Cutting Edge: Heterozygote Advantage in Autoimmune Disease: Hierarchy of Protection/Susceptibility Conferred by HLA and Killer Ig-Like Receptor Combinations in Psoriatic Arthritis1

Functionally relevant combinations of HLA and killer Ig-like receptor (KIR) genotypes influence resistance to several diseases in humans. Analysis of genetic data from such studies is challenging because it involves multiple linked and unlinked loci that exert their influence in an epistatic manner. We previously reported that subjects with certain activating receptors were susceptible to developing psoriatic arthritis (PsA), an effect that was strongest when HLA ligands for corresponding homologous inhibitory receptors were missing. In this study, we present a novel model in which susceptibility to PsA is determined by the overall balance of activating and inhibitory composite KIR-HLA genotypes. This model fits our knowledge of clonal NK cell expression of KIR and regulation of NK cell activity better than does the previous model, as reflected in a robust trend for increasing susceptibility to PsA with more activating genotypes. These data emphasize the remarkable influence of KIR/HLA combinations on this disease.

[1]  Michael J. Wilson,et al.  Cutting Edge: Susceptibility to Psoriatic Arthritis: Influence of Activating Killer Ig-Like Receptor Genes in the Absence of Specific HLA-C Alleles1 , 2002, The Journal of Immunology.

[2]  Keith Hoots,et al.  Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS , 2002, Nature Genetics.

[3]  L. Lanier,et al.  Face off--the interplay between activating and inhibitory immune receptors. , 2001, Current opinion in immunology.

[4]  Daniel J. Schaid,et al.  Major Histocompatibility Complex Class I–Recognizing Receptors Are Disease Risk Genes in Rheumatoid Arthritis , 2001, The Journal of experimental medicine.

[5]  P. Parham,et al.  Genetic control of human NK cell repertoire , 2001 .

[6]  R. Biassoni,et al.  Surface receptors delivering opposite signals regulate the function of human NK cells. , 2000, Seminars in immunology.

[7]  F. Vély,et al.  Signaling pathways engaged by NK cell receptors: double concerto for activating receptors, inhibitory receptors and NK cells. , 2000, Seminars in immunology.

[8]  J. Strominger,et al.  Differential binding to HLA-C of p50-activating and p58-inhibitory natural killer cell receptors. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[9]  P Parham,et al.  Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. , 1997, Immunity.

[10]  H. Ljunggren,et al.  In search of the 'missing self': MHC molecules and NK cell recognition. , 1990, Immunology today.