ROLE OF CYTOKINE SIGNALING PATHWAYS IN THE DEVELOPMENT OF AUTOIMMUNE DISORDERS

Abstract

The imbalance of Th17/Treg is thought to be controlled by the dysregulation of the cytokine network in systemic lupus erythematosus (SLE) and other autoimmune diseases, but little is known about the quantitative relationships underlying this imbalance. This study aimed to model and experimentally test the mechanism of Treg suppression resistance that is bestowed by cytokines. 135 patients (active SLE, inactive SLE, and healthy controls) were included in a Cytokine Dysregulation Index (CDI) from ODE modeling, in vitro co-culture suppression, and ex vivo peripheral blood mononuclear cell (PBMC) analysis, and these yielded a Cytokine Dysregulation Index area under the curve (AUC) of 0.942 and a diagnostic odds ratio (DOR) of 84.9 for the diagnosis of active SLE. The half-maximal inhibitory concentration of TREG-mediated suppressions was changed to 1:29.6 with SLE-like cytokine cocktails, and the transdifferentiation index of FoxP3+ T cells to ROR-gamma+FoxP3+ doubled to 1.58. Sensitivity analysis results revealed that the most elastic was IL-21 (elasticity index 2.08), and kinetic analysis results revealed that differences in the Th17/TREG ratio were seen at 6 days of exposure to the SLE serum. The results of the SEM indicated that the mediation of structural equation modeling between the effect of cytokines on TREG dysfunction was 67-72% CDI. Given these findings, a rebalancing of the networks rather than a blockade with cytokines should be the therapeutic target, and the CDI can be used as a quantitative measure of autoimmune disease.