Variants in Nicotinamide Adenine Dinucleotide Phosphate Oxidase Complex Components Determine Susceptibility to Very Early Onset Inflammatory Bowel Disease

An inflammatory bowel disease–risk variant in INAVA decreases pattern recognition receptor–induced outcomes

“…This was associated with an INAVA-dependent role for induction of the autophagy-associated gene, ATG5, whereas induction of ATG10 and immunity-related GTPase M (IRGM) expression was not INAVA dependent ( Figure 9E). We verified that ATG5 was required for optimal NOD2-induced autophagy (Supplemental Figure 20, C and D) and bacterial clearance (Supplemental Figure clearance can increase the risk for IBD (5,(36)(37)(38), and PRR-initiated pathways contribute to intracellular bacterial clearance (2). As the rs7554511 IBD risk variant leads to reduced INAVA expression and reduced PRR-induced signaling and cytokines, we questioned if INAVA was required for optimal macrophage-mediated bacterial clearance.…”

“…been well described to be associated with early-onset IBD (36,37,48). The decreased responses through PRR-initiated pathways in INAVA risk carriers may also contribute to impaired recruitment of immune cells and other critical innate functions, including innateinstructed adaptive immune outcomes.…”

NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL-1α/G-CSF axis

“…4,9,28,41 Chronic inflammatory complications as well as autoimmune manifestations are associated with CGD, and hypomorphic phox alleles are linked to autoimmunity and inflammatory bowel disease. 1,[7][8][9][10] How NADPH oxidase deficiency contributes to these disorders is incompletely understood. Prior studies in murine CGD have focused on pathogen or pathogen-dependent molecular pattern (PAMP)-dependent models to demonstrate hyperinflammatory responses in CGD, which have been associated with amplified nuclear factor-kB (NF-kB) activation, elevated proinflammatory cytokines such as TNFa, IL-6 Figure 4.…”

“…[2][3][4][5][6] Moreover, NADPH oxidase gene variants are linked to lupus, rheumatoid arthritis, and inflammatory bowel disease. [7][8][9][10] However, insights into the role of NADPH oxidase in regulating inflammatory responses to sterile endogenous ligands are lacking, an important question given the association of NADPH oxidase deficiency with noninfectious inflammatory disorders. "Sterile inflammation" is an important component of many autoimmune diseases, trauma, ischemic or toxic injury, and is primarily driven by endogenous danger-associated molecular patterns (DAMPs).…”

Systemic Lupus Erythematosus-associated Neutrophil Cytosolic Factor 2 Mutation Affects the Structure of NADPH Oxidase Complex

“…Our assessment that this variant has reduced function is further supported by the fact that the NCF2 His-389 3 Gln variant was reported in patients with very early onset inflammatory bowel disease. At least in one such subject, impaired ROS production and function was reported in primary leukocytes (30). The occurrence of this NCF2 variant in two different autoimmune diseases strongly supports its functional importance.…”