Innate Immunity in Type 1 Diabetes.

Type 1 diabetes (T1D) results from the destruction of pancreatic β cells by the immune system, to which both pancreatic β-cell dysfunction and pathological activation of the immune system contribute. This paper is focused on understanding the modalities of this activation, and the genetic and environmental factors increasing its risk. Innate immunity has a critical role in the loss of self-tolerance and promotion of inflammation either directly using innate effector mechanisms or by providing activation signals to anti-islet adaptive autoimmunity. We provide an overview of various deleterious and protective roles of innate immunity in T1D inside pancreatic islets, regional lymph nodes, and distant locations such as the gut.

Bertrand L ，Chervonsky AV ，Lehuen A 《Cold Spring Harbor Perspectives in Medicine》

The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes.

Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by T cell-mediated destruction of the insulin-producing pancreatic β cells. A combination of genetic and environmental factors eventually leads to the loss of functional β cell mass and hyperglycemia. Both innate and adaptive immunity are involved in the development of T1D. In this review, we have highlighted the most recent findings on the role of innate immunity, especially the pattern recognition receptors (PRRs), in disease development. In murine models and human studies, different PRRs, such as toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat-containing (or Nod-like) receptors (NLRs), have different roles in the pathogenesis of T1D. These PRRs play a critical role in defending against infection by sensing specific ligands derived from exogenous microorganisms to induce innate immune responses and shape adaptive immunity. Animal studies have shown that TLR7, TLR9, MyD88 and NLPR3 play a disease-predisposing role in T1D, while controversial results have been found with other PRRs, such as TLR2, TLR3, TLR4, TLR5 and others. Human studies also shown that TLR2, TLR3 and TLR4 are expressed in either islet β cells or infiltrated immune cells, indicating the innate immunity plays a role in β cell autoimmunity. Furthermore, some human genetic studies showed a possible association of TLR3, TLR7, TLR8 or NLRP3 genes, at single nucleotide polymorphism (SNP) level, with human T1D. Increasing evidence suggest that the innate immunity modulates β cell autoimmunity. Thus, targeting pathways of innate immunity may provide novel therapeutic strategies to fight this disease.

Tai N ，Wong FS ，Wen L 《-》

Type 1 Diabetes: A Chronic Anti-Self-Inflammatory Response.

Clark M ，Kroger CJ ，Tisch RM 《Frontiers in Immunology》

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 《-》

Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and β-cell apoptosis.

Genome-wide association studies (GWAS) have identified more than 50 loci associated with genetic risk of type 1 diabetes (T1D). Several T1D candidate genes have been suggested or identified within these regions, but the molecular mechanisms by which they contribute to insulitis and β-cell destruction remain to be clarified. More than 60% of the T1D candidate genes are expressed in human pancreatic islets, suggesting that they contribute to T1D by regulating at least in part pathogenic mechanisms at the β-cell level. Recent studies by our group indicate that important genetically regulated pathways in β-cells include innate immunity and antiviral activity, involving RIG-like receptors (particularly MDA5) and regulators of type I IFNs (i.e. PTPN2 and USP18), and genes related to β-cell phenotype and susceptibility to pro-apoptotic stimuli (i.e. GLIS3). These observations reinforce the concept that the early pathogenesis of T1D is characterized by a dialogue between the immune system and pancreatic β-cells. This dialogue is probably influenced by polymorphisms in genes expressed at the β-cell and/or immune system level, leading to inadequate responses to environmental cues such as viral infections. Further studies are needed to clarify how these disease-associated variants affect pancreatic β-cell responses to inflammation and the subsequent triggering of autoimmune responses and progressive β-cell loss.

Santin I ，Eizirik DL 《-》