RT Journal Article
SR Electronic
T1 T-Cell Specificity Influences Disease Heterogeneity in Multiple Sclerosis
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e1075
DO 10.1212/NXI.0000000000001075
VO 8
IS 6
A1 Carolina Cruciani
A1 Marco Puthenparampil
A1 Paula Tomas-Ojer
A1 Ivan Jelcic
A1 Maria Jose Docampo
A1 Raquel Planas
A1 Praveena Manogaran
A1 Roland Opfer
A1 Carla Wicki
A1 Markus Reindl
A1 Ilijas Jelcic
A1 Andreas Lutterotti
A1 Roland Martin
A1 Mireia Sospedra
YR 2021
UL http://nn.neurology.org/content/8/6/e1075.abstract
AB Background and Objectives Encouraged by the enormous progress that the identification of specific autoantigens added to the understanding of neurologic autoimmune diseases, we undertook here an in-depth study of T-cell specificities in the autoimmune disease multiple sclerosis (MS), for which the spectrum of responsible autoantigens is not fully defined yet. The identification of target antigens in MS is crucial for therapeutic strategies aimed to induce antigen-specific tolerance. In addition, knowledge of relevant T-cell targets can improve our understanding of disease heterogeneity, a hallmark of MS that complicates clinical management.Methods The proliferative response and interferon gamma (IFN-γ) release of CSF-infiltrating CD4+ T cells from patients with MS against several autoantigens was used to identify patients with different intrathecal T-cell specificities. Fresh CSF-infiltrating and paired circulating lymphocytes in these patients were characterized in depth by ex vivo immunophenotyping and transcriptome analysis of relevant T-cell subsets. Further examination of these patients included CSF markers of inflammation and neurodegeneration and a detailed characterization with respect to demographic, clinical, and MRI features.Results By testing CSF-infiltrating CD4+ T cells from 105 patients with MS against seven long-known myelin and five recently described GDP-l-fucose synthase peptides, we identified GDP-l-fucose synthase and myelin oligodendrocyte glycoprotein (35-55) responder patients. Immunophenotyping of CSF and paired blood samples in these patients revealed a significant expansion of an effector memory (CCR7− CD45RA−) CD27− Th1 CD4+ cell subset in GDP-l-fucose synthase responders. Subsequent transcriptome analysis of this subset demonstrated expression of Th1 and cytotoxicity-associated genes. Patients with different intrathecal T-cell specificities also differ regarding inflammation- and neurodegeneration-associated biomarkers, imaging findings, expression of HLA class II alleles, and seasonal distribution of the time of the lumbar puncture.Discussion Our observations reveal an association between autoantigen reactivity and features of disease heterogeneity that strongly supports an important role of T-cell specificity in MS pathogenesis. These data have the potential to improve patient classification in clinical practice and to guide the development of antigen-specific tolerization strategies.CP=control patient; EM=effector memory; FLAIR=fluid-attenuated inversion recovery; GDP-L-FS=GDP-l-fucose synthase; HD=healthy donor; HLA=human leukocyte antigen; IFN=interferon; IgG=immunoglobulin G; MBP=myelin basic protein; LP=lumbar puncture; MOG=myelin oligodendrocyte glycoprotein; MOGAD=myelin oligodendrocyte glycoprotein antibody–associated disease; MPRAGE=Magnetization Prepared - RApid Gradient Echo; MS=multiple sclerosis; PBMC=peripheral blood mononuclear cell; RA=rheumatoid arthritis; SI=stimulation index; TF=transcription factor