RT Journal Article SR Electronic T1 Genetic determinants of the humoral immune response in MS JF Neurology - Neuroimmunology Neuroinflammation JO Neurol Neuroimmunol Neuroinflamm FD Lippincott Williams & Wilkins SP e827 DO 10.1212/NXI.0000000000000827 VO 7 IS 5 A1 Gasperi, Christiane A1 Andlauer, Till F.M. A1 Keating, Ana A1 Knier, Benjamin A1 Klein, Ana A1 Pernpeintner, Verena A1 Lichtner, Peter A1 Gold, Ralf A1 Zipp, Frauke A1 Then Bergh, Florian A1 Stangel, Martin A1 Tumani, Hayrettin A1 Wildemann, Brigitte A1 Wiendl, Heinz A1 Bayas, Antonios A1 Kümpfel, Tania A1 Zettl, Uwe K. A1 Linker, Ralf A. A1 Ziemann, Ulf A1 Knop, Matthias A1 Warnke, Clemens A1 Friese, Manuel A. A1 Paul, Friedemann A1 Tackenberg, Björn A1 Berthele, Achim A1 Hemmer, Bernhard YR 2020 UL http://nn.neurology.org/content/7/5/e827.abstract AB 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 (β = 0.58 [0.47 to 0.68], lowest adjusted p = 2.32 × 10−23), and lower intrathecal immunoglobulin M (β = −0.56 [−0.67 to −0.46], p = 2.06 × 10−24) and A (β = −0.42 [−0.54 to −0.31], p = 7.48 × 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 × 10−7) and HLA-B*44:02 with lower (β = −0.35 [−0.54 to −0.17], p = 1.38 × 10−2) immunoglobulin G levels. Of interest, different HLA alleles were associated with lower intrathecal immunoglobulin M (HLA-C*02:02, β = −0.45 [−0.61 to −0.28], p = 1.01 × 10−5) and higher immunoglobulin A levels (HLA-DQA1*01:03-DQB1*06:03-DRB1*13:01 haplotype, β = 0.40 [0.21 to 0.60], p = 4.46 × 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.CIS=clinically isolated syndrome; GWAS=genome-wide association study; HLA=human leukocyte antigen; IgA=immunoglobulin A; IgG=immunoglobulin G; IGHC=immunoglobulin heavy chain constant; IGHG=immunoglobulin heavy constant gamma; IgM=immunoglobulin M; LD=linkage disequilibrium; MHC=major histocompatibility complex; SNP=single nucleotide polymorphism