A novel CD93 polymorphism in non-obese diabetic (NOD) and NZB/W F1 mice is linked to a CD4+ iNKT cell deficient state

Abstract

In the present study, we characterize a polymorphism in the CD93 molecule, originally identified as the receptor for the C1q complement component (i.e., C1qRp, or AA4.1) in non-obese diabetic (NOD) mice. This allele carries a coding polymorphism in the first epidermal growth factor-like domain of CD93, which results in an amino acid substitution from Asn→His at position 264. This polymorphism does not appear to influence protein translation or ecto-domain cleavage, as CD93 is detectable in bone-marrow-derived macrophage and B-cell precursor lysates and in soluble form in the serum. The NOD CD93 isoform causes a phenotypic aberrancy in the early B-cell developmental stages (i.e., pro-, pre-, immature, and transitional), likely related to a conformational variation. Interestingly, the NZB/W F1 strain, which serves as a murine model of Lupus, also expresses an identical CD93 sequence polymorphism. Cd93 is located within the NOD Idd13 locus and is also tightly linked to the NZB/W F1 Wbw1 and Nkt2 disease susceptibility loci, which are thought to regulate natural killer T (NKT) cell homeostasis. Consistent with this genetic linkage, we found B6 CD93−/− and B6.NODIdd13 mice to be susceptible to a profound CD4+ NKT cell deficient state. These data suggest that Cd93 may be an autoimmune susceptibility gene residing within the Idd13 locus, which plays a role in regulating absolute numbers of CD4+ NKT cells.

Enhanced responsiveness to T‐cell help causes loss of B‐lymphocyte tolerance to a β‐cell neo‐self‐antigen in type 1 diabetes prone NOD mice

“…1C). CD93 was not used due to defective expression by NOD mice [33]. No significant differences (p40.05, t-test) between Sgl and Dbl-Tg mice on the same genetic background in any experiment.…”

Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse

“…The Idd13 locus contains multiple susceptibility genes, including the candidate genes β 2 -microglobulin (B2m), Cd93, Nkt2 and Bim [26,27,[30][31][32]. In inbred mouse populations, there are three allelic variants of B2m that encode isoforms differing by a single amino acid at residue 85 [28,29].…”

“…As such, although humans are non-polymorphic at the B2m loci, there may be related changes in the expression level of MHC class I that influence antigen presentation, thereby modulating thymic selection and/or peripheral activation of CD8 + T-cells [26]. In NOD mice, the Cd93 gene has a SNP that results in a conformational change in the CD93 protein [27]. Although the function of this protein is not yet well defined, its absence in C57Bl/6 (B6) CD93 − / − mice results in a reduced number of iNKT cells, which may promote T1D in NOD mice [27].…”

Intrinsic Molecular Factors Cause Aberrant Expansion of the Splenic Marginal Zone B Cell Population in Nonobese Diabetic Mice

“…Subsets were distinguished in both strains utilizing the gating strategy described by Allman and colleagues (25), with the exception that CD24 was used instead of CD93 to gate TR B cells due to the following: 1) defective expression of the latter by NOD mice (26), and 2) the fact that CD24 and CD93 are expressed similarly on B6 TR B cells (Supplemental Fig. 1A).…”