title: Pancreatic islet autoimmunity.
abstract: 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.
authors.affiliation: Inserm, U986, 75014 Paris, France. christian.boitard@htd.aphp.fr
authors.forename: Christian
authors.initials: C
authors.lastname: Boitard
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000502:physiology; D001324:Autoantigens / Q000276:immunology / Q000627:therapeutic use; D015551:Autoimmunity / Q000235:genetics / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D006801:Humans; D007167:Immunotherapy / Q000379:methods / Q000639:trends; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012307:Risk Factors
chemical_list: D001323:Autoantibodies; D001324:Autoantigens