ROLE OF KILLER INHIBITORY RECEPTOR GENES IN AUTOIMMUNE AND INFECTIOUS DISEASES

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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 inhibitory 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 viruses that inhibit class I molecule expression and thereby avoid 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. The host defense system may be crippled effectively by reducing CTL activity through Nef downregulation of HLA-A and -B, along with curtailment of NK activity by not affecting the expression of HLA-C. Evidence for downregulation of class I by human papilloma virus (HPV) has also been reported. We have developed a molecular typing technique for the 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 and hepatitis B virus). Haplotypes of the KIR genes complex vary in the number of KIR genes present and some of the genes are slightly polymorphic. Our initial approach has been to determine presence or absence of each KIR gene, but we have also begun to develop means for typing alleles at each locus. Our protocol involves polymerase chain reaction (PCR) amplification performed with primers specific for each locus (PCR-SSP). We use the same amplification conditions for all loci, greatly enhancing the efficiency of the assay. Internal control primers for a 796-bp fragment of the third intron of DRB1 are also included in each PCR reaction. In order to confirm the presence or absence of a particular locus, two sets of primers have been designed for each locus. The entire typing protocol can be performed in a 96-well format, thereby providing a potential means for semi-automation. Recognition of HLA-C molecules by several of the KIR gene products led us to speculate that synergistic interactions between HLA and KIR genes might be most obvious in data sets obtained from diseases associated with HLA-C. HLA associations with autoimmune diseases appear to be less complex than those involving infectious diseases. Thus, we have typed a group of individuals with (PSA), a disease that has been shown to be associated with HLA-Cw*06. Frequencies of the KIR genes among individuals in the PSA group who are Cw*06 will also be will determined and compared to a control data set. This data is being analysed presently. We have also begun to type these genes using samples from a group of patients with ankylosing spondylitis and a group of HIV-1-infected individuals. Role of Killer Inhibitory Receptor Genes in AIDS - Natural killer cells, Killer inhibitory receptors, HLA, - Human Tissues, Fluids, Cells, etc.