Proceedings of the 31st European Paediatric Rheumatology Congress: part 1

Introduction: Mevalonate kinase deficiency (MKD) is an autoinflammatory disease with an autosomal recessive inheritance caused by a mutation in the mevalonate kinase enzyme gene.Mevalonate Kinase enzyme contributes to the conversion of Mevalonate-5-Phosphate, an intermediate metabolite, which is essential for synthesis of main proteins involved in cholesterol biosynthesis, ubiquinones production, and protein prenylation.Existing research supports the idea that mevalonate metabolism, in particular, negatively influences the frequency of regulatory T cells (Treg) and T-helper 2 cells (Th2).Furthermore, mevalonate metabolism also has an impact on cell size and proliferation.Changes caused by MVK deficiency in macrophages/ antigen-presenting cells have been questioned in MKD patients until now.Despite the significant role of T cells in metabolism, the changes caused by MVK deficiency in T cells in MKD patients and their contribution to attacks and immunological disorders have not yet been studied.Objectives: Our study aims to investigate the changes in CD4+ T and Innate Lymphoid Cells (ILCs) which are counterparts of T lymphocytes, immunobiology resulting from mutations that lead to MVK deficiency in MKD patients.We hypothesized that individuals with MVK deficiency may induce certain changes, particularly in the development of Th17 and Treg cells.Methods: We categorised the patients as HIDS MKD patients in attack and HIDS patients in remission, paediatric patients using statins that simultaneously inhibit mevalonate metabolism and cholesterol biosynthesis, and healthy controls.We collected peripheral blood samples and isolated peripheric mononuclear blood cells (PBMC) from these patients and healthy volunteers.We collected serum samples from blood and quantified them using a LEGENDplex HU Th Cytokine Panel (12-plex) w/ VbP V02 panel.1x10 6 PBMC were investigated for CD4+ T cells phenotypes; Th1, Th2, Th17 and Treg cells.We stained the cell surfaces directly with ILCspecific antibodies.Results: There was no change in total ILCs, Th1 and Th17 cells, a significant decrease in Th2 cells and a significant increase in Treg cells in MVK patients.TCR-mediated T cell proliferation and activation were impaired in MVK patients. Conclusion:In patients with MVK deficiency, alterations in T cell phenotypes and T cell responses were observed, in particular a reduced type 2 immune response.These results support that MVK deficiency leads to defects in CD4+ T cell subtypes and T cell activation and proliferation in general, and shed light on the broad spectrum of immunodeficiency defects in the adaptive immune system Factor analysis was performed on the 37-gene MGS to model interrelationships among individual genes.While certain groups of genes were found to have shared variance, we identified a set of 18 genes with unique contributions to the overall MGS.Calculating a factor score for each sample, we showed that mitochondrial dysfunction is significantly abnormal in JDM treatment nave patients and it is still abnormal at early/later on-treatment timepoints even, relative to controls.This demonstrated that current treatment does not resolve this pathological mitochondrial signature even in those patients that have improved disease.This finding was observed in the PBMC RNAseq data as well.We found significant positive correlation between the MGS factor score derived from JDM treatment nave monocytes with the Manual Muscle Test (MMT8) score (p=0.0007,R 2 =0.4841).These data suggest that the signature could have strong clinical utility for biomarker development in blood. Conclusion:This study identified and validated a dysregulated mitochondrial signature in treatment nave JDM CD14+ monocytes, further validated in PBMCs, which positively correlated with muscle weakness by MMT8 score tool.This signature could have clinical implications as a biomarker of mitochondrial health in JDM, potentially useful for patient treatment optimisation.