A novel CD93 polymorphism in non-obese diabetic (NOD) and NZB/W F1 mice is linked to a CD4+ iNKT cell deficient state |
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Authors: | Ghazal Zekavat Raha Mozaffari Vanessa J. Arias Susan Y. Rostami Armen Badkerhanian Andrea J. Tenner Kim E. Nichols Ali Naji Hooman Noorchashm |
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Affiliation: | (1) Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA;(2) School of Medicine, University of California Irvine, Irvine, CA, USA;(3) Children’s Hospital of Philadelphia, Philadelphia, PA, USA; |
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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. |
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