The overall goal of this project is to fully describe and characterize the role of the Killer-cell Immunoglobulinlike Receptor (KIR) loci in neurological disease. This project is submitted as a key component of the larger INDIGO (Immunogenetics of Neurological DIseases working GrOup) consortium effort. This international collaboration builds on the driving principle that through collaboration and synergy, collectively we will make rapid progress towards understanding the genetic causes of neuroinflammation and neurodegeneration. Using modern sequencing methods and state of the art bioinformatics and analytics, the purpose of Project 2 is to establish and refine the association of KIR genetic polymorphism with multiple sclerosis, myasthenia gravis, neuromyelitis optica, Parkinson?s disease and schizophrenia. Central to immunity and critically important for human health, KIR molecules and their Human Leukocyte Antigen (HLA) ligands are encoded by complex genetic systems with extraordinarily high levels of sequence and structural variation and complex expression patterns. Building on the work by the principal and co-investigators and others, and fueled by the discovery of combinatorial associations of KIR and HLA alleles with infectious, autoimmune diseases, transplantation outcome and pregnancy, the field of immunogenomic research is now flourishing. However, studies to-date of KIR in diseases of the central nervous system have been few and limited to very low resolution genotyping. Synergized with Project 1, which focuses on variation of HLA in the same cohorts, this project will ascertain the impact of KIR variation, including promoter region polymorphism, and the interaction of KIR with HLA in neurological disease. In the proposed work we will characterize the nature and extent of the association of KIR variation achieved via high-throughput, high-resolution Next-Generation Sequencing (NGS) KIR genotyping and applied across a set of established and well-characterized cohorts of unprecedented size and diversity with respect to disease, phenotype and ethnicity. Characterization of KIR variation at high resolution will permit us to fully appreciate the impact of this diversity across a wide range of neurological diseases. We will leverage the extensive available experience within our consortium in clinical neuroscience, immunogenetics, and immunology, with sophisticated data management, bioinformatics, and statistical analysis expertise, coupled with state of the art laboratory methodology to improve our understanding of the role of KIR in neurological disease.

Public Health Relevance

Our goal is to characterize the immunogenetic determinants of disease risk in diseases of the central nervous system. To address this challenge, we leverage the power of novel methodological innovations such as nextgeneration sequencing with informative sample collections and abundant data-management and analysis expertise.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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University of California San Francisco
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Misra, Maneesh K; Damotte, Vincent; Hollenbach, Jill A (2018) The immunogenetics of neurological disease. Immunology 153:399-414
Amorim, Leonardo M; Santos, Tiago H S; Hollenbach, Jill A et al. (2018) Cost-effective and fast KIR gene-content genotyping by multiplex melting curve analysis. HLA 92:384-391
Misra, Maneesh K; Damotte, Vincent; Hollenbach, Jill A (2018) Structure-based selection of human metabolite binding P4 pocket of DRB1*15:01 and DRB1*15:03, with implications for multiple sclerosis. Genes Immun :
Wagner, Ines; Schefzyk, Daniel; Pruschke, Jens et al. (2018) Allele-Level KIR Genotyping of More Than a Million Samples: Workflow, Algorithm, and Observations. Front Immunol 9:2843
Nemat-Gorgani, Neda; Hilton, Hugo G; Henn, Brenna M et al. (2018) Different Selected Mechanisms Attenuated the Inhibitory Interaction of KIR2DL1 with C2+ HLA-C in Two Indigenous Human Populations in Southern Africa. J Immunol 200:2640-2655
Creary, Lisa E; Mallempati, Kalyan C; Gangavarapu, Sridevi et al. (2018) Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis. Mult Scler :1352458518770019
Misra, Maneesh K; Augusto, Danillo G; Martin, Gonzalo Montero et al. (2018) Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop. Hum Immunol 79:825-833
Isobe, Noriko; Keshavan, Anisha; Gourraud, Pierre-Antoine et al. (2016) Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis. JAMA Neurol 73:795-802
Norman, Paul J; Hollenbach, Jill A; Nemat-Gorgani, Neda et al. (2016) Defining KIR and HLA Class I Genotypes at Highest Resolution via High-Throughput Sequencing. Am J Hum Genet 99:375-91
Hollenbach, J A; Pando, M J; Caillier, S J et al. (2016) The killer immunoglobulin-like receptor KIR3DL1 in combination with HLA-Bw4 is protective against multiple sclerosis in African Americans. Genes Immun 17:199-202

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