ABSTRACT
Both cholinergic dysfunction and protein citrullination are the hallmarks of rheumatoid arthritis (RA), but the relationship between the two phenomena remains unclear. We explored whether and how cholinergic dysfunction accelerates protein citrullination and consequently drives the development of RA. Cholinergic function and protein citrullination levels in patients with RA and collagen-induced arthritis (CIA) mice were collected. In both neuron-macrophage coculture system and CIA mice, the effect of cholinergic dysfunction on protein citrullination and expression of peptidylarginine deiminases (PADs) was assessed by immunofluorescence. The key transcription factors for PAD4 expression were predicted and validated. Cholinergic dysfunction in the patients with RA and CIA mice negatively correlated with the degree of protein citrullination in synovial tissues. The cholinergic or alpha7 nicotinic acetylcholine receptor (α7nAChR) deactivation and activation resulted in the promotion and reduction of protein citrullination in vitro and in vivo, respectively. Especially, the activation deficiency of α7nAChR induced the earlier onset and aggravation of CIA. Furthermore, deactivation of α7nAChR increased the expression of PAD4 and specificity protein-3 (SP3) in vitro and in vivo. Our results suggest that cholinergic dysfunction-induced deficient α7nAChR activation, which induces the expression of SP3 and its downstream molecule PAD4, accelerating protein citrullination and the development of RA.
ABSTRACT
Porphyromonas gingivalis peptidylarginine deiminase (PPAD), an isoenzyme of animal endogenous peptidylarginine deaminase, is secreted by the Por system and catalyzes the citrullination of arginine. Recent studies have found that PPAD can affect the formation of Porphyromonas gingivalis biofilm and reduce the body′s immune defense function, which is related to the occurrence and development of many diseases such as periodontal diseases and rheumatoid arthritis. In this paper, we reviewed the molecular characteristics of PPAD, including the genetic and functional characteristics, as well as the mechanisms related to the inflammatory and autoimmune diseases. We also pointed some issues that should be pay attention to in the further study.
ABSTRACT
Objective: Review the existing scientific literature regarding the pathogenicity of Porphyromonas gingivalis, linked to periodontal disease (PD) (oral dysbiosis), and its association with the activation of pathophysiological mechanisms of rheumatoid arthritis (RA), in order to expose the new mechanisms biomolecular involved. Methods: Systematic search in the MeSH, pubmed, Science Direct, Nature y Google academic database, using the keywords: Aggregatibacter actinomycetemcomitans; rheumatoid arthritis; citrullination; dysbiosis; dentistry; periodontitis; porphyromonas gingivalis; rheumatology. Out of a total of 297 publications, 52 were selected, all from 2018; based on the inclusion and exclusion criteria established by the authors. Results: Pg infection linked to periodontal disease is strongly implicated in the pathogenesis and development of RA. Their relationship is linked to the citrullination process and production of citrullinated antipeptide antibodies. Associations have been identified between the microbial virulence of this agent and the expression of multiple genes related to the activation of the immune response and the onset of the chronic inflammatory process. Conclusions: There is a high association between the pathogenesis of both diseases, where microorganisms linked to PD such as Pg have the ability to increase citrullination, galactosylation, fucosylation, as well as excessive glycosylation of fragments antigen-binding (Fab), and therefore the aggressiveness of RA.
Objetivo: revisar la literatura científica existente con respecto a la patogenicidad de Porphyromonas gingivalis, ligada a enfermedad periodontal (EP) (disbiosis oral), y su asociación con la activación de mecanismos fisiopatológicos en la artritis reumatoide (AR), a fin de exponer los nuevos mecanismos biomoleculares implicados. Métodos: búsqueda sistemática en la base de datos del Medical Subject Headings (MeSH), PubMed, Science Direct, Nature y Google académico usando las palabras clave: Aggregatibacter actinomycetemcomitans; artritis reumatoide; citrulinación; disbiosis; odontología; periodontitis; Porphyromonas gingivalis y reumatología. De un total de 297 publicaciones, se seleccionaron 52, todas a partir del año 2018; la selección fue hecha a partir de los criterios de inclusión y exclusión establecidos por los autores. Resultados: la infección por Porphyromonas gingivalis, ligada a la EP, está fuertemente implicada en la patogénesis y desarrollo de AR. Su relación se vincula con el proceso de citrulinación y producción de anticuerpos antipéptidos citrulinados. Se han identificado asociaciones entre la virulencia microbiana de dicho agente y la expresión de múltiples genes, relacionados con la activación de la respuesta inmune y el inicio del proceso inflamatorio crónico. Conclusiones: existe una alta asociación entre la patogenia de ambas enfermedades, donde microorganismos ligados a la EP, como Porphyromonas gingivalis, tienen la capacidad de aumentar la citrulinación, galactosilación, fucosilación, así como la excesiva glicosilación de Fragmentos de unión al antígeno (Fab), y por lo tanto, la agresividad de la AR.
