■ AbstractThe metabolic syndrome is a combination of metabolic disorders, such as dyslipidemia, hypertension, impaired glucose tolerance, compensatory hyperinsulinemia and the tendency to develop fat around the abdomen. Individuals with the metabolic syndrome are at high risk for atherosclerosis and, consequently, cardiovascular disease. However, as a result of several epidemiologic studies and some clinical trials, it has been suggested that people with the metabolic syndrome may benefit from intensive lifestyle modifications including dietary changes and adopting a physically more active lifestyle. In this review we summarize the effects of diet and physical activity on the development of the metabolic syndrome.

■ AbstractT cell apoptosis is a process necessary for central and peripheral tolerance. It ensures the proper removal of autoreactive T cells during thymic development as well as T cell homeostasis and the downregulation of immune responses against antigens in the periphery. Thus it is essential for the prevention of autoimmunity. Apoptotic pathways can be triggered by intrinsic (mitochondria-based) and extrinsic (receptor-based) stimuli. Both pathways involve a cascade of proteolytic enzymes called caspases whose activation commits the cell to death. In the periphery, autoreactive lymphocytes can be silenced by developmental arrest (anergy), or deleted by programmed cell death (apoptosis) through receptor-based activation-induced cell death (AICD). Central tolerance seems to rely more heavily on the mitochondria-based, T cell receptor (TCR)-stimulated apoptotic pathway, since thymocytes lacking the pro-apoptotic Bcl-2 family member Bim are resistant to TCR-induced apoptosis. Furthermore, defects in the intrinsic pathway of apoptosis may impair clonal deletion of autoreactive T cells. Several animal models exist in which impaired apoptosis results in autoimmunity. Here, we discuss data that suggest defects in T cell apoptosis in type 1 diabetes mellitus.

■ AbstractThe onset and development of type 1 diabetes (T1D) occurs in genetically predisposed individuals, and is attributed to autoimmune destruction of pancreatic β-cells involving a multitude of immune mechanisms. Defects in immune regulation may play a central role in T1D, involving impaired function and communication of both myeloid and lymphoid cells of the innate and adaptive immune compartments. Dendritic cells and regulatory T (Treg) cells are part of this network, which seem to be hampered in their quest to control and regulate tissue-destructive autoimmunity. Recent studies have shown that in vivo activated CD16 -blood monocytes exhibiting proinflammatory features are present in diabetic subjects. These monocytes may govern T cellmediated immune responses towards the development of tissue-destructive Th1 and Th17 subtypes, and give rise to inflammatory macrophages in tissues. Differential effects of cytokines IFN-γ and IL-4 in the development of inflammatory macrophages, and the distinct developmental pathways of proinflammatory or tissue-repair-associated monocytes suggest that controlling the activity of these monocytes could be part of an immune intervention strategy to prevent T1D. Similarly, strategies to target autoantigens to immature, steady-state dendritic cells could guide the immune response away from Th1 and Th17 immune effectors. This review examines potential approaches to this goal by manipulation of myeloid and lymphoid cell regulatory networks in T1D.

■ AbstractThe use of DNA-based genetic typing has enabled the identification of type 1 diabetes mellitus (T1DM) susceptible and protective major histocompatibility complex (MHC) class II alleles and haplotypes. The application of this approach has also progressed to locate MHC class I alleles that contribute to the clinicopathology of T1DM. Recent studies have shown a widespread involvement of genes from the MHC class I gene region in the clinicopathology of T1DM. These genes are demonstrated to be involved in contributing to progression from the preclinical stage of the disease, which is characterized by the occurrence of islet-specific antibodies, to clinical disease and also to the occurrence of autoimmunity. They can either contribute directly to disease development or indirectly in concert with other susceptible MHC class II alleles or haplotypes via linkage disequilibrium. Class I alleles may also be negatively associated with T1DM. These findings are useful for the development of future strategies in designing tolerogenic approaches for the prevention or even reversal of T1DM. In this article, the latest evidence for the different kinds of participation of HLA class I genes in the etiology of T1DM is reviewed. A metaanalysis which included existing association studies was also carried out in order to re-assess the relevance of class I genes in diabetes development. The analysis of an enlarged heterogeneous sample confirmed the involvement of previously detected serotypes in the etiology of T1DM, such as A24, B8 and B18, and revealed hitherto unknown associations with B60 and B62. The analysis points out that much of the conflicting results of previous association studies originate from inadequate sample sizes and accentuate the value of future investigations of larger samples for identifying linkage in multigenic diseases.Keywords: type 1 diabetes · HLA class I · cross-study analysis · serotype association Introduction ype 1 diabetes mellitus (T1DM) is a multifactorial and multigenic autoimmune organ disease characterized by progressive T cell-mediated destruction of the pancreatic β-cells . The major determinants of this disease are genes of the human leucocyte antigen (HLA) region, which are highly polymorphic. In a multiplicative model, they account for between 20 and 53% of T1DM susceptibility markers [1]. Gene products of HLA class I genes function as antigen presenting molecules for CD8 + cytotoxic T lymphocytes (CTL) and determine the antigen specificity of the CTL-mediated immune response against pathogens and self-antigens. T cell reactions with islet-specific self-antigens may lead to clonal proliferation of autoreactive CTLs directed against pancreatic β-cells provoking destruction of these organ cells.Initial genetic analyses clearly rejected a dominant major locus. In contrast, a series of other genes, such as the coding sequences for TAP (transporters associated with antigen processing), LMP (large multifunc- Copyright © by the SBDR tional proteases) and TNF-α, the MIC-A (MHC class I chain-r...

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