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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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Plasma IL-12p40 levels.Groups of patients with AChR-MG, MuSK-MG under immunosuppressive treatment [IS (+)], untreated [IS (-)] and CON are shown. Horizontal lines indicate mean values.
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pone.0123546.g003: Plasma IL-12p40 levels.Groups of patients with AChR-MG, MuSK-MG under immunosuppressive treatment [IS (+)], untreated [IS (-)] and CON are shown. Horizontal lines indicate mean values.

Mentions: The effects of IS were evaluated separately in plasma and cell culture supernatants, because a considerable proportion of the patient groups were on treatment. A decrease in plasma IL-12p40 levels was observed in IS treated AChR-MG patients (n: 16) compared with untreated (n: 25) patients (p = 0.005), whereas the difference to CON was not statistically significant (Fig 3). A similar effect was also detected in IS treated MuSK-MG patients (n: 19), who had significantly lower IL-12p40 levels than CON (p = 0.004, Fig 3). This effect was found out to be more pronounced when the entire MG cohort (both AChR- and MuSK-Ab positive patients) was analyzed. IS treated MG patients had lower plasma levels of IL-12p40 (1.5 pg/ml) than non-treated MG patients (3.6 pg/ml, p < 0.001) and CON (2.5 pg/ml, p = 0.006). Plasma levels of IL-13, IL-10, IFN-γ and IL-17A were not significantly different between these subgroups (not shown).


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)

Plasma IL-12p40 levels.Groups of patients with AChR-MG, MuSK-MG under immunosuppressive treatment [IS (+)], untreated [IS (-)] and CON 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.g003: Plasma IL-12p40 levels.Groups of patients with AChR-MG, MuSK-MG under immunosuppressive treatment [IS (+)], untreated [IS (-)] and CON are shown. Horizontal lines indicate mean values.
Mentions: The effects of IS were evaluated separately in plasma and cell culture supernatants, because a considerable proportion of the patient groups were on treatment. A decrease in plasma IL-12p40 levels was observed in IS treated AChR-MG patients (n: 16) compared with untreated (n: 25) patients (p = 0.005), whereas the difference to CON was not statistically significant (Fig 3). A similar effect was also detected in IS treated MuSK-MG patients (n: 19), who had significantly lower IL-12p40 levels than CON (p = 0.004, Fig 3). This effect was found out to be more pronounced when the entire MG cohort (both AChR- and MuSK-Ab positive patients) was analyzed. IS treated MG patients had lower plasma levels of IL-12p40 (1.5 pg/ml) than non-treated MG patients (3.6 pg/ml, p < 0.001) and CON (2.5 pg/ml, p = 0.006). Plasma levels of IL-13, IL-10, IFN-γ and IL-17A were not significantly different between these subgroups (not shown).

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