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Gasperi, C.* ; Andlauer, T.F.M.* ; Keating, A.* ; Knier, B.* ; Klein, A.* ; Pernpeintner, V.* ; Lichtner, P. ; Gold, R.* ; Zipp, F.* ; Then Bergh, F.* ; Stangel, M.* ; Tumani, H.* ; Wildemann, B.* ; Wiendl, H.* ; Bayas, A.* ; Kümpfel, T.* ; Zettl, U.K.* ; Linker, R.A.* ; Ziemann, U.* ; Knop, M.* ; Warnke, C.* ; Friese, M.A.* ; Paul, F.* ; Tackenberg, B.* ; Berthele, A.* ; Hemmer, B.*

Genetic determinants of the humoral immune response in MS.

Neurol. Neuroimmunol. Neuroinflammation 7:e827 (2020)
Verlagsversion DOI
Open Access Gold
Creative Commons Lizenzvertrag
ObjectiveIn this observational study, we investigated the impact of genetic factors at the immunoglobulin heavy chain constant locus on chromosome 14 and the major histocompatibility complex region on intrathecal immunoglobulin G, A, and M levels as well as on B cells and plasmablasts in the CSF and blood of patients with multiple sclerosis (MS).MethodsUsing regression analyses, we tested genetic variants on chromosome 14 and imputed human leukocyte antigen (HLA) alleles for associations with intrathecal immunoglobulins in 1,279 patients with MS or clinically isolated syndrome and with blood and CSF B cells and plasmablasts in 301 and 348 patients, respectively.ResultsThe minor alleles of variants on chromosome 14 were associated with higher intrathecal immunoglobulin G levels (beta = 0.58 [0.47 to 0.68], lowest adjusted p = 2.32 x 10(-23)), and lower intrathecal immunoglobulin M (beta = -0.56 [-0.67 to -0.46], p = 2.06 x 10(-24)) and A (beta = -0.42 [-0.54 to -0.31], p = 7.48 x 10(-11)) levels. Alleles from the HLA-B*07:02-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype were associated with higher (lowest p = 2.14 x 10(-7)) and HLA-B*44:02 with lower (beta = -0.35 [-0.54 to -0.17], p = 1.38 x 10(-2)) immunoglobulin G levels. Of interest, different HLA alleles were associated with lower intrathecal immunoglobulin M (HLA-C*02:02, beta = -0.45 [-0.61 to -0.28], p = 1.01 x 10(-5)) and higher immunoglobulin A levels (HLA-DQA1*01:03-DQB1*06:03-DRB1*13:01 haplotype, beta = 0.40 [0.21 to 0.60], p = 4.46 x 10(-3)). The impact of HLA alleles on intrathecal immunoglobulin G and M levels could mostly be explained by associations with CSF B cells and plasmablasts.ConclusionAlthough some HLA alleles seem to primarily drive the extent of humoral immune responses in the CNS by increasing CSF B cells and plasmablasts, genetic variants at the immunoglobulin heavy chain constant locus might regulate intrathecal immunoglobulins levels via different mechanisms.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Diagnostic-criteria; Multiple-sclerosis; Igg; Guidelines; Allotypes; Variants
e-ISSN 2332-7812
Zeitschrift Neurology Neuroimmunology & Neuroinflammation
Quellenangaben Band: 7, Heft: 5, Seiten: , Artikelnummer: e827 Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Philadelphia, Pa.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
Förderungen biobank of the Department of Neurology as part of the Joint Biobank Munich
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy
European Union's Horizon 2020 Research and Innovation Program (grant MultipleMS)
German Research Foundation (DFG)
German Federal Ministry for Education and Research