Subject(s)
Humans , Arthritis, Rheumatoid , Porphyromonas gingivalis , Periodontitis , Aggregatibacter actinomycetemcomitans , Oral MedicineABSTRACT
OBJECTIVE@#To investigate the expression of citrullinated epitopes in articular cartilage protein and whether its expression is sufficient to induce anti-citrullinated protein antibody (ACPA) response in mice.@*METHODS@#The experimental group was treated with different concentrations of lipopolysaccharide (LPS), heat-inactivated bacteria ( and ) or specific monoclonal antibody against type Ⅱ collagen to induce citrullination of articular cartilage protein, with PBS as the control. Immunohistochemistry with the monoclonal antibody ACC4 (IgG1) that specifically binds to the citrullinated epitope of cartilage protein was performed for detecting the expression of citrullinated protein, with ACC1 (IgG2a) as a positive control antibody and L243 (IgG2a) and Hy2.15 (IgG1) as the negative isotype control. In the in vivo experiment, SD rats were subjected to injection of different doses of LPS in the right knee (with PBS as the controls in the left knee), and 3 days later frozen sections were prepared for immunohistochemical detection of the expression of citrullinated protein. Models of collagen-induced arthritis (CIA) established in different mouse strains were observed for incidence and severity of CIA. Serum samples collected from these models and the sera from rheumatoid arthritis patients were examined for anti-citrullinated protein antibody, and immunohistochemistry was performed to detect the expression of citrullinated protein in the cartilage of the mouse.@*RESULTS@#The citrullinated CII epitope-specific antibody ACC4 did not bind to articular cartilage tissues with different treatments as compared with the positive control antibody ACC1. The ACC4 antibody and the antibodies from patients with rheumatoid arthritis with high titers of anti-citrullinated protein antibody were capable of binding to the synovial tissue around the articular cartilage of the CIA. Luminex analysis showed that the anti-citrullinated protein antibody was lowly expressed in mouse serum, but the anti-type Ⅱ collagen triple helix structure peptide antibody exhibited strong reactivity.@*CONCLUSIONS@#Mild acute inflammatory response is not enough to cause citrullination of articular cartilage protein, and the expression of specific epitope requires a high-intensity inflammatory response. Inflammatory articular cartilage protein can express citrullinated epitopes in type Ⅱ collagen-induced arthritis in mice, but the expression of citrullinated epitopes is not sufficient to induce an immune response to anti-citrullinated antibodies. Stronger stimulation signals are required to induce an immune response for producing anti-citrullinated protein antibodies.
Subject(s)
Animals , Humans , Mice , Rats , Arthritis, Experimental , Autoantibodies , Cartilage, Articular , Citrulline , Inflammation , Rats, Sprague-DawleyABSTRACT
La Enfermedad Periodontal (EP) y la Artritis Reumatoide (AR) guardan una estrecha relación entre sí: son enfermedades crónicas e inflamatorias, autoinmunes por un desequilibrio inmunológico del huésped, deterioran la calidad de vida de los pacientes, requieren un diagnóstico temprano y un tratamiento oportuno para limitar su progresión. Objetivos: Evidenciar la importancia que tiene el manejo interdisciplinario de periodoncistas y reumatólogos en el reconocimiento y tratamiento de la EP y la AR. Material y Métodos: Se realiza búsqueda bibliográfica con 5 años de antecedentes en la base de datos NCBI (National Center for Biotechnology Information), usando las palabras clave: enfermedad periodontal, artritis reumatoide, citrulinación, disbiosis oral y Porphyromonas gingivalis, seleccionándose 52 artículos, se realiza la lectura crítica de ellos y la elaboración de mapas mentales para sistematizar la información organizándola de acuerdo a los aspectos particulares de cada patología, mecanismos que comparten y los aspectos importantes para su manejo interdisciplinario a nivel preventivo y terapéutico de periodoncistas y reumatólogos. Resultados: La EP ocasiona deterioro del sistema masticatorio y la AR del sistema locomotor, ambas son inflamatorias, relacionándose la bacteria Porphyromonas gingivalis. Se requiere un manejo interdisciplinario con un enfoque preventivo y terapéutico para eliminar todo proceso inflamatorio gingival considerando los factores de riesgo que puedan propiciarlo. Conclusiones: Existe una interrelación entre la EP y la AR, por lo que cobra importancia un manejo interdisciplinario considerando la susceptibilidad de cada paciente, el estado periodontal, antecedentes hereditarios; así como la prevención ante los factores de riesgo. Ambas enfermedades afectan la calidad de vida de los pacientes.
