The potential benefits could include the identification of new ECM remodeling biomarkers with increased tissue specificity when used in conjunction with ECM degradation fragments.
Their sensitivity and specificity for the diagnosis of RA is similar (sensitivity about 50–60%, specificity about 85–95%) (Mjaavatten et al., 2010; Neogi et al., 2010; Nicaise-Roland et al., 2013). Citrullination is a posttranslational modification of a protein (deimination of arginine carried out by petidylarginine deiminases [PADs]); such modifications are increasingly being recognized as targets of autoimmunity.7 Although most ACPA-positive patients are also rheumatoid factor positive, ACPAs have higher specificity for RA. 1.
Induction of protein citrullination and auto-antibodies production in murine exposed to nickel nanomaterials. A number of therapeutic options are available.71 The introduction of targeted biological therapies directed against cytokines, such as tumor necrosis factor or interleukin-6, or against immune cell populations, such as T cells and B cells, has greatly improved the outcome of the disease in a large number of patients. doi: 10.1038/nrgastro.2017.183, 38. The editor and reviewers' affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review.
doi: 10.1038/cgt.2015.21, 17. For example, the principal nucleus of the bed nucleus of the stria terminalis is sexually dimorphic, with males having a larger volume and more cells compared to females in most species studied. Cook et al. Brentville VA, Metheringham RL, Gunn B, Symonds P, Daniels I, Gijon M, et al. The citrullination modification process is catalyzed by the peptidyl arginine deiminases (PADIs) family. Importantly, disrupting the acetylation of histone H3 and H4 within the preoptic area (POA), the major brain region controlling adult sexual behavior disrupts components of adult male sex behavior (Matsuda et al., 2011). Citrullination modification of proteins may be an important event for the host to recognize foreign antigens.
Qu et al. From: Kelley and Firestein's Textbook of Rheumatology (Tenth Edition), 2017, Gary S. Firestein, in Kelley and Firestein's Textbook of Rheumatology (Tenth Edition), 2017. The immune complexes (ICs), conjugates of antibodies with their target antigens, activate innate immune cells via the Fcr receptors on their cell surface and augment inflammation.
Witalison EE, Cui X, Causey CP, Thompson PR, Hofseth LJ.
H3K27me3 is deposited at both promoters and enhancers by the polycomb repressive complex 2 (PRC2) and mediates recruitment of PRC1, resulting in chromatin condensation and transcriptional repression.
Figure 3.7. Ju and Wang (50) provided a user-friendly web-server for CKSAAP_CitrSite. This review focuses on the mechanisms, regulation, and the clinical significance of citrullinated proteins in the field of gastrointestinal diseases.
Ju Z, Wang SY. A key characteristic of anti-CCP antibodies that adds to their overall value is … Gene (2018) 664:78–83. Bioorg Med Chem Lett. In the cancer immunity area, the new epitopes caused by post-translational modification of proteins may provide a novel target for cancer-specific immune therapy. This type of protein modification has been linked to apoptosis and terminal differentiation of cells, conditions that enables activation of PAD by increasing intracellular calcium levels. Both smoking and P. gingivalis have been suggested to facilitate RA autoimmunity by promoting citrullination.
Citrullination of CXCL8 by peptidylarginine deiminase alters receptor usage, prevents proteolysis, and dampens tissue inflammation. Longitudinal course of rheumatoid arthritis from preclinical stages to joint damage and systemic manifestations of the chronic inflammatory joint disease. However, it remains unclear the extent to which antibodies contribute to the bone loss in arthritis.
Proteins that normally contain citrulline residues include myosin basic protein, fillagrin, and several histone proteins, whereas other proteins such as fibrinogen, fibrin, and vimentin can be citrullinated during cell death and tissue inflammation [93]. Second, ACPA-positive RA patients exhibit more severe bone loss than ACPA-negative RA patients (Hecht et al., 2017; Syversen et al., 2010).
Their results suggested that safety of the nanoparticles needs to be evaluated further.
