title: Differential Cytokine Changes in Patients with Myasthenia Gravis with Antibodies against AChR and MuSK.
abstract: Neuromuscular transmission failure in myasthenia gravis (MG) is most commonly elicited by autoantibodies (ab) to the acetylcholine receptor or the muscle-specific kinase, constituting AChR-MG and MuSK-MG. It is controversial whether these MG subtypes arise through different T helper (Th) 1, Th2 or Th17 polarized immune reactions and how these reactions are blunted by immunosuppression. To address these questions, plasma levels of cytokines related to various Th subtypes were determined in patients with AChR-MG, MuSK-MG and healthy controls (CON). Peripheral blood mononuclear cells (PBMC) were activated in vitro by anti-CD3, and cytokines were quantified in supernatants. In purified blood CD4+ T cells, RNA of various cytokines, Th subtype specific transcription factors and the co-stimulatory molecule, CD40L, were quantified by qRT-PCR. Plasma levels of Th1, Th2 and Th17 related cytokines were overall not significantly different between MG subtypes and CON. By contrast, in vitro stimulated PBMC from MuSK-MG but not AChR-MG patients showed significantly increased secretion of the Th1, Th17 and T follicular helper cell related cytokines, IFN-γ, IL-17A and IL-21. Stimulated expression of IL-4, IL-6, IL-10 and IL-13 was not significantly different. At the RNA level, expression of CD40L by CD4+ T cells was reduced in both AChR-MG and MuSK-MG patients while expression of Th subset related cytokines and transcription factors were normal. Immunosuppression treatment had two effects: First, it reduced levels of IL12p40 in the plasma of AChR-MG and MuSK-MG patients, leaving other cytokine levels unchanged; second, it reduced spontaneous secretion of IFN-γ and increased secretion of IL-6 and IL-10 by cultured PBMC from AChR-MG, but not MuSK-MG patients. We conclude that Th1 and Th17 immune reactions play a role in MuSK-MG. Immunosuppression attenuates the Th1 response in AChR-MG and MuSK-MG, but otherwise modulates immune responses in AChR-MG and MuSK-MG patients differentially.
authors.affiliation: Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
authors.forename: Vuslat
authors.initials: V
authors.lastname: Yilmaz
authors.affiliation: Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
authors.forename: Piraye
authors.initials: P
authors.lastname: Oflazer
authors.affiliation: Department of Neurology, Bakirkoy Research and Training Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey.
authors.forename: Fikret
authors.initials: F
authors.lastname: Aysal
authors.affiliation: Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
authors.forename: Hacer
authors.initials: H
authors.lastname: Durmus
authors.affiliation: Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Poulas
authors.affiliation: Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
authors.forename: Sibel P
authors.initials: SP
authors.lastname: Yentur
authors.affiliation: Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
authors.forename: Yesim
authors.initials: Y
authors.lastname: Gulsen-Parman
authors.affiliation: Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Socrates
authors.initials: S
authors.lastname: Tzartos
authors.affiliation: Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Marx
authors.affiliation: Department of Neuroscience, Institute for Experimental Medical Research, University of Istanbul, Istanbul, Turkey.
authors.forename: Erdem
authors.initials: E
authors.lastname: Tuzun
authors.affiliation: Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
authors.forename: Feza
authors.initials: F
authors.lastname: Deymeer
authors.affiliation: Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
authors.forename: Güher
authors.initials: G
authors.lastname: Saruhan-Direskeneli
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000276:immunology*; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism; D002469:Cell Separation; D016207:Cytokines / Q000097:blood*; D003710:Demography; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D053762:Interleukin-12 Subunit p40 / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D009157:Myasthenia Gravis / Q000097:blood* / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D017252:CD3 Complex; D016207:Cytokines; D053762:Interleukin-12 Subunit p40; D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D023201:CD40 Ligand; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases