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Principal Investigator: Emmanuel J Mignot
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $623,609
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <Affect><After Care><After-Treatment><Aftercare><Age><Age of Onset><Allele Frequency><Alleles><Allelomorphs><Antigens><Area><Autoantibodies><Autoimmune><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Blood Plasma><Blood Serum><Body Tissues><Brain><Brain Inflammation><Brain Nervous System><CASPR><CNS Nervous System><CNTNAP1><CNTNAP1 gene><CSF1><CSF1 gene><Cancer Patient><Cancers><Cell Communication and Signaling><Cell Signaling><Central Nervous System><Cerebellar Ataxia><Cerebellar Incoordination><Clinical><Clinical Data><Communicable Diseases><Complement><Complement Proteins><Complex><Contactin-Associated Protein><Contactin-Associated Protein 1><Contactin-Associated Transmembrane Receptor p190><Country><Cytotoxic cell><DNA><Data><Data Bases><Data Set><Databases><Demyelinating Diseases><Demyelinating Disorders><Deoxyribonucleic Acid><Devic Disease><Devic's Syndrome><Disease><Disorder><Disseminated Sclerosis><Dysfunction><EPTP><Eaton-Lambert Syndrome><Encephalitis><Encephalon><Epitempin><Ethnic Origin><Ethnicity><Exclusion><Frequencies><Functional disorder><GEM gene><GEM protein><GTP-Binding Mitogen-Induced T-Cell Protein><GWA study><GWAS><Gelineau Syndrome><Gene Copy Number><Gene Dosage><Gene Frequency><Gene Modified><Genes><Genetic><Genetic Polymorphism><Genotype><HSV encephalitis><Haplotypes><Herpes Simplex Encephalitis><Herpes encephalitis><Herpetic Encephalitis><Heterogeneity><IB1099><Immune mediated therapy><Immune system><Immunologically Directed Therapy><Immunotherapy><In Vitro><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Intracellular Communication and Signaling><Investigators><K lymphocyte><KIR gene><KIR protein><Kinase-Inducible RAS-like Protein><LGI1><LGI1 gene><Lambert-Eaton Myasthenic Syndrome><Lambert-Eaton Syndrome><Leucine-Rich Gene, Glioma-Inactivated 1><Ligands><Limbic Encephalitis><Literature><MCSF><MGC31930><Malignant Neoplasms><Malignant Tumor><Mediating><Modeling><Moersch-Woltmann Syndrome><Multiple Sclerosis><Myasthenia Gravis><Myopathic-Myasthenic Syndrome of Lambert-Eaton><NCP1><NGS Method><NGS system><NK Cells><NRXN4><Narcolepsy><Narcoleptic Syndrome><Natural Killer Cells><Nature><Nervous System Paraneoplastic Syndromes><Neuraxis><Neurexin 4><Neurexin IV><Neuroimmune><Neurology><Neuromyelitis Optica><Nucleotides><Orphan Disease><Outcome><Ovarian Germ Cell Teratoma><Ovarian Teratoma><PNS Diseases><Paralysis Agitans><Paraneoplastic Limbic Encephalitis><Paraneoplastic Syndromes><Paranodin><Parkinson><Parkinson Disease><Paroxysmal Sleep><Pathology><Peripheral Nerve Diseases><Peripheral Nervous System Diseases><Peripheral Nervous System Disorders><Peripheral Neuropathy><Physiopathology><Plasma><Plasma Serum><Primary Parkinsonism><Rare Diseases><Rare Disorder><Reaction><Reporting><Research><Research Personnel><Researchers><Resolution><Reticuloendothelial System, Serum, Plasma><Role><Sample Size><Sampling><Serum><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Single Base Polymorphism><Single Nucleotide Polymorphism><Stiff-Man Syndrome><Stiff-Person Syndrome><Stiffman Syndrome><Stratification><Surface><Survey Instrument><Surveys><Symptoms><Syndrome><T-Cells><T-Lymphocyte><Techniques><Testing><Tissues><Tumor Immunity><Update><Work><ages><allelic frequency><amphiphysin><anti-cancer immunotherapy><anti-tumor immunity><anticancer immunotherapy><antitumor immunity><autoimmune antibody><autoreactive antibody><biological signal transduction><cancer immunity><cancer immunotherapy><complementation><data base><de-myelinating diseases><de-myelinating disorders><demyelinating conditions><demyelination diseases><demyelination disorders><disease severity><dosage><gene modification><genetically modified><genome scale><genome wide analysis><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genome wide studies><genome-wide><genome-wide analysis><genome-wide identification><genomewide><genomewide association scan><genomewide association studies><genomewide association study><herpes simplex virus 1 encephalitis><herpes simplex virus encephalitis><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunoneurology><immunotherapy for cancer><immunotherapy of cancer><insular sclerosis><malignancy><neoplasm/cancer><neuroimmunology><next gen sequencing><next generation sequencing><nextgen sequencing><novel><orphan disorder><ovary germ cell teratoma><ovary teratoma><paraneoplastic neurologic disorders><paraneoplastic neurological disorders><pathophysiology><polymorphism><post treatment><prevent><preventing><resolutions><response to therapy><response to treatment><sample collection><self reactive antibody><sex><single nucleotide variant><social role><specimen collection><symptom cluster><therapeutic response><therapy response><thymus derived lymphocyte><treatment response><treatment responsiveness><tumor><whole genome association analysis><whole genome association studies><whole genome association study>