Role of Killer Inhibitory Receptor Genes in Autoimmune a

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Natural killer (NK) cells are a unique group of lymphocytes involved in surveillance and killing of foreign or infected cells through a mechanism involving recognition of HLA molecules by an extremely diverse set of receptors on the NK cell surface. The killer immunoglobulin-like receptor genes (KIRs) map to chromosome 19q13.4 along with other related genes. Some of these genes encode molecules that recognize HLA-C ligands, whereas others bind HLA-A and -B molecules. In contrast to cytotoxic T lymphocyte (CTL) recognition of peptide as presented by class I, NK cells destroy targets that lack expression of class I, and they are inhibited by recognition of class I on the cell surface. NK cells play an important role in defense against virally infected cells and tumor cells that down regulate class I molecule expression, thereby avoiding recognition by CTL. For example, HIV-1 downregulates cell surface expression of HLA-A and -B molecules (but not -C) and one mechanism to explain rapid progression to AIDS in individuals with certain HLA types may involve alteration of NK cell activity (see Project number Z01 BC 10269-05 LGD). Evidence for downregulation of class I by human papilloma virus (HPV) has also been reported. Haplotypes of the KIR gene complex vary in the number of KIR genes present and some of the genes are polymorphic. We have developed a molecular typing technique determining the presence or absence of each of the 15 KIR genes in order to study potential effects of these genes on autoimmune (psoriatic arthritis [PsA], ankylosing spondylitis and multiple sclerosis) and infectious diseases (those associated with HIV-1, hepatitis C virus, hepatitis B virus, and HPV). Defining KIR haplotypes will be necessary for rigorous disease association studies with this locus. Thus, we have embarked on a study to define KIR haplotypes and their frequencies using segregation analysis. To date, we have typed 59 CEPH families for presence or absence of the KIR genes, which represents nearly 1,400 KIR haplotypes (about 370 independent chromosomes and 1,000 meioses). Some KIR genes are found on almost all KIR haplotypes, so when one parent has two copies of a gene (one on each chromosome) and the other parent has one or two, all offspring are positive for the gene and it is not possible to determine whether one chromosome may be missing that gene locus. In some cases, it may be possible to resolve this problem by typing polymorphic loci in that gene. Thus, we have designed a sequence-based typing system for two of the common KIR genes, KIR2DL4 and KIR3DL1, and sequencing in the families has begun. It is clear from the data we have collected thus far that KIR haplotypes are extremely complex, and the most obvious mechanism for haplotypic variation appears to be unequal crossing over. However, the family data do not indicate a hotspot for recombination within the KIR gene complex. Ongoing typing and analyses of these haplotypes are underway. NK cell cytotoxicity is controlled by a complex array of activating and inhibitory signals occurring in part through the interaction between KIR on the NK cell surface and their respective HLA class I ligands. Given the functional relationship of these molecules, which are both encoded by highly polymorphic, unlinked regions of the genome, it is possible that diseases influenced by certain HLA alleles may also be affected by the genes encoding the corresponding KIR molecules. HLA-Cw*0602 has previously been shown to associate with psoriatic arthritis, which we confirm in a large sample of individuals with the disease (OR=1.97). The data also show an independent disease association with KIR haplotypes that contain KIR2DS1 (OR=1.56). KIR2DS1 encodes a receptor correlated with NK cell killing of target cells expressing the N77K80 motif, which is present in Cw*0602. A particularly strong B*27 association with disease phenotype was also observed (OR=3.56) and the strength of the association was even greater when both B*27 and KIR3DS1 were present (OR=4.57). However, a dominant effect of KIR3DS1 on PsA independent of B*27 was not observed, suggesting that KIR3DS1 may exacerbate the susceptibility effect of B*27. The data indicate that predisposition to psoriatic arthritis involves genes encoding a receptor-ligand pair known to regulate NK cell function. Thus, it is likely that the HLA class I effects on this disease are complex, and that HLA-KIR interactions account for part of the total HLA influence on pathogenesis of psoriatic arthritis. We have recently received 110 additional cases and controls (bringing the totals to 367 and 330 for cases and controls, respectively), providing added power and further clarification of the effects these loci have on the disease.