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

> **NIH NIH U01** · STANFORD UNIVERSITY · 2024 · $623,609

## Abstract

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.

## Key facts

- **NIH application ID:** 10928149
- **Project number:** 5U01NS120885-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Emmanuel J Mignot
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $623,609
- **Award type:** 5
- **Project period:** 2020-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10928149

## Citation

> US National Institutes of Health, RePORTER application 10928149, KIR and HLA effects in CNS paraneoplastic syndromes and related neuroimmune conditions (5U01NS120885-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10928149. Licensed CC0.

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