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KIR-HLA GENOTYPES PROVIDING WEAK INHIBITION AND STRONG ACTIVATION PREDISPOSE SUSCEPTIBILITY TO UVEITIS.
Zeying Du Ph.D. , Ralph D. Levinson M.D. , Elaine F. Reed Ph.D. and Raja Rajalingam Ph.D. . 1 UCLA Immunogenetics Center, Dept. of Pathology and Lab. Medicine, Los Angeles, CA .
By recognizing certain self-HLA class I molecules, the inhibitory KIR receptors provide NK cells tolerance to healthy cells. Four distinct inhibitory KIR-HLA pairs have been defined: 2DL1-CK80, 2DL2/3-CN80, 3DL1-Bw4, 3DL2-A3/11. KIR and HLA are encoded by unlinked polymorphic gene families, and their independent segregation results inheritance of variable number and type of KIR-HLA pairs in individuals. We hypothesize that individuals carrying fewer inhibitory KIR-HLA pairs predispose susceptibility to autoimmune disorder. To test our hypothesis, we have characterized KIR-HLA pairs in patients with uveitis (n=57) and healthy controls form the same ethnic background (n=64). Considering the presence and absence of inhibitory KIR (iKIR), structurally homologous activating KIR (aKIR), and cognate HLA ligands, we have developed the following algorithm to grade their combinations in NK function: iKIR+aKIR-HLA+=strong inhibition, iKIR+aKIR+HLA+=weak inhibition, iKIR+aKIR-HLA-=no inhibition, iKIR-aKIR+HLA+=weak activation, and iKIR+aKIR+HLA- or positive for structurally distinct activating KIR 2DS3/2DS4 full/2DS5=strong activation. KIR-HLA genotypes providing strong inhibition are more frequent in controls as compared to uveitis. The genotypes suggestive of weak inhibition are predominant in uveitis. Further, genotypes of strong activation, particularly 2DS5 are more frequent in patients (49% vs. 28% in controls). KIR-HLA genotypes providing weak inhibition but strong activation could generate NK cells and NK-like T cells with dominant activating receptor repertoire, which presumably will breakdown the self-tolerance upon certain infection and systemic inflammation in eye.