Pancreatic islet autoimmunity.

Type 1 diabetes (T1D) represents 10 to 15% of all forms of diabetes. Its incidence shows a consistent rise in all countries under survey. Evidence for autoimmunity in human T1D relies on the detection of insulitis, of islet cell antibodies, of activated β-cell-specific T lymphocytes and on the association of T1D with a restricted set of class II major histocompatibility complex (MHC) alleles. However, mechanisms that initiate the failure of immune tolerance to β-cell autoantigens remain elusive in common forms of T1D. T1D commonly develop as a multifactorial disease in which environmental factors concur with a highly multigenic background. The disease is driven by the activation of T-lymphocytes against pancreatic β-cells. Several years elapse between initial triggering of the autoimmune response to β cells, as evidenced by the appearance or islet cell autoantibodies, and the onset of clinical diabetes, defining a prediabetes stage. Active mechanisms hold back autoreactive effector T-cells in prediabetes, in particular a subset of CD4+ T-cells (T(reg)) and other regulatory T-cells, such as invariant NKT cells. There is evidence in experimental models that systemic or local infections can trigger autoimmune reactions to β-cells. However, epidemiological observations that have accumulated over years have failed to identify undisputable environmental factors that trigger T1D. Moreover, multiple environmental factors may intervene in the disease evolution and protective as weel as triggering environmental factors may be involved. Available models also indicate that local signals within the islets are required for full-blown diabetes to develop. Many autoantigens that are expressed by β-cells but also by the other endocrine islet cells and by neurons are recognized by lymphocytes along the development of T1D. The immune image of β-cells is that of native components of the β-cell membrane, as seen by B-lymphocytes, and of fragments of intracellular β-cell proteins in the form of peptides loaded onto class I MHC molecules on the β-cell surface and class I and class II molecules onto professional antigen presenting cells. Given the key role of T lymphocytes in T1D, the cartography of autoantigen-derived peptides that are presented to class I-restricted CD8(+) T-cells and class II-restricted CD4(+) T-cells is of outmost importance and is a necessary step in the development of diagnostic T-cell assays and of immunotherapy of T1D.

Boitard C 《-》

Autoimmune diabetes: the role of T cells, MHC molecules and autoantigens.

Durinovic-Belló I 《AUTOIMMUNITY》

CD8 T-cell reactivity to islet antigens is unique to type 1 while CD4 T-cell reactivity exists in both type 1 and type 2 diabetes.

Previous cross-sectional analyses demonstrated that CD8(+) and CD4(+) T-cell reactivity to islet-specific antigens was more prevalent in T1D subjects than in healthy donors (HD). Here, we examined T1D-associated epitope-specific CD4(+) T-cell cytokine production and autoreactive CD8(+) T-cell frequency on a monthly basis for one year in 10 HD, 33 subjects with T1D, and 15 subjects with T2D. Autoreactive CD4(+) T-cells from both T1D and T2D subjects produced more IFN-γ when stimulated than cells from HD. In contrast, higher frequencies of islet antigen-specific CD8(+) T-cells were detected only in T1D. These observations support the hypothesis that general beta-cell stress drives autoreactive CD4(+) T-cell activity while islet over-expression of MHC class I commonly seen in T1D mediates amplification of CD8(+) T-cells and more rapid beta-cell loss. In conclusion, CD4(+) T-cell autoreactivity appears to be present in both T1D and T2D while autoreactive CD8(+) T-cells are unique to T1D. Thus, autoreactive CD8(+) cells may serve as a more T1D-specific biomarker.

Sarikonda G ，Pettus J ，Phatak S ，Sachithanantham S ，Miller JF ，Wesley JD ，Cadag E ，Chae J ，Ganesan L ，Mallios R ，Edelman S ，Peters B ，von Herrath M ... -  《-》

Pathological changes in the islet milieu precede infiltration of islets and destruction of beta-cells by autoreactive lymphocytes in a transgenic model of virus-induced IDDM.

von Herrath M ，Holz A 《JOURNAL OF AUTOIMMUNITY》

Customized cell-based treatment options to combat autoimmunity and restore beta-cell function in type 1 diabetes mellitus: current protocols and future perspectives.

Fändrich F ，Ungefroren H 《Advances in Experimental Medicine and Biology》