Periodontal Disease (PD) and Rheumatoid Arthritis (RA) are closely related to each other: both are chronic, inflammatory, and autoimmune diseases, due to an immune imbalance of the host deteriorating patient´s life quality, it is required an early diagnosis and timely treatment to limit their progression. Objectives: To demonstrate the importance of the interdisciplinary management of periodontists and rheumatologists in the recognition and treatment of Periodontal Disease and Rheumatoid Arthritis. Material and Methods: A bibliographic search was carried out with 5 years of background in the NCBI database (National Center for Biotechnology Information), using key words: periodontal disease, rheumatoid arthritis, citrullination, oral dysbiosis and Porphyromonas gingivalis, selecting 52 articles. After a critical reading, mental maps were done to systematize the information, and organizing according to particular aspects of each pathology, the share mechanisms between them, and the important aspects for its interdisciplinary management by periodontists and rheumatologists at preventive and therapeutic level. Results: PD causes masticatory system deterioration, meanwhile RA causes on locomotor system, both processes are inflammatory, and the bacterium Porphyromonas gingivalis is associated to them. An interdisciplinary management with a preventive and therapeutic approach is required to eliminate all gingival inflammatory process and risk factors must be avoided. Conclusions: There is an interrelation between PD and RA, that is why is important to consider: an interdisciplinary management, susceptibility of each patient, periodontal status, hereditary antecedents, as well as, risk factors prevention. Both diseases affect patient's quality of life.
ABSTRACT
Citrullination is a post-translational modification of arginine caused by peptidyl arginine deiminase in the presence of calcium ions.Up-regulation of citrullination plays a significant role in the progress of numerous disorders,and it has important physiologic and pathological significance.High-throughput and quantitative methods with high specificity and sensitivity are still needed to identify the citrullinated sites in tissue cells.With the development of chemical derivatization and mass spectrometry, new rapid and accurate proteomics technology still has a good prospect of development and application.This article aimed to provide new ideas and directions to identify the citrullinated sites in the complex biological samples by introducing strategies available to identify citrullinated peptides, such as color development reagent analysis, immunodetection and mass spectrometry.
ABSTRACT
Neutrophils are the major antimicrobial cells of the innate immune system, which are recruited rapidly to the sites of infection and provide the primary defense against pathogens. Recent evidence suggests that neutrophils undergo a distinct cell death mechanism called NETosis, which not only contributes to the host defense, but also leads to severe pathological immune responses in cases of dysregulation. Here, we review the general features of NETosis as well as the generation of autoantigens and damage-associated molecular patterns by NETosis in autoimmune diseases. This review discusses the pathogenic role of NETosis in rheumatoid arthritis and systemic lupus erythematosus, where neutrophils may play a key role in the pathogenesis of these diseases, and suggest the possibility of neutrophil extracellular traps as biomarkers and therapeutic targets for the treatment of autoimmune diseases.
Subject(s)
Arthritis, Rheumatoid , Autoantigens , Autoimmune Diseases , Biomarkers , Cell Death , Immune System , Lupus Erythematosus, Systemic , NeutrophilsABSTRACT
The multiple post-translational modifications of proteins display specific gain- or loss-of-function under normal and abnormal conditions. These modifications are precisely regulated by post-translational modification enzymes. The altered molecular status perturbs the pattern of gene expression and decides on a direction to signal transduction cascades as well as intrinsic properties of the proteins. Ultimately, it strictly maintains intracellular environment or results in disease manifestations. Recently, it has become that enzyme-dependent modification of arginine residue to citrulline exerts an important role in the induction of autoimmunity including rheumatoid arthritis, multiple sclerosis, and cancer. The modification of arginine residue to citrulline on proteins is called 'citrullination' or 'deimination' and is regulated by the calcium-dependent enzyme peptidylarginine deiminase (PAD). Now many effective PAD inhibitors (for example, Cl-amidine) have developed that ameliorates disease phenotypes. In this review, we discuss crucial roles of PAD enzyme and citrullination, the effectiveness of PAD inhibitors, and the implication in pathology.