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Review
. 2016 Jul:71:26-34.
doi: 10.1016/j.jaut.2016.03.006. Epub 2016 Mar 24.

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

Ningwen Tai  1 , F Susan Wong  2 , Li Wen  3
Affiliations
Review

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

Ningwen Tai et al. J Autoimmun. 2016 Jul.

Abstract

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.

Keywords: Adaptive immunity; Innate immunity; Pattern recognition receptors; Type 1 diabetes; β cells.

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Figures

Figure 1
Figure 1. The innate immune response affects adaptive immunity and β cells
Immature macrophages or dendritic cells (DCs) express pattern-recognition receptors (PRRs) either on the outer membranes or in the internal endosomes. Recognition of pathogen-associated molecular patterns (PAMPs) associated with groups of pathogens such as bacteria, virus or fungi, or danger-associated molecular pattern molecules (DAMPs) by PRRs, results in the activation of downstream transcription factors NF-κB or IRFs, which induce the production of inflammatory cytokines or type 1 interferons (IFN). Activation of the NLRP3 inflammasome triggers innate immune responses and releases active IL-1β. These secreted cytokines and type 1 IFNs can cause islet beta cell stress and also facilitate the activation of naïve T cells that are primed with the islet beta cell autoantigens presented by macrophages or DCs. The primed T cells will differentiate into different types of effective cell subsets in draining lymph nodes and pancreatic islets. This event attracts more mature macrophages, DCs and effector T cells to migrate to the pancreatic islets to both directly damage the β cells and indirectly via the pro-inflammatory cytokines.
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