Distinct genetic control of autoimmune neuropathy and diabetes in the non-obese diabetic background

Abstract

The non-obese diabetic (NOD) mouse is susceptible to the development of autoimmune diabetes but also multiple other autoimmune diseases. Over twenty susceptibility loci linked to diabetes have been identified in NOD mice and progress has been made in the definition of candidate genes at many of these loci (termed Idd for insulin-dependent diabetes). The susceptibility to multiple autoimmune diseases in the NOD background is a unique opportunity to examine susceptibility genes that confer a general propensity for autoimmunity versus susceptibility genes that control individual autoimmune diseases. We previously showed that NOD mice deficient for the costimulatory molecule B7-2 (NOD-B7-2KO mice) were protected from diabetes but spontaneously developed an autoimmune peripheral neuropathy. Here, we took advantage of multiple NOD mouse strains congenic for Idd loci to test the role of these Idd loci the development of neuropathy and determine if B6 alleles at Idd loci that are protective for diabetes will also be for neuropathy. Thus, we generated NOD-B7-2KO strains congenic at Idd loci and examined the development of neuritis and clinical neuropathy. We found that the NOD-H-2g7 MHC region is necessary for development of neuropathy in NOD-B7-2KO mice. In contrast, other Idd loci that significantly protect from diabetes did not affect neuropathy when considered individually. However, we found potent genetic interactions of some Idd loci that provided almost complete protection from neuritis and clinical neuropathy. In addition, defective immunoregulation by Tregs could supersede protection by some, but not other, Idd loci in a tissue-specific manner in a model where neuropathy and diabetes occurred concomitantly. Thus, our study helps identify Idd loci that control tissue-specific disease or confer general susceptibility to autoimmunity, and brings insight to the Treg-dependence of autoimmune processes influenced by given Idd region in the NOD background.

Clinical Recommendations for the Use of Islet Cell Autoantibodies to Distinguish Autoimmune and Non-Autoimmune Gestational Diabetes

“…There is enormous literature on both main types of diabetes -T1D and T2D, including the role of microflora [107,108], inflammatory responses, including gestational influences [109][110][111][112], interventional studies in both humans and animal models [113][114][115][116][117], the role of vitamin D and other nutritional factors [118][119][120][121], and better definition of genetic control, autoantibodies, and the implications of offspring of the diabetic mother [122][123][124]. In this manuscript, we have focused on the research data that reflects the metabolic conditions of pregnancy and adiposity.…”

Peripheral Neuropathy in Mouse Models of Diabetes

“…The advantage gained from studying pathogenic mechanisms of diabetic neuropathy in genetic models of diabetes is uncertain. Indeed, NOD mice are generally avoided in neuropathy research due to the potential for direct damage to nerves by the immune system (Bour-Jordan et al, 2013). …”

The Spontaneous Autoimmune Neuromyopathy in ICOSL−/− NOD Mice Is CD4+ T-Cell and Interferon-γ Dependent

“…This interval overlaps with the Idd regions 5.1, 5.2, and 5.3 (Table 1). However, Idd5 has been experimentally excluded to have any effect on neuropathy (26). …”

“…While the Icos −/− strain contains a large non-NOD-derived interval on mouse chromosome 1 containing several genes encoding costimulatory molecules genes such as Ctla4, Icos , and Cd28 , the Icosl −/− strain genome contains almost only NOD alleles on all chromosomes and few NOD alleles around the candidate gene locus. In addition, this region does neither overlap with known Idd candidate regions or QTLs presently known to be involved in neuropathy (26). We therefore concentrated our phenotypical analysis on the Icosl −/− strain rather than Icos −/− strain.…”

“…The main region controlling the targeting of β-cells is the MHC, but other regions have been evidenced in double congenic mice (20–24). Finally, genes controling costimulatory T-cells molecules have been shown to play a key role in directing autoimmunity, as observed in B7.2-knockout NOD mice, which fail to develop diabetes but develop autoimmune peripheral neuropathy (25, 26). …”