Rheumatoid Arthritis
Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide in Clinical Innovation in Rheumatology, 2023
RF and ACPA are the most clinically relevant autoantibodies in RA. RF targets the Fc region of IgG,40 whereas ACPAs target citrullinated peptides resulting from the posttranslational modification of arginine facilitated by peptidyl arginine deiminase (PAD) enzymes.41 While enzymatically mediated protein citrullination is not specific to RA, tolerance loss to these peptides is. Several antigen-specific citrullinated proteins have been found to be the targets of ACPAs in RA, including α-enolase, fibrinogen, filaggrin, vimentin, and type II collagen, among others.42 Studies leveraging biobanked blood samples of RA patients from the prediagnostic period have shown that RF and ACPA antibodies are detectable in the serum years before the development of clinical signs or symptoms of inflammatory arthritis.43–45 In the absence of joint inflammation, it is hypothesized that RA-related autoimmunity may originate at mucosal sites, such as the lung, intestine, or oral mucosa.46 Evidence suggests that RF and ACPA antibodies may be pathogenic through the ability to stimulate pro-inflammatory cytokine production, an effect that is synergistic among those dual positive for RF and ACPA,47 as well as through direct activation of osteoclasts and pain receptors.48
Celiac disease
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
The role of posttranslational modifications in generating immunogenic peptides is also reported for other autoimmune diseases. For example, in the case of rheumatoid arthritis, the posttranslational modification and the MHC molecules associated with the disease are citrullination and DR4, respectively. The overall underlying theme involves a favorable combination of MHC molecule, tissue enzyme, and antigen that optimizes binding of the causative antigen to the disease-associated MHC molecule and promotes T-cell responses of sufficient amplitude to induce a pathogenic immune response associated with tissue damage. Because posttranslational modifications of antigen can promote loss of immune tolerance to that antigen, enzymes promoting posttranslational modifications must be under tight control. Understanding the regulation of TG2 and its role in celiac disease pathogenesis will also enhance more general understanding of the role of posttranslational modifications by tissue enzymes in autoimmunity.
Diagnosis and Pathobiology
Franklyn De Silva, Jane Alcorn in The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
ADP-ribosylation is another important epigenetic mechanism regulating gene expression. Histone glutamate and arginine residues can be poly-ADP ribosylated (PARylation) by enzymes of the poly-ADP-ribose polymerase (PARP) family, while ADP-ribosylation is reversed by enzymes of the poly-ADP-ribose-glycohydrolase (PARG) family (i.e., hydrolases that cleave the glycosidic bonds) [387, 433–437]. Mono-ADP-ribosylation (MARylation) is performed by mono-ADP-ribosyltransferases (ARTs), and these modifications play a prominent role during the DNA damage response [387, 435, 438]. Nicotinamide adenine dinucleotide (NAD+) is used as a cofactor by enzymes catalyzing ADP-ribosylation [434, 435, 438]. Proline isomerases facilitate the interconversion of the cis and trans conformations of the dihedral angle of a peptidyl proline's peptide bond, that can affect peptide configurations [387, 390]. This process is referred to as histone proline isomerization and this is not considered a true covalent modification [387, 390]. The conversion of an arginine to a citrulline on histones by peptidyl deiminase (PADI4) is referred eaminationnation/citrullination [387, 390, 439]. In addition, PADI4 can convert monomethyl arginine to citrulline and therefore can function like an arginine demethylase [387, 439–441]. Citrullinated histone H3 might serve as a new prognostic marker for advanced malignancies [441]. However, it is not a “true demethylase” because the reaction does not regenerate an unmodified arginine, and additionally, chromatin decondensation can be promoted by hypercitrullination, especially under inflammatory conditions [387, 390, 442, 443].
