Here we aimed to shed light on the role of the NOX2 complex in handling of secondary necrotic cells (SNECs) and associated consequences for inflammation and autoimmunity during lupus.
Though recent reports suggest that neutrophil extracellular traps (NETs) are a source of antigenic nucleic acids in systemic lupus erythematosus (SLE), we recently showed that inhibition of NETs by targeting the NADPH oxidase complex via cytochrome b-245, β polypeptide (cybb) deletion exacerbated disease in the MRL.Faslpr lupus mouse model.
We found that NCF1 and NADPH oxidase 2 (NOX2) complex-derived ROS is an important regulator of several chronic inflammatory disorders by using models for rheumatoid arthritis, multiple sclerosis, psoriasis and psoriasis arthritis, gout, and lupus.
These data confirm the effects of rs3813946 on CR2 transcription, identifying the 5' UTR to be a novel regulatory element for the CR2 gene in which variation may alter gene function and modify the development of lupus.
Single-nucleotide polymorphism 1 (rs3813946), located in the 5' untranslated region of the CR2 gene, altered transcriptional activity, suggesting a potential mechanism by which CR2 could contribute to the development of lupus.
Characterization of type I complement C2 deficiency MHC haplotypes. Strong conservation of the complotype/HLA-B-region and absence of disease association due to linked class II genes.
OPN production has been associated with several pathological conditions, including autoimmune diseases (e.g. lupus, multiple sclerosis and rheumatoid arthritis) and cancer.
We further detected five distinct inflammatory and metabolic pathways such as TWEAK, osteopontin, endochondral ossification, fluropyrimidine activity and urea cycle and metabolism of amino groups that significantly contribute to the pathogenesis of lupus (P < 0.05).
We examined a polymorphism of osteopontin for an association with lupus in humans in an effort to determine whether there is any evidence that a genetic predisposition to altered osteopontin expression might explain the overexpression seen in human SLE patients.
Glomerular expression of osteopontin in biopsies of human crescentic glomerulonephritis (N = 25), IgA nephropathy with crescents (N = 2), and diffuse proliferative lupus glomerulonephropathy with crescents (N = 1) was studied by immunohistochemistry, in situ hybridization, and combined immunohistochemistry/in situ hybridization.
Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.
The identification of new mutation in C1qA gene that disrupts the start codon (ATG to AGG (Met1Arg)) has not been reported previously and it expands the knowledge and importance of the C1q gene in the pathogenesis of lupus especially in the high-risk African-American population.
Further, we confirmed the genetic association between lupus and 5 additional lupus susceptibility loci (ITGAM, MSH5, CFB, STAT4, and FCGR2A; P = 7.5 × 10⁻¹¹, P = 5.2 × 10⁻⁸, P = 8.7 × 10⁻⁷ , P = 0.0058, and P = 0.0070, respectively), and provided evidence, for the first time, of genome-wide significance for the association between lupus in African American patients and ITGAM and MSH5 (HLA region).