KIR and HLA effects in CNS paraneoplastic syndromes and related neuroimmune conditions

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Abstract Novel neuroimmune disorders defined by the presence of autoantibodies in plasma and/or CSF have recently been discovered, most often first described in the context of paraneoplastic syndromes, only later to be also found unassociated with tumors. These include limbic encephalitis (e.g., anti-NMDAR, anti-AMPAR, anti- GABABR, anti-LGI1, anti-CASPR2), cerebellar ataxias (e.g., anti-Yo, anti-DNER, anti-GAD), stiff-person syndrome (anti-GAD, anti-amphiphysin, anti-GlyR) and others (anti-Hu). Although little is known regarding the pathophysiology of these disorders, some are believed to be more B-cell or T-cell mediated, hypotheses mostly suggested by observed therapeutic responses and the surface/intracellular nature of antigens. Involvement of KIR and HLA is unexplored in these disorders. Intriguingly, our preliminary data support a strong Genome-Wide Association Study (GWAS) significant association of anti-NMDAR encephalitis with activatory KIR2DS1, the strongest KIR association ever reported, suggesting KIR-NK cell axis to be a key regulator for these disorders. We propose to conduct a genetic survey of the HLA and KIR repertoires in these diseases. Our specific aims 1 and 2, we will do a detailed characterization of symptoms and collect serum and DNA on 2000 cases (~1000 cases already collected). Our specific aim 3 will leverage state of the art advances in KIR and HLA next- generation sequencing to perform high resolution genotyping in cases and controls, in addition, we will also perform genome-wide single nucleotide typing in all cases and controls which will guide our association analysis. In our specific aim 4, we will perform association analyses of the genome wide genotyping, compare frequencies of HLA and KIR alleles in cases and controls. In our specific aim 5, any disorder with KIR and/or HLA finding(s) we will conduct KIR-HLA interaction analyses focusing on KIR with known HLA ligands. This will involve comparing frequencies of interacting KIR-HLA ligand pairs in cases versus controls; further, we will correlate KIR/HLA findings with disease severity or symptom clusters. The study of these disorders will benefit neurology, neuroimmunology, cancer, and infectious disease work. The fact these disorders are occurring in the setting of heightened tumor immunity is notable and relevant to cancer immunotherapy, a growing area. These datasets will be made available through ImmPort, which will allow countless researchers to prioritize basic studies of B cells, T and NK cells in these disorders and associated tumors.