Neutrophils Lose the Capacity to Suppress T Cell Proliferation Upon Migration Towards Inflamed Joints in Juvenile Idiopathic Arthritis

Abstract

Neutrophils are highly abundant in synovial fluid of rheumatic inflamed joints. In oligoarticular juvenile idiopathic arthritis (JIA), synovial fluid neutrophils have impaired effector functions and altered phenotype. We hypothesized that these alterations might impact the immunoregulatory interplay between neutrophils and T cells. In this study we analyzed the suppressive effect of neutrophils, isolated from blood and synovial fluid of oligoarticular JIA patients, on CD4+ T cells activated by CD3/CD28 stimulation. JIA blood neutrophils suppressed T cell proliferation but synovial fluid neutrophils from several patients did not. The loss of T cell suppression was replicated in an in vitro transmigration assay, where healthy control neutrophils migrated into synovial fluid through transwell inserts with endothelial cells and synoviocytes. Non-migrated neutrophils suppressed proliferation of activated CD4+ T cells, but migrated neutrophils had no suppressive effect. Neutrophil suppression of T cells was partly dependent on reactive oxygen species (ROS), demonstrated by impaired suppression in presence of catalase. Migrated neutrophils had reduced ROS production compared to non-migrated neutrophils. A proteomic analysis of transwell-migrated neutrophils identified alterations in proteins related to neutrophil ROS production and degranulation, and biological processes involving protein transport, cell-cell contact and inflammation. In conclusion, neutrophils in synovial fluid of children with JIA have impaired capacity to suppress activated T cells, which may be due to reduced oxidative burst and alterations in proteins related to cell-cell contact and inflammation. The lack of T cell suppression by neutrophils in synovial fluid may contribute to local inflammation and autoimmune reactions in the JIA joint.

Exposure to proton pump inhibitors is associated with the development of pediatric autoimmune diseases

“…In addition, ROS are necessary in suppression of T-cells. Therefore, lack of this suppression may contribute to local inflammations and autoimmune reactions ( 47 ). Hence, the link between recent PPI exposures, neutrophil's ROS production, and the onset of ADs require further studies.…”

Suppression of T-Cell Proliferation by Normal Density Granulocytes Led to CD183 Downregulation and Cytokine Inhibition in T-Cells

“…A few studies report that blood NDGs must be activated to exhibit MDSC function (4)(5)(6)(7)(8). However, we and other authors have observed inhibitory capacities without neutrophil activators (12,21,22). In our previous study, we showed that NDGs are not activated during the isolation process, but become activated approximately one hour after coincubation with activated T-cells, as measured by the surface expression of the neutrophil activation markers CD11b and CD66b (21).…”

Synovial Monocytes Drive the Pathogenesis in Oligoarticular Juvenile Idiopathic Arthritis via IL-6/JAK/STAT Signalling and Cell-Cell Interactions

“…SF polarization of healthy monocytes does not replicate the increased co-stimulatory capabilities observed in the patients’ synovial monocytes; nor does it induce a decrease in ROS production and phagocytosis, as previously observed (7). We have recently shown that migration through a transwell system influences the effector functions of neutrophils (8). To determine how the patient’s synovial monocytes may acquire the remaining features, we investigated the effect of migration through an artificial synovial membrane towards SF on healthy monocytes ( supplementary figure 5A ).…”

“…Here, we confirmed that synovial monocytes express high levels of co-stimulatory markers and further showed that the monocytes induce proliferation and activation of T-cells. We have recently shown that synovial neutrophils lose their capacity to suppress T-cell proliferation, and that healthy neutrophils lose this ability upon migration (8). Thus, an increase in activation of T-cells by monocytes, and a loss of suppressive capability by neutrophils may explain the expansion and activation of T-cells within the joint of patients with oJIA.…”

“…T-and B-cells are thought to play a role, given the genetic relationship to MHC class II alleles and the presence of ANAs (4)(5)(6). Though, the contribution of members from the innate immune system, such as monocytes, is becoming increasingly recognized (7)(8)(9)(10).…”