These results attest to the utility of molecular network analyses in identifying novel Idds or genes not in known Idds that could act interactively upstream or downstream of Idd regions to contribute to diabetes development.

The role of these genes needs to be confirmed in future studies. Several groups have determined that resistance genes in Idd9/11 (Chr4) regulate the diabetogenic activity of CD4 T-cells [ 5, 10, 18, 19]. Interestingly, two of the NOD altered genes (Khdrbs1 and Ptp4a2) lie within Idd9/11, with Khdrbs1 (an adaptor protein involved in signal transduction cascades of several receptor systems, including Ulixertinib in vivo T-cell signaling) being common to all 3 ages. In support of possible involvement of interaction

of genes on several genetic regions in suppressing the diabetogenic activity of NOR CD4 T-cells, Chen et al. [ 5] reported that CD4 T-cells from NOR mice were somewhat more protective against diabetes than CD4 T-cells from NOD mice congenic for just the NOR-derived Idd9/11. Our study provides support suggesting that resistance genes within Idd13 (and their downstream genes) may act interactively with those in Idd9/11 (and possibly in unidentified Idd on Chr11) to regulate click here the diabetogenic activity of CD4 T-cells. In addition to the NOD CD4 T-cell altered genes discussed above, several other altered genes also lie within Idds ( Table 1, Table 2, Table 3 and Table 4). All (except Idd5.4a/5.4) have been identified as conferring resistance to diabetes (http://www.t1dbase.org). An interesting family of genes highlighted is the tripartite-motif (Trim) family. Compared to the leukocyte study, the current study expanded the list of Trim family members. These genes, whose expression was repressed in NOD mice, with that of Trim5/12c and 12a virtually undetectable, all lie within Idd27 on Chr7. Trim proteins, which bear several domains, including three zinc-binding

domains, constitute a family of ∼60 molecules with diverse biological functions, including regulation of inflammation and innate immunity [ 31, 32]. The order of 5-FU mw the domains is conserved throughout evolution supporting a common molecular property for these proteins. We propose that one (or several) of the Trim family members identified in our studies may play an important role in immune cells in initiation of autoimmune diabetes. To this end, Trim21, a gene that for a long time has been implicated in human autoimmune diseases Sjögren’s syndrome and systemic lupus erythematosus, in which patients exhibit Trim21 autoreactivity [ 33], has been reported recently to regulate the innate immune response to intracellular dsDNA [ 34]. Another Trim (Trim28) has also been reported recently to be involved in the global regulation of CD4 T-cells [ 35].