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5 pages, 179 KiB

Open AccessEditorial

The Pathogenesis of Rheumatoid Arthritis Breakthroughs in Molecular Mechanisms 1 and 2

by Yuki Nanke

Int. J. Mol. Sci. 2023, 24(13), 11060; https://doi.org/10.3390/ijms241311060 - 4 Jul 2023

Cited by 4 | Viewed by 2762

Abstract

The pathogenesis of rheumatoid arthritis (RA) consists of the formation of synovial villi, inflammation, immune abnormalities, and bone–cartilage destruction [...] Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)

Research

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12 pages, 1035 KiB

Open AccessArticle

Novel Chimeric Peptides Based on the Enolase Peptide Antigen (CEP-1) Bearing Three Post-Translational Modifications (Citrullination, Homocitrullination and Acetylation) for Determining the Diagnosis and Severity of Rheumatoid Arthritis

by María José Gómara, Juan C. Sarmiento-Monroy, Raul Castellanos-Moreira, José A Gómez-Puerta, Raimon Sanmartí and Isabel Haro

Int. J. Mol. Sci. 2024, 25(19), 10654; https://doi.org/10.3390/ijms251910654 - 3 Oct 2024

Viewed by 798

Abstract

With the aim of improving the uncertainties associated with the correct diagnosis of seronegative rheumatoid arthritis (RA) and identifying those at risk of developing interstitial lung disease (ILD), we have designed new peptide antigens bearing three post-translational modifications (PTMs) (citrulline, homocitrulline and acetyl-lysine) [...] Read more.

With the aim of improving the uncertainties associated with the correct diagnosis of seronegative rheumatoid arthritis (RA) and identifying those at risk of developing interstitial lung disease (ILD), we have designed new peptide antigens bearing three post-translational modifications (PTMs) (citrulline, homocitrulline and acetyl-lysine) related to RA that could complement existing tests based on anti-citrullinated peptide/protein antibodies (ACPAs). Several chimeric peptides were synthesized and comparatively tested as antigens in ELISAs with two cohorts of sera: 178 RAs and 110 healthy blood donors. The results indicated that although chimeric peptides containing all three PTMs and vimentin and enolase domains do not significantly outperform existing ACPA tests in terms of sensitivity and specificity, they show potential to complement current assays, especially when detecting antibodies in some seronegative patients. Furthermore, the presence of these autoantibodies significantly identified patients with RA and ILD. We can conclude that the identification of specific autoantibody profiles using synthetic antigens containing peptide domains derived from proteins present in the human joint could help in the early detection of the risk of ILD in patients with RA and be useful for adapting follow-up strategies and guiding decisions during treatment. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)

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15 pages, 2359 KiB

Open AccessArticle

Helper T Cells are Hyperactive and Contribute to the Dysregulation of Antibody Production in Patients with Rheumatoid Arthritis

by Mustafa Talib, Balázs Gyebrovszki, Dorottya Bőgér, Réka Csomor, Anna Mészáros, Anna Fodor, Bernadette Rojkovich and Gabriella Sármay

Int. J. Mol. Sci. 2024, 25(18), 10190; https://doi.org/10.3390/ijms251810190 - 23 Sep 2024

Viewed by 1023

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease, mediated by a complex interaction between B cells and various subsets of T cells. Dysfunction of helper T (Th) and regulatory T (Treg) cells may contribute to the breakdown of self-tolerance and the progression of [...] Read more.