Latest models for the discovery and development of rheumatoid arthritis drugs
Published in Expert Opinion on Drug Discovery, 2022
Bartosz Szostak, Anna Gorący, Bartłomiej Pala, Jakub Rosik, Łukasz Ustianowski, Andrzej Pawlik
The greatest challenge for novel RA modeling could be the complex pathogenesis of the disease. The involvement of innate and adaptive immune responses, but also the role of autoantibodies, limit the abilities of current models to mimic RA pathogenesis. Furthermore, ACPA-positive and ACPA-negative subtypes of the disease develop via various pathways and are associated with different genetic and environmental risk factors. ACPA-positive RA is highly associated with HLA-DRB1 shared epitope alleles and smoking. Upregulation of citrullination and emergence of autoantibodies leads to gradual development of the disease, as ACPA induces the immune response. These mechanisms are probably crucial for RA progression. The genetic risk factors of ACPA-negative RA differ from those associated with ACPA-positive RA, highlighting the need in separate modeling for both subtypes of RA. 2D cell cultures are an appropriate model to conduct a large-scale trial, taking into account their simplicity and cost-effectiveness. Unfortunately, it is not an impeccable method. The problem of an oversimplification of the actual conditions is reduced in a more developed model. 3D cell cultures or an OCC better mimic real condition; however, they are much more challenging to establish and use. Tissue explants, on the contrary, appear to recreate an even more adequate environment to generate valid results.
Pulmonary fibrosis associated with rheumatoid arthritis: from pathophysiology to treatment strategies
Published in Expert Review of Respiratory Medicine, 2022
Auto-immunity and inflammation cooperate in inducing signals resulting in the infiltration of the lung by numerous cell types. As compared to typical UIP, RA-UIP presents with more infiltrating CD4+ lymphocytes and dendritic cells. The appearance of myofibroblasts also differs between the two diseases [58,59]. Infiltration of the lungs by T-cells and B-cells is increased in lung biopsies of RA-ILD patients as compared to patients with IIPs, and some data suggest that this increase is emphasized in lung areas with high citrullination [47,59,60]. Whether citrullination is a marker or a cause of increased inflammation remains unclear. Inducible bronchus-associated lymphoid tissue (iBALT) is found in the lungs of patients suffering from a variety of ILD but is more developed in RA-ILD patients. Furthermore, well-formed iBALT correlates with increased mediators implicated in RA pathogenesis and tissue damage in the lung, suggesting a role of iBALT in the incidence of RA-ILD [61]. Regulatory B cells (Bregs) may be key players in RA-related inflammation. This subtype of LB is characterized by its immunosuppressive properties and the secretion of IL-10, IL-35, TGF-β [62]. Circulating Bregs are decreased in number and in function in RA patients (as well as in other CTDs) and correlates negatively with disease severity [63,64]. The phenotype of B cells infiltrating the lung remains largely undetermined. Additionally, infiltrating mast cells are increased in both RA-ILD and IPF, consistent with their supposed role in fibrogenesis [65].
Advances in the diagnosis of autoimmune diseases based on citrullinated peptides/proteins
Published in Expert Review of Molecular Diagnostics, 2021
Mohammed F. Alghamdi, Elrashdy M. Redwan
Citrullination is a post-translation modification process of proteins induced by a catalytic enzyme called peptidylarginine deiminase (PAD). PADs are a family of five calcium-dependent enzymes (PAD1-4 and PAD6) that converts the arginine residue of certain proteins to citrulline (Figure 1) [18]. Citrullination is involved in many physiological and pathological processes. During the last years, citrullination has attracted the great attention of many researchers. Although citrullination is essential for certain physiological processes; hence, it plays an important role in the terminal differentiation of the epidermis, gene regulation, central nervous system’s (CNS) plasticity, and the formation of neutrophil extracellular traps (NETs) [19–21], it is found implicated in human pathologies such as carcinogenesis and autoimmunity (such as RA, MS, and psoriasis) [22,23]. Several studies have successfully correlated this process to the immunopathogenesis of such ADs [23,24].
Related Knowledge Centers
- Arginine Deiminase
- Citrulline
- Genetic Code
- Imine
- Urea Cycle
- Amino Acid
- Arginine
- Post-Translational Modification
- Nitric Oxide Synthase
- Protein-Arginine Deiminase