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March 2022; 9 (2) ArticleOpen Access

Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis

Vicente Peris Sempere, View ORCID ProfileSergio Muñiz-Castrillo, View ORCID ProfileAditya Ambati, View ORCID ProfileSophie Binks, Anne-Laurie Pinto, View ORCID ProfileVeronique Rogemond, Sean J. Pittock, Divyanshu Dubey, Michael D. Geschwind, View ORCID ProfileJeffrey Marc Gelfand, Sonam Dilwali, Soon-Tae Lee, Julian Knight, View ORCID ProfileKatherine S. Elliott, View ORCID ProfileSarosh Irani, Jérôme Honnorat, View ORCID ProfileEmmanuel Mignot
First published February 3, 2022, DOI: https://doi.org/10.1212/NXI.0000000000001140
Vicente Peris Sempere
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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  • For correspondence: vsempereperis@gmail.com
Sergio Muñiz-Castrillo
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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  • ORCID record for Sergio Muñiz-Castrillo
  • For correspondence: ext-sergio.muniz@chu-lyon.fr
Aditya Ambati
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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Sophie Binks
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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Anne-Laurie Pinto
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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  • For correspondence: anne-laurie.pinto@chu-lyon.fr
Veronique Rogemond
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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Sean J. Pittock
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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  • For correspondence: pittock.sean@mayo.edu
Divyanshu Dubey
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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Michael D. Geschwind
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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Jeffrey Marc Gelfand
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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Sonam Dilwali
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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  • For correspondence: sonam.dilwali@ucsf.edu
Soon-Tae Lee
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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Julian Knight
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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Katherine S. Elliott
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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Sarosh Irani
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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  • For correspondence: sarosh.irani@ndcn.ox.ac.uk
Jérôme Honnorat
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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  • For correspondence: jerome.honnorat@chu-lyon.fr
Emmanuel Mignot
From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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Citation
Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis
Vicente Peris Sempere, Sergio Muñiz-Castrillo, Aditya Ambati, Sophie Binks, Anne-Laurie Pinto, Veronique Rogemond, Sean J. Pittock, Divyanshu Dubey, Michael D. Geschwind, Jeffrey Marc Gelfand, Sonam Dilwali, Soon-Tae Lee, Julian Knight, Katherine S. Elliott, Sarosh Irani, Jérôme Honnorat, Emmanuel Mignot
Neurol Neuroimmunol Neuroinflamm Mar 2022, 9 (2) e1140; DOI: 10.1212/NXI.0000000000001140

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Abstract

Background and Objectives To study human leukocyte antigen (HLA) allele associations in anti-leucine–rich glioma-inactivated 1 (LGI1) encephalitis.

Methods A multiethnic cohort of 269 patients with anti-LGI1 encephalitis and 1,359 controls was included. Four-digit HLA sequencing and genome wide association single-nucleotide polymorphism typing imputation (0.99 concordance) were used for HLA typing. Significance of primary and secondary associations was tested using χ2, Fisher exact tests, or logistic regression with the control of population stratification covariates when applicable.

Results DRB1*07:01 and DQA1*02:01, 2 alleles in strong linkage disequilibrium, were associated with the disease (90% vs 24%, OR = 27.8, p < 10e−50) across ethnicity independent of variation at DRB3 and DQB1, 2 flanking HLA loci. DRB1*07:01 homozygosity was associated with a doubling of risk (OR = 2.1, p = 0.010), suggesting causality. DRB1*07:01 negative subjects were younger (p = 0.003) and more frequently female (p = 0.015). Three patients with malignant thymomas did not carry DRB1*07:01, whereas patients with other tumors had high DRB1*07:01 frequency, suggesting that the presence of tumors other than thymomas may be coincidental and not causal. In both DRB1*07:01 heterozygous individuals and DRB1*07:01 negative subjects, DRB1*04:02 was associated with anti-LGI1 encephalitis, indicating an independent effect of this allele (OR = 6.85, p = 4.57 × 10−6 and OR = 8.93, p = 2.50 × 10−3, respectively). DRB1*04:02 was also independently associated with younger age at onset (β = −6.68, p = 9.78 × 10−3). Major histocompatibility complex peptide-binding predictions using LGI1-derived peptides revealed divergent binding propensities for DRB1*04:02 and DRB1*07:01 alleles, suggesting independent pathogenic mechanisms.

Discussion In addition to the established primary DRB1*07:01 association in anti-LGI1 encephalitis, we observe a secondary effect of DRB1*04:02 with lower age at onset. Our study provides evidence for secondary effects within HLA locus that correlate with clinical phenotypes in anti-LGI1 encephalitis.

Glossary

EPTP=
epitempin;
FBDS=
faciobrachial dystonic seizure;
FDR=
false discovery rate;
HLA=
human leukocyte antigen;
LGI1=
leucine-rich glioma-inactivated 1;
LRR=
leucine-rich repeat;
mRS=
modified Rankin score;
PCA=
principal component analysis

Footnotes

  • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

  • ↵* These authors contributed in equal proportions to the analysis and the interpretation of the data, and design of the study as co-first authors.

  • ↵† These authors designed, planned, and theorized the study from the beginning and have coordinated the collection and analysis of the data as co-last authors.

  • The Article Processing Charge was funded by the authors.

  • Received August 23, 2021.
  • Accepted in final form December 27, 2021.
  • Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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