Rheumatoid arthritis (RA) is a systemic autoimmune disease, mediated by a complex interaction between B cells and various subsets of T cells. Dysfunction of helper T (Th) and regulatory T (Treg) cells may contribute to the breakdown of self-tolerance and the progression of autoimmune disease. In this study, we investigated the activity of Th and Treg cells on the differentiation of autologous B cells in vitro using cell cultures from the peripheral blood of healthy controls (HCs) and RA patients. The expressions of programmed death 1 (PD-1) and IL-21 were monitored as activation markers for Th cells. Unstimulated Th cells from RA patients showed remarkably higher PD-1 expression than HC samples. Stimulation of Th cells from RA patients with Staphylococcus enterotoxin B (SEB) in the presence of B cells significantly induced their PD-1 and IL-21 expression at a considerably higher level in RA compared to HCs, and Treg cells did not affect IL-21 production. When monitoring B-cell differentiation, a significantly higher frequency of plasma cells was observed, even in unstimulated samples of RA patients compared to HCs. In the SEB-stimulated co-cultures of the RA samples, plasma cell frequency and IgG production were considerably higher than in HCs and were not significantly affected by Tregs. These findings demonstrate that Th cells are constitutively active in RA, and their hyperactivity upon interaction with diseased B cells may lead to uncontrolled antibody production. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)

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13 pages, 1572 KiB

Open AccessCommunication

Serum Levels of IFABP2 and Differences in Lactobacillus and Porphyromonas gingivalis Abundance on Gut Microbiota Are Associated with Poor Therapeutic Response in Rheumatoid Arthritis: A Pilot Study

by Oscar Zaragoza-García, Natividad Castro-Alarcón, Gloria Pérez-Rubio, Ramcés Falfán-Valencia, Olivia Briceño, José Eduardo Navarro-Zarza, Isela Parra-Rojas, Mario Tello and Iris Paola Guzmán-Guzmán

Int. J. Mol. Sci. 2023, 24(3), 1958; https://doi.org/10.3390/ijms24031958 - 19 Jan 2023

Cited by 4 | Viewed by 2235

Abstract

Intestinal dysbiosis is related to the physiopathology and clinical manifestation of rheumatoid arthritis (RA) and the response to pharmacologic treatment. The objectives of this study were (1) to analyze the effect of conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) on the abundance of [...] Read more.

Intestinal dysbiosis is related to the physiopathology and clinical manifestation of rheumatoid arthritis (RA) and the response to pharmacologic treatment. The objectives of this study were (1) to analyze the effect of conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) on the abundance of gut microbiota’s bacteria; (2) to evaluate the relationship between the differences in microbial abundance with the serum levels of intestinal fatty-acid binding protein 2 (IFABP2), cytokines, and the response phenotype to csDMARDs therapy in RA. A cross-sectional study was conducted on 23 women diagnosed with RA. The abundance of bacteria in gut microbiota was determined with qPCR. The ELISA technique determined serum levels of IFABP2, TNF-α, IL-10, and IL-17A. We found that the accumulated dose of methotrexate or prednisone is negatively associated with the abundance of Lactobacillus but positively associated with the abundance of Bacteroides fragilis. The Lactobacillus/Porphyromonas gingivalis ratio was associated with the Disease Activity Score-28 for RA with Erythrocyte Sedimentation Rate (DAS28-ESR) (r = 0.778, p = 0.030) and with the levels of IL-17A (r = 0.785, p = 0.027) in the group treated with csDMARD. Moreover, a relation between the serum levels of IFABP2 and TNF-α (r = 0.593, p = 0.035) was observed in the group treated with csDMARD. The serum levels of IFABP2 were higher in patients with secondary non-response to csDMARDs therapy. In conclusion, our results suggest that the ratios of gut microbiota’s bacteria and intestinal permeability seems to establish the preamble for therapeutic secondary non-response in RA. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)

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13 pages, 1312 KiB

Open AccessArticle

Anti-Citrullinated Peptide Antibodies Control Oral Porphyromonas and Aggregatibacter species in Patients with Rheumatoid Arthritis

by Marina I. Arleevskaya, Eugenia A. Boulygina, Regina Larionova, Shamil Validov, Olga Kravtsova, Elena I. Shagimardanova, Lourdes Velo, Geneviève Hery-Arnaud, Caroline Carlé and Yves Renaudineau

Int. J. Mol. Sci. 2022, 23(20), 12599; https://doi.org/10.3390/ijms232012599 - 20 Oct 2022

Cited by 6 | Viewed by 1887

Abstract

Oral microbiome changes take place at the initiation of rheumatoid arthritis (RA); however, questions remain regarding the oral microbiome at pre-RA stages in individuals with clinically suspect arthralgia (CSA). Two cross-sectional cohorts were selected including 84 Tatarstan women (15 early-RA as compared to [...] Read more.

