PMID- 34841709 OWN - NLM STAT- MEDLINE DCOM- 20220314 LR - 20220314 IS - 2328-9503 (Electronic) IS - 2328-9503 (Linking) VI - 8 IP - 12 DP - 2021 Dec TI - Impact of T cells on neurodegeneration in anti-GAD65 limbic encephalitis. PG - 2289-2301 LID - 10.1002/acn3.51486 [doi] AB - OBJECTIVE: Direct pathogenic effects of autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GAD65) in autoimmune limbic encephalitis (LE) have been questioned due to its intracellular localization. We therefore hypothesized a pathogenic role for T cells. METHODS: We assessed magnet resonance imaging, neuropsychological and peripheral blood, and CSF flow cytometry data of 10 patients with long-standing GAD65-LE compared to controls in a cross-sectional manner. These data were related to each other within the GAD65-LE group and linked to neuropathological findings in selective hippocampectomy specimen from another two patients. In addition, full-resolution human leukocyte antigen (HLA) genotyping of all patients was performed. RESULTS: Compared to controls, no alteration in hippocampal volume but impaired memory function and elevated fractions of activated HLADR(+) CD4(+) and CD8(+) T cells in peripheral blood and cerebrospinal fluid were found. Intrathecal fractions of CD8(+) T cells negatively correlated with hippocampal volume and memory function, whereas the opposite was true for CD4(+) T cells. Consistently, antigen-experienced CD8(+) T cells expressed increased levels of the cytotoxic effector molecule perforin in peripheral blood, and perforin-expressing CD8(+) T cells were found attached mainly to small interneurons but also to large principal neurons together with wide-spread hippocampal neurodegeneration. 6/10 LE patients harbored the HLA-A*02:01 allele known to present the immunodominant GAD65(114-123) peptide in humans. INTERPRETATION: Our data suggest a pathogenic effect of CD8(+) T cells and a regulatory effect of CD4(+) T cells in patients with long-standing GAD65-LE. CI - (c) 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. FAU - Dik, Andre AU - Dik A AUID- ORCID: 0000-0003-4695-4136 AD - Department of Neurology with Institute of Translational Neurology, University of Munster, Munster, Germany. FAU - Widman, Guido AU - Widman G AD - Department of Epileptology, University Hospital Bonn, Bonn, Germany. FAU - Schulte-Mecklenbeck, Andreas AU - Schulte-Mecklenbeck A AD - Department of Neurology with Institute of Translational Neurology, University of Munster, Munster, Germany. FAU - Witt, Juri-Alexander AU - Witt JA AUID- ORCID: 0000-0001-5640-2592 AD - Department of Epileptology, University Hospital Bonn, Bonn, Germany. AD - Institute of Neuropathology, Medical Faculty, University of Bonn, Section for Translational Epilepsy Research, Bonn, Germany. FAU - Pitsch, Julika AU - Pitsch J AD - Department of Epileptology, University Hospital Bonn, Bonn, Germany. FAU - Golombeck, Kristin S AU - Golombeck KS AD - Department of Neurology with Institute of Translational Neurology, University of Munster, Munster, Germany. FAU - Wagner, Jan AU - Wagner J AD - Department of Epileptology, University Hospital Bonn, Bonn, Germany. FAU - Gallus, Marco AU - Gallus M AD - Department of Neurology with Institute of Translational Neurology, University of Munster, Munster, Germany. FAU - Strippel, Christine AU - Strippel C AD - Department of Neurology with Institute of Translational Neurology, University of Munster, Munster, Germany. FAU - Hansen, Niels AU - Hansen N AD - Department of Epileptology, University Hospital Bonn, Bonn, Germany. FAU - Monig, Constanze AU - Monig C AD - Department of Neurology with Institute of Translational Neurology, University of Munster, Munster, Germany. FAU - Rauber, Saskia AU - Rauber S AUID- ORCID: 0000-0001-8901-5572 AD - Department of Neurology with Institute of Translational Neurology, University of Munster, Munster, Germany. FAU - Wiendl, Heinz AU - Wiendl H AD - Department of Neurology with Institute of Translational Neurology, University of Munster, Munster, Germany. FAU - Elger, Christian E AU - Elger CE AD - Department of Epileptology, University Hospital Bonn, Bonn, Germany. FAU - Surges, Rainer AU - Surges R AD - Department of Epileptology, University Hospital Bonn, Bonn, Germany. FAU - Meuth, Sven G AU - Meuth SG AD - Department of Neurology with Institute of Translational Neurology, University of Munster, Munster, Germany. FAU - Helmstaedter, Christoph AU - Helmstaedter C AD - Department of Epileptology, University Hospital Bonn, Bonn, Germany. FAU - Gross, Catharina C AU - Gross CC AD - Department of Neurology with Institute of Translational Neurology, University of Munster, Munster, Germany. FAU - Becker, Albert J AU - Becker AJ AUID- ORCID: 0000-0003-2661-3705 AD - Department of Epileptology, University Hospital Bonn, Bonn, Germany. AD - Institute of Neuropathology, Medical Faculty, University of Bonn, Section for Translational Epilepsy Research, Bonn, Germany. FAU - Melzer, Nico AU - Melzer N AD - Department of Neurology with Institute of Translational Neurology, University of Munster, Munster, Germany. LA - eng GR - Novartis Pharma/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211128 PL - United States TA - Ann Clin Transl Neurol JT - Annals of clinical and translational neurology JID - 101623278 RN - EC 4.1.1.15 (Glutamate Decarboxylase) RN - EC 4.1.1.15 (glutamate decarboxylase 2) RN - Autoimmune limbic encephalitis SB - IM MH - Adult MH - Autoimmune Diseases/blood/cerebrospinal fluid/*immunology/*pathology MH - *CD4-Positive T-Lymphocytes MH - *CD8-Positive T-Lymphocytes MH - Cross-Sectional Studies MH - Female MH - Glutamate Decarboxylase/*immunology MH - Humans MH - Limbic Encephalitis/blood/cerebrospinal fluid/*immunology/*pathology MH - Magnetic Resonance Imaging MH - Male MH - Middle Aged MH - Young Adult PMC - PMC8670322 COIS- All authors declare no conflicts of interest. EDAT- 2021/11/30 06:00 MHDA- 2022/03/15 06:00 PMCR- 2021/11/28 CRDT- 2021/11/29 06:56 PHST- 2021/11/01 00:00 [revised] PHST- 2021/09/15 00:00 [received] PHST- 2021/11/15 00:00 [accepted] PHST- 2021/11/30 06:00 [pubmed] PHST- 2022/03/15 06:00 [medline] PHST- 2021/11/29 06:56 [entrez] PHST- 2021/11/28 00:00 [pmc-release] AID - ACN351486 [pii] AID - 10.1002/acn3.51486 [doi] PST - ppublish SO - Ann Clin Transl Neurol. 2021 Dec;8(12):2289-2301. doi: 10.1002/acn3.51486. Epub 2021 Nov 28.