Reactive oxygen species (ROS) are a heterogeneous group of highly reactive molecules that oxidize targets in a biologic system. During steady-state conditions, ROS are constantly produced in the electron-transport chain during cellular respiration and by various constitutively active oxidases. ROS production can also be induced by activation of the phagocyte NADPH oxidase 2 (NOX2) complex in a process generally referred to as an oxidative burst. The induced ROS have long been considered proinflammatory, causing cell and tissue destruction. Recent findings have challenged this inflammatory role of ROS, and today, ROS are also known to regulate immune responses and cell proliferation and to determine T-cell autoreactivity. NOX2-derived ROS have been shown to suppress antigen-dependent T-cell reactivity and remarkably to reduce the severity of experimental arthritis in both rats and mice. In this review, we discuss the role of ROS and the NOX2 complex as suppressors of autoimmunity, inflammation, and arthritis. Antioxid. Redox Signal. 15, 2197–2208.

Psoriasis (Ps) and psoriasis arthritis (PsA) are poorly understood common diseases, induced by unknown environmental factors, affecting skin and articular joints. A single i.p. exposure to mannan from Saccharomyces cerevisiae induced an acute inflammation in inbred mouse strains resembling human Ps and PsA-like disease, whereas multiple injections induced a relapsing disease. Exacerbation of disease severity was observed in mice deficient for generation of reactive oxygen species (ROS). Interestingly, restoration of ROS production, specifically in macrophages, ameliorated both skin and joint disease. Neutralization of IL-17A, mainly produced by γδ T cells, completely blocked disease symptoms. Furthermore, mice depleted of granulocytes were resistant to disease development. In contrast, certain acute inflammatory mediators (C5, Fcγ receptor III, mast cells, and histamine) and adaptive immune players (αβ T and B cells) were redundant in disease induction. Hence, we propose that mannan-induced activation of macrophages leads to TNF-α secretion and stimulation of local γδ T cells secreting IL-17A. The combined action of activated macrophages and IL-17A produced in situ drives neutrophil infiltration in the epidermis and dermis of the skin, leading to disease manifestations. Thus, our finding suggests a new mechanism triggered by exposure to exogenous microbial components, such as mannan, that can induce and exacerbate Ps and PsA.

Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations inSTAT3(21%) and RAS-MAPK pathway genes (21%) as well as inDDX3X(29%) and epigenetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies.

Aims: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the phagocyte reactive oxygen species (ROS)–producing NOX2 enzyme complex and characterized by recurrent infections associated with hyperinflammatory and autoimmune manifestations. A translational, comparative analysis of CGD patients and the corresponding ROS-deficient Ncf1 ^m1J mutated mouse model was performed to reveal the molecular pathways operating in NOX2 complex deficient inflammation. Results: A prominent type I interferon (IFN) response signature that was accompanied by elevated autoantibody levels was identified in both mice and humans lacking functional NOX2 complex. To further underline the systemic lupus erythematosus (SLE)-related autoimmune process, we show that naïve Ncf1 ^m1J mutated mice, similar to SLE patients, suffer from inflammatory kidney disease with IgG and C3 deposits in the glomeruli. Expression analysis of germ-free Ncf1 ^m1J mutated mice reproduced the type I IFN signature, enabling us to conclude that the upregulated signaling pathway is of endogenous origin. Innovation: Our findings link the previously unexplained connection between ROS deficiency and increased susceptibility to autoimmunity by the discovery that activation of IFN signaling is a major pathway downstream of a deficient NOX2 complex in both mice and humans. Conclusion: We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans. Antioxid. Redox Signal . 21, 2231–2245.

Clonal hematopoiesis (CH) is a phenomenon in which somatic mutations originating from hematopoietic progenitors are detected in peripheral blood cells 1,2. The prevalence of CH increases with age, and CH can be detected in 10-25% of healthy, elderly individuals 1-4. Very sensitive methods may allow somatic mutation detection in blood cells in 95% of 50-60-year olds 5. CH confers risk for myeloid malignancy and death 1,2. In addition, recent data has suggested that CH is also a risk factor for cardiovascular disease 1,6,7. In mice, Tet2 loss-offunction in myeloid cells alone promoted atherosclerosis and proinflammatory cytokine production 6. Proinflammatory and dysregulated immune responses play roles in the pathogenesis of multiple diseases. As an example, rheumatoid arthritis (RA) is a chronic autoimmune disease which leads to joint destruction. Despite improved disease outcomes with modern treatments, RA patients have increased risk for death and cardiovascular disease. CH has not been studied in the context of RA previously, except for one study containing self-reported disease history of arthritis 3. Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome (hMDS) are characterized by hypocellular bone marrow and peripheral-blood cytopenias, and are difficult to distinguish 8. Although T cells cause hematopoietic stem cell destruction in AA, cytogenetic abnormalities occur in 4-11%, and CH occurs in up to 50% of AA cases 8. AA confers a substantial risk for hematological malignancy 8 .

Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.