Over the last decade, a significant body of emerging evidence has supported a role for PTMs of several auto antigens in the pathogenesis of diverse autoimmune dis eases. Modified autoantigens kinase inhibitor Afatinib have been shown to relocalize to other cellular compartments including apoptotic blebs during cell stress. Such modified autoantigens have been proposed to elicit immune responses because they appear foreign to T and B cells or because the modifications may alter their processing and presentation by antigen presenting cells. For example, many diverse autoantigens are substrates for cleavage by caspases, and some autoanti bodies are better able to recognize cleaved antigens than native counterparts.

Similarly, we and others have shown that many different antigens are phosphorylated, for instance, transient phosphorylation of serine argi nine rich splicing family members during apoptosis leads Inhibitors,Modulators,Libraries to their association with the U1 snRNP and U3 snoRNP autoantigen complexes, and can commonly be Inhibitors,Modulators,Libraries recognized by SLE sera in a phosphorylation dependent manner. However, to date, few studies have specifically exam ined the role of post translational modifications in the context of NETs within SLE. For instance, while van Bavel and colleagues identified in a subset of patients with SLE autoantibodies against acetylated his tone H2B tails, histone H4 and histone H3K27Me3, the relationship of these marks to those within NETs remains unclear, and SLE autoanti bodies may recognize other histone PTMs.

Such PTMs may play an important role in SLE pathogenesis, since a unifying characteristic of most SLE associated autoanti gens is that they contain Inhibitors,Modulators,Libraries either DNA or RNA with many of the associated protein components targeted by PTMs. While NETs represent a strong candidate as a source of diverse exposed cryptic epitopes that may lead to autoimmunity, only a single PTM found on NET his tones has been well characterized. Inhibitors,Modulators,Libraries Specifically, NET his tones harbor citrulline residues, a PTM mediated by the peptidyl arginine deiminase family of enzymes during reversible deimination of arginine residues. Autoantibodies directed against citrullinated proteins are highly specific at diagnosis of rheumatoid arthritis, and have also been found in a collagen induced arthritis model of RA. Citrullination of histones arising from PAD 4 activity during NETosis was recently shown to be a specific marker of NETs and necessary for NET formation.

Accordingly, anti bacterial innate immunity is considerably inhibited in PAD 4 deficient mice. To date, while the protein components of NETs have been Inhibitors,Modulators,Libraries systematically identified, such no studies have broadly profiled the PTM state of their histones. We, therefore, hypothesized that NETs and unique associated histone PTMs are capable of inducing auto antibodies that target histones and lead to subsequent autoimmunity.