Background/Purpose: Juvenile dermatomyositis (JDM) is a debilitating pediatric autoimmune disease manifesting with characteristic rash and proximal muscle weakness. We investigated signaling abnormalities in immune cell subsets from treatment-naïve JDM patients and healthy controls.

Methods: To delineate signaling abnormalities, mass cytometry coupled with phosphoprotein antibodies was performed with peripheral blood mononuclear cells from seventeen treatment-naïve JDM patients and controls.

Results: The percentages of peripheral NK cells were lower while frequencies of naïve Β cells and naïve CD4 T cells were higher in JDM patients than controls. These cell frequency differences were attenuated in paired patient samples with cessation of active disease. A large number of signaling differences were identified in treatment-naïve JDM patients compared to controls. Classification models incorporating feature selection demonstrated that differences in PLCγ2 phosphorylation comprised 10 of the 12 features (i.e., phosphoprotein in a specific immune cell subset) distinguishing the JDM patients from healthy controls. As NK cells represented 5 of these 12 features, further studies focused on the critical PLCγ2 pathway in NK cells which is responsible for stimulating calcium flux and cytotoxic granule movement. No differences were detected in upstream kinases (Itk/Btk, Syk/ZAP70) or total PLCγ2 protein levels. The decreased phosphorylation of NK cell PLCγ2 and downstream MAPKAPK2 was partially attenuated in treatment-naïve JDM patients with cessation of active disease. Furthermore, suppressed PLCγ2 phosphorylation in treatment-naïve JDM patient NK cells resulted in decreased calcium flux.

Conclusion: The novel identification of dysregulation of PLCγ2 phosphorylation and decreased calcium flux in NK cells from treatment-naïve JDM patients provides potential mechanistic insight into JDM pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dysregulated-nk-cell-plc/