During the late embryonic period, males have higher levels of H3 acetylation contrasted to females within combined cortex/hippocampus samples. More intriguingly, up to 30% of ACPA− patients have ACarPs, including IgG and IgA antibodies.68 Like ACPAs, these novel antibodies, such as to carbamylated fibrinogen, can occur before the onset of clinical disease in nearly 40% of patients with RA.69 The antibodies can participate in the inflammatory response, and mice immunized with carbamylated peptides can develop erosive arthritis. These results were thought to represent clear evidence of an interaction between an environmental factor (smoking) and genetic susceptibility (the shared epitope alleles), with smoking-induced loss of tolerance to citrullinated proteins, and thus susceptibility changes. Citrullinated proteins may be recognized as new antigens, and are promising for targeted therapy or CAR-T/NK cell-specific recognition targets.
Tantalizing similarities and epidemiologic associations exist between periodontitis and RA, including the presence of bone erosions, association with similar class II MHC alleles and smoking, and enrichment of severe periodontal disease in patients with RA.220-224 These connections have focused attention on the study of oral pathogens that express enzymes with PAD activity, specifically Porphyromonas gingivalis,225 a Gram-negative bacterium commonly present as a biofilm in the gingival crevice and intra-cellularly in oral epithelial cells. View all
Nat Rev Gastroenterol Hepatol.
Finally, it is possible that ACPA may arise through a breach in tolerance to native proteins that later spreads to citrullinated proteins through cross-reactivity or epitope-spreading, as has been suggested by the HLA-DRB1∗0401 transgenic mouse arthritis model induced by immunization with α-enolase [5]. Until now, multiple proteins have been found as substrates of citrullination, including NF-κB p65 (22), CXCL8 (23), CXCL12 (24), E2F-1 (25), GSK3β (26), MEK1 (27), VEGFR2 (28), and so on. In contrast, the SE association with antibodies to citrullinated fibrinogen peptides tends to be weaker, and negligible with the CII peptides studied [7].
Robert G Cooper, ... Ingrid E. Lundberg, in Between the Lines of Genetic Code, 2014. Enolases are common targets of the immune response to bacteria.
Although it is possible that none of the detailed mechanisms currently defined represent the unifying mechanism of pathogenesis in RA, the broader view of potential immunizing environments and the search for a frequent worldwide environmental exposure is of great importance.
Makrygiannakis D, af Klint E, Lundberg IE, Löfberg R, Ulfgren AK, Klareskog L, et al.
Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response. Indeed, several mice studies have shown that ACPAs directly promote osteoclastogenesis in vitro and in vivo (Harre et al., 2012; Krishnamurthy et al., 2016; Harre et al., 2015; Negishi-Koga et al., 2015).
PADIs members have similar structural regions, which can be divided into three sections: nitrogen zone, middle zone, and carbon end catalytic zone.
Neeli I, Khan SN, Radic M. Histone deimination as a response to inflammatory stimuli in neutrophils. The proportion of H3Cit-positive neutrophils was increased in more serious patients. PADI2 had been shown to be undergoing nuclear translocation in some cells for modifying histones (10). Sci Adv.
Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity. Witalison EE, Cui X, Hofseth AB, Subramanian V, Causey CP, Thompson PR, et al. A functional role for histone modifications in organizing sex differences in the developing brain is evident in sex differences in histone acetylation by HATs and deacetylation by histone deacetylases (HDACs) that modify chromatin structure differently between males and females.
(2010) 104:1143–9. Markus Hoffmann, ... Günter Steiner, in Rheumatology (Sixth Edition), 2015, Citrullination is the posttranslational conversion of peptidylarginine to peptidylcitrulline, a process catalyzed by a family of calcium-dependent peptidylarginine deiminases (PADs)14 (Fig.
Regulation of histone modification and chromatin structure by the p53-PADI4 pathway.
Leppkes M, Maueröder C, Hirth S, Nowecki S, Günther C, Billmeier U, et al.
The genes of these five isozymes are located on chromosome 1p36.13.
There are numerous histone modifications that exist, including phosphorylation, methylation, ubiquitination, sumoylation, Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. The great success that citrullinated proteins have had in RA diagnosis and prognosis could potentially be replicated in other diseases with similar clinical manifestations.
Onco Targets Ther.
Felipe Andrade, ... Antony Rosen, in Kelley and Firestein's Textbook of Rheumatology (Tenth Edition), 2017.