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Differential Cytokine Changes in Patients with Myasthenia Gravis with Antibodies against AChR and MuSK.

Yilmaz V, Oflazer P, Aysal F, Durmus H, Poulas K, Yentur SP, Gulsen-Parman Y, Tzartos S, Marx A, Tuzun E, Deymeer F, Saruhan-Direskeneli G - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.

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.

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CD40L mRNA levels in the isolated CD4+ T cells.Expression levels from both treated and untreated patients in AChR-MG, MuSK-MG and CON groups are shown. Horizontal lines indicate mean values.
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pone.0123546.g002: CD40L mRNA levels in the isolated CD4+ T cells.Expression levels from both treated and untreated patients in AChR-MG, MuSK-MG and CON groups are shown. Horizontal lines indicate mean values.

Mentions: As an indispensable costimulatory molecule for specific ab production by B cells, CD40L mRNA expression was measured in freshly isolated CD4+ T cells as well. Expression of CD40L was lower both in MuSK-MG and AChR-MG groups compared with CON (p = 0.005 and p = 0.003, Fig 2).


Differential Cytokine Changes in Patients with Myasthenia Gravis with Antibodies against AChR and MuSK.

Yilmaz V, Oflazer P, Aysal F, Durmus H, Poulas K, Yentur SP, Gulsen-Parman Y, Tzartos S, Marx A, Tuzun E, Deymeer F, Saruhan-Direskeneli G - PLoS ONE (2015)

CD40L mRNA levels in the isolated CD4+ T cells.Expression levels from both treated and untreated patients in AChR-MG, MuSK-MG and CON groups are shown. Horizontal lines indicate mean values.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403992&req=5

pone.0123546.g002: CD40L mRNA levels in the isolated CD4+ T cells.Expression levels from both treated and untreated patients in AChR-MG, MuSK-MG and CON groups are shown. Horizontal lines indicate mean values.
Mentions: As an indispensable costimulatory molecule for specific ab production by B cells, CD40L mRNA expression was measured in freshly isolated CD4+ T cells as well. Expression of CD40L was lower both in MuSK-MG and AChR-MG groups compared with CON (p = 0.005 and p = 0.003, Fig 2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.

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.

Show MeSH
Related in: MedlinePlus