Cutting Edge: Processing of Oxidized Peptides in Macrophages Regulates T Cell Activation and Development of Autoimmune Arthritis

Abstract

APCs are known to produce NADPH oxidase (NOX) 2derived reactive oxygen species; however, whether and how NOX2-mediated oxidation affects redox-sensitive immunogenic peptides remains elusive. In this study, we investigated a major immunogenic peptide in glucose-6-phosphate isomerase (G6PI), a potential autoantigen in rheumatoid arthritis, which can form internal disulfide bonds. Ag presentation assays showed that presentation of this G6PI peptide was more efficient in NOX2-deficient ( mutant) mice, compared with wild-type controls. IFN-γinducible lysosomal thiol reductase (GILT), which facilitates disulfide bond-containing Ag processing, was found to be upregulated in macrophages from Ncf1 mutant mice. Ncf1 mutant mice exhibited more severe G6PI peptide-induced arthritis, which was accompanied by the increased GILT expression in macrophages and enhanced Ag-specific T cell responses. Our results show that NOX2-dependent processing of the redox-sensitive autoantigens by APCs modify T cell activity and development of autoimmune arthritis.

Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells

“…Besides being important for the defense against infectious organisms, ROS are believed to modify signaling within and between cells. ROS could regulate inflammation by 1) acting as a synaptic transmitter, which down‐regulates the interacting T cell , 2) increasing the pH in endosomes thereby modifying peptide loading on the MHC , and 3) modifying intracellular signaling pathways by oxidizing protein thiols . It is thus probable that NOX‐2–derived ROS affect autoimmune disease and inflammatory pathways in general, both via effects on pathways within the NOX‐2–expressing macrophages and via effects on interacting cells such as T cells.…”

Regulatory T cells control epitope spreading in autoimmune arthritis independent of cytotoxic T‐lymphocyte antigen‐4

“…11 The explanation could be that GPI is uniquely precipitated on the joint surface and the activation of GPI- reactive T and B cells occurs in joint-draining lymph nodes. 10,14 The GIA model is an acute (self-limited in time) arthritis model with remission occurring within 30 days in WT mice. However, ablation of Treg cells at either the priming or onset phase, results in a previously unobserved chronicity of the disease (Fig.…”

“…GIA is an acute autoimmune disease model with typical arthritis symptoms appearing on days 10-12 and remission within 30 days after immunization. 14 In contrast to the rebound expansion of Treg cells in naive DEREG mice after DT treatment, there was no obvious increase in Treg cells during the disease development in the GIA model between DEREG and control mice upon DT treatment (see Supplementary material, Fig. S2).…”

Inflammatory consequences of inherited disorders affecting neutrophil function

“…This may involve altered oxidation of the T-cell surface, antigen processing, or oxidation of presented autoantigens. [101][102][103] Interestingly, mice with an NCF4 phosphatidylinositol 3-phosphate-binding mutation show enhanced susceptibility to collagen-induced arthritis but not to mannoseinduced psoriatic arthritis, whereas NCF1-deficient mice are susceptible to both. 104 This suggests that the effects of NADPH oxidase ROS can depend on the level and/or compartment in which they are generated.…”