Platelet activation linked to inflammation in MG

By Litha Mfiki

A study published in Nature Communications shows that platelets play a pro-inflammatory role in acetylcholine receptor–positive immunotherapy-naive myasthenia gravis (nMG), with activation markers and immune interactions correlating with disease severity.

“Our findings reveal that nMG platelets exhibit a distinct pro-inflammatory phenotype, driving NETs [neutrophil extracellular trap] formation, which in turn amplifies platelet activation, establishing a reciprocal activation loop,” write Qi Wen (Xuanwu Hospital, Capital Medical University, Beijing) and colleagues.

This “may play a critical role in sustaining and exacerbating systemic inflammation in MG, potentially driving disease progression,” they say.

The researchers analyzed peripheral blood mononuclear cells from 209 patients with nMG, 119 with minimal clinical status (MMS), and 114 healthy controls. They observed increased platelet counts in patients with nMG compared with controls, and increased platelet activation in those with nMG and those with MMS versus controls, with platelets from these patients showing increased expression of the activation marker CD62P.

Compared with control platelets, those from patients with nMG also had higher levels of soluble CD40 ligand, which is released by activated platelets, and this correlated positively with quantitative MG score. Platelets from patients with nMG and those with MMS had reduced size and complexity versus those from controls, consistent with the release of granular contents upon activation.

Together this suggests “a chronic state of platelet activation in MG patients, which is associated with disease severity,” say the researchers.

Platelets from patients with nMG formed aggregates with leukocytes, particularly neutrophils, in line with disease severity. Notably, aggregate formation decreased after intravenous immunoglobulin treatment. Neutrophils from patients with nMG promoted NET formation, which in turn further activated platelets, establishing a reciprocal loop.

In vitro, platelets from patients with nMG enhanced CD4+ T-cell proliferation and promoted differentiation into T helper (Th)1 and Th17 subsets, while suppressing regulatory T-cell responses.

The inflammatory molecule RANTES (chemokine ligand 5) emerged as a key mediator. Neutralizing RANTES reduced Th1 cytokine production and sCD40L levels. Plasma RANTES levels correlated positively with MG severity.

“These findings highlight platelet activation as a key contributor to MG-associated inflammation and suggest a potential therapeutic target for modulating immune dysregulation in MG,” the authors conclude.

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