MHC I recycling pathways and quality control mechanisms. By providing MHC I molecules cross-presenting antigens, these pathways may play an important role in one of the key functions of DCs, priming of T cell responses against pathogens and tumors. In this review, we will focus on endocytic recycling of MHC I molecules in various experimental conditions and cell types. We discuss the organization of the recycling pathway in model cell lines compared to DCs, highlighting the differences in the recycling rates and pathways of MHC I molecules between various cell types, and their putative functional consequences. Reviewing the literature, we find that conclusive evidence for significant recycling of MHC I molecules in primary DCs has yet to be demonstrated. We conclude that endocytic trafficking of MHC class I in DCs remains poorly understood and should be further studied because of its likely role in antigen cross-presentation.