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