Our finding certain of these plasma proteins can signal through T

Our finding certain of these plasma proteins can signal through TLR4 to induce the production of an array of inflammatory cytokines, including those upregulated in OA. Our find ings suggest that plasma selleckchem Abiraterone proteins present in OA synovial fluid, whether through exudation from the plasma or production by synovial tissues, could contribute Inhibitors,Modulators,Libraries to low grade inflammation in OA by functioning as DAMPs. Inhibitors,Modulators,Libraries Introduction Neutrophil extracellular traps were first described in 2004 as web like structures that trap and neutralize microbes at sites of infection. Neutrophils, a first line of defense against microorganisms during such encounters, produce these highly modified chroma tin webs through a cellular suicide program distinct from apoptosis Inhibitors,Modulators,Libraries and necrosis, termed NETosis.

In addition to neutrophil antimicrobial proteins, NETs are comprised of chromatin components, Inhibitors,Modulators,Libraries including histones. Because NETs are extracellular and typically in an inflammatory environment, their proximity to compo nents of the adaptive and innate immune systems might provide an immunogenic substrate for autoimmune responses during regular encounters with commensal and pathogenic microbes. Indeed, an emerging and growing body of literature supports a putative link between NETs and autoimmu nity. Baker et al. identified circulating NETs in the blood of pediatric patients with malaria, a subset of whom also exhibited signs of an autoimmune response. A more recent study identified a subset of patients with lupus nephritis whose sera were impaired in degrading NETs, suggesting that such impairment could be pathogenic.

Two recent studies reported activa tion of plasmacytoid dendritic cells by com plexes between NETs and antimicrobial peptides such as LL 37 that engage Toll like receptor 9 and result in Type I interferon production, a process known to be associated with SLE. Anti histone antibodies are found in 70% to 80% of patients with idiopathic SLE, and in more Inhibitors,Modulators,Libraries than 90% of patients with drug induced lupus. Furthermore, the presence KPT-330 mechanism of such antibodies is a highly specific sero logical feature that distinguishes both of these lupus var iants from other autoimmune diseases. Patients with drug induced lupus due to procainamide or hydra lazine most commonly do not have antibodies directed against non histone nuclear antigens, a serological fea ture frequently used to distinguish between drug induced and idiopathic SLE. Further, the ten dency and degree to which such drugs are covalently modified by acetylation critically influences their ten dency to induce anti histone antibodies and lupus. Finally, the capacity of several drugs to serve as neutrophil myeloperoxidase substrates in vitro is asso ciated with their ability to induce lupus in vivo.

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