Gasperi, Christiane, Andlauer, Till F. M., Keating, Ana, Knier, Benjamin, Klein, Ana, Pernpeintner, Verena, Lichtner, Peter, Gold, Ralf, Zipp, Frauke, Bergh, Florian Then, Stangel, Martin, Tumani, Hayrettin, Wildemann, Brigitte, Wiendl, Heinz, Bayas, Antonios, Kuempfel, Tania, Zettl, Uwe K., Linker, Ralf A., Ziemann, Ulf, Knop, Matthias, Warnke, Clemens, Friese, Manuel A., Paul, Friedemann, Tackenberg, Bjoern, Berthele, Achim and Hemmer, Bernhard (2020). Genetic determinants of the humoral immune response in MS. Neurol.-Neuroimmunol. Neuroinflammation, 7 (5). PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 2332-7812

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Abstract

Objective In 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). Methods Using 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. Results The 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. Conclusion Although 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Gasperi, ChristianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andlauer, Till F. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keating, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knier, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pernpeintner, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lichtner, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gold, RalfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zipp, FraukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bergh, Florian ThenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stangel, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tumani, HayrettinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wildemann, BrigitteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiendl, HeinzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bayas, AntoniosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuempfel, TaniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zettl, Uwe K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Linker, Ralf A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ziemann, UlfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knop, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warnke, ClemensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Friese, Manuel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paul, FriedemannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tackenberg, BjoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berthele, AchimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hemmer, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-321204
DOI: 10.1212/NXI.0000000000000827
Journal or Publication Title: Neurol.-Neuroimmunol. Neuroinflammation
Volume: 7
Number: 5
Date: 2020
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Place of Publication: PHILADELPHIA
ISSN: 2332-7812
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DIAGNOSTIC-CRITERIA; MULTIPLE-SCLEROSIS; IGG; GUIDELINES; ALLOTYPES; VARIANTSMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/32120

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