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Rheumatoid Arthritis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Brent A. Luedders, Ted R. Mikuls, James R. O’Dell, Bryant R. England
Several novel RA autoantibodies show promise for filling these roles. Antibodies to malondialdehyde-acetaldehyde (MAA) are elevated in the serum and synovium of RA patients and correlate with ACPA positivity.102Anti-MAA antibodies are also closely associated with the presence of RA-ILD, and MAA-modified proteins colocalize with citrullinated peptides and immune effector cells in RA-ILD lungs.103Antibodies to peptidyl arginine deiminase (PAD), the enzymes that produce citrullinated peptides, suggest a better treatment response and decreased radiographic progression (PAD4)104 as well as higher risk of RA-ILD (PAD3/4).105 Antibodies to carbamylated proteins (anti-CarP) appear to predict a more severe disease course in patients negative for anti-CCP antibodies106 and are linked to the presence of RA-ILD.107 Antiacetylated peptide antibodies (AAPA) have been detected in RA and may improve classification of RA beyond traditional RA autoantibodies.108, 109 With these novel autoantibodies, RA phenotyping may evolve from simplistic RF and/or ACPA seropositivity to more detailed phenotyping based on “multiplex” autoantibody assessments.
Biochemical Markers in Ophthalmology
Published in Ching-Yu Cheng, Tien Yin Wong, Ophthalmic Epidemiology, 2022
Abdus Samad Ansari, Pirro G. Hysi
Proteomic analysis of retinal and vitreous tissue has also shown 122 identified proteins linked with the pathophysiology of Alzheimer’s disease. A pathway analysis of these differentially regulated proteins highlighted the possibility of defects in mitochondrial oxidative phosphorylation [154]. Proteomics analyses have also implicated peptidyl arginine deiminase 2 (PAD2) and optic nerve citrullination as pressure-related proteins [153].
Hair Follicle Keratins
Published in John P. Sundberg, Handbook of Mouse Mutations with Skin and Hair Abnormalities, 2020
George E. Rogers, Barry C. Powell
The primary structure and consideration of models of secondary structure of the molecule of trichohyalin, the major protein of the IRS and medulla, have been obtained through cDNA and gene isolation and sequencing.15,16 The trichohyalin molecule has a mass of about 200 kD, and much of the single polypeptide chain consists of amino acid repeats of 23 or 24 amino acid residues. It is characterized by a high content of glutamine and of ionizable side chains, such as those of glutamic acid, lysine, and arginine, which leads to the conclusion that the molecule is stabilized into a rigid rod configuration by numerous salt-links. The side-chains can participate in the formation of isopeptide bonds (from glutamine and lysine) catalyzed by transglutaminase and in the formation of the amino acid citrulline (from arginine) through the action of peptidylarginine deiminase. Isopeptide bond crosslinks and citrulline are abundant in the proteins of both mature IRS and medulla cells. At its N-terminus the trichohyalin molecule has two so-called EF hands that can chelate calcium and are found in many characterized calcium-binding proteins, but the functional significance of the binding of the calcium by the EF hands of trichohyalin is not known.
Pulmonary fibrosis associated with rheumatoid arthritis: from pathophysiology to treatment strategies
Published in Expert Review of Respiratory Medicine, 2022
Rheumatoid arthritis occurs on a strong genetic background, as heritability of the disease is estimated to be about 60%, about half of it associated with genes in the human leukocyte antigen (HLA) class II system [26,27]. HLA-DRB1 alleles encode the third hypervariable region of the immunocompatibility antigen beta-chain and disease-associated alleles contain a five amino acid sequence referred to as the ‘shared epitope’ [28]. These alleles constitute the single strongest genetic risk factor for RA [29]. Another major genetic component of RA is a missense single nucleotide polymorphism in the gene encoding the protein tyrosine phosphatase PTPN22, potentially altering its function of T-cell negative regulation [30]. In addition, cytotoxic lymphocyte T antigen 4 (CTLA4) gene polymorphisms and haplotypes of peptidylarginine deiminase type 4 gene are involved in the susceptibility to RA [31,32].
Periodontal sources of citrullinated antigens and TLR agonists related to RA
Published in Autoimmunity, 2018
Ljubomir Vitkov, Matthias Hannig, Bernd Minnich, Martin Herrmann
Citrullination is a physiological process and only in specific cases might trigger autoimmune responses. Due to citrullination, neo-antigens emerge and as consequence T cells may get activated. This in turn will provide neo-antigen-specific T cell help to B cells in order to produce autoantibodies, some of these directed against citrullinated epitopes (ACPA). The human peptidylarginine deiminase PAD2 and PAD4 preferentially citrullinate internal arginine residues. In contrast, the P. gingivalis PAD (PPAD) exhibits a specificity for C-terminal arginine residue created by gingipain, a protease of P. gingivalis [22,23]. As a consequence, the couple gingipain/PPAD fashions neo-antigens that differ from those produced by the human PADs. This difference between human PADs (involved in tolerance induction) and PPAD products (involved in immunopathology) might explain the pathogenic potential of the periodontal pathogen P. gingivalis.
Burning controversies in NETs and autoimmunity: The mysteries of cell death and autoimmune disease
Published in Autoimmunity, 2018
The activation of the enzyme peptidylarginine deiminase during the neutrophil response to infections serves both as a useful characteristic of the innate immune activation by the pathogen, and as a tag for the tolerance breakdown that ensues. The citrullinated autoantigens, which most notably include core and linker histones, are a useful marker for the cell death that ensues due to NET release. Thus, it was possible to unambiguously exclude apoptosis as the stimulus for PAD4 activation. Moreover, the model depicted in Figure 1 is supported by the prominent presence of anti-citrullinated protein autoantibodies (ACPA), which have been observed in numerous systemic autoimmune disorders. The production of ACPA argues for the concept that NETs are the source of the inciting autoantigens and also implies that tolerance may be broken by the presence of post-translational modification in the central autoantigens that define various autoimmune conditions. However, the proposed model that is illustrated in Figure 1 is certainly too simplistic and raises additional questions or constraints on the true events that may connect an infection, the neutrophil response to the infection and the activation of the adaptive immune system.