A novel CD93 polymorphism in non-obese diabetic (NOD) and NZB/W F1 mice is linked to a CD4+ iNKT cell deficient state.
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.NOD(Idd13) 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.
Zekavat
Ghazal
G
Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Mozaffari
Raha
R
Arias
Vanessa J
VJ
Rostami
Susan Y
SY
Badkerhanian
Armen
A
Tenner
Andrea J
AJ
Nichols
Kim E
KE
Naji
Ali
A
Noorchashm
Hooman
H
D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002874:Chromosome Mapping; D018655:Lymphocyte Count; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008814:Mice, Inbred NZB; D008969:Molecular Sequence Data; D055611:Natural Killer T-Cells / Q000276:immunology*; D011110:Polymorphism, Genetic; D011951:Receptors, Complement / Q000235:genetics* / Q000502:physiology
D008562:Membrane Glycoproteins; D011951:Receptors, Complement; C032402:complement 1q receptor
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