Oral microbiome changes take place at the initiation of rheumatoid arthritis (RA); however, questions remain regarding the oral microbiome at pre-RA stages in individuals with clinically suspect arthralgia (CSA). Two cross-sectional cohorts were selected including 84 Tatarstan women (15 early-RA as compared to individuals with CSA ranging from CSA = 0 [n = 22], CSA = 1 [n = 19], CSA = 2 [n = 11], and CSA ≥ 3 [n = 17]) and 42 women with established RA (median: 5 years from diagnosis [IQ: 2–11]). Amplicon sequence variants (ASVs) obtained from oral samples (16S rRNA) were analyzed for alpha and beta diversity along with the abundance at the genus level. A decrease in oral Porphyromonas sp. is observed in ACPA-positive individuals, and this predominates in early-RA patients as compared to non-RA individuals irrespective of their CSA score. In the RA-established cohort, Porphyromonas sp. and Aggregatibacter sp. reductions were associated with elevated ACPA levels. In contrast, no associations were reported when considering individual, genetic and clinical RA-associated factors. Oral microbiome changes related to the genera implicated in post-translational citrullination (Porphyromonas sp. and Aggregatibacter sp.) characterized RA patients with elevated ACPA levels, which supports that the role of ACPA in controlling the oral microbiome needs further evaluation. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)

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12 pages, 1632 KiB

Open AccessArticle

Subgingival Microbiome in Rheumatoid Arthritis Patients with Periodontitis

by Yi-Jing Chen, Wei-Chun Hung, Yu-Hsiang Chou, Chern-Hsiung Lai, Po Peng, Pei-Syuan Jhou, Min-Ru Tsai, Jim Jinn-Chyuan Sheu and Jeng-Hsien Yen

Int. J. Mol. Sci. 2022, 23(17), 9883; https://doi.org/10.3390/ijms23179883 - 31 Aug 2022

Cited by 5 | Viewed by 2349

Abstract

Rheumatoid arthritis (RA) and periodontitis are suggested to be closely linked based on microbial dysbiosis, but limited subgingival bacteria have been proven in the pathogenesis of RA. We enrolled 30 RA patients and 25 controls and divided them into three groups with matched [...] Read more.

Rheumatoid arthritis (RA) and periodontitis are suggested to be closely linked based on microbial dysbiosis, but limited subgingival bacteria have been proven in the pathogenesis of RA. We enrolled 30 RA patients and 25 controls and divided them into three groups with matched age, gender, and diabetes statuses: group AM (all of the matched participants), group PD (periodontally diseased), and group PH (periodontally healthy). Their subgingival microbial composition was determined by V3–V4 16S rRNA gene sequencing. Significant differences in subgingival microbial clustering between the RA patients and controls were observed in groups AM and PD. Among the taxa enriched in RA, Aminipila butyrica and Peptococcus simiae were the only two species displaying positive correlation to the level of anti-citrullinated protein antibodies (ACPAs) in both of the groups. Surprisingly, the median of relative abundances of A. butyrica and P. simiae were 0% in the controls of group PD. Furthermore, a gene encoding arginine deiminase with the capability to produce citrulline was addressed in the complete genome sequence of A. butyrica. This is the first study to elucidate the important roles of A. butyrica and P. simiae as periodontal bacteria leading to RA possibly through the induction of ACPA production. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)

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Review

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17 pages, 2501 KiB

Open AccessReview

New Insights into the Role of Synovial Fibroblasts Leading to Joint Destruction in Rheumatoid Arthritis

by Kotaro Matsuda, Naoto Shiba and Koji Hiraoka

Int. J. Mol. Sci. 2023, 24(6), 5173; https://doi.org/10.3390/ijms24065173 - 8 Mar 2023

Cited by 16 | Viewed by 3349

Abstract

Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by multiple-joint synovitis with subsequent destruction of bone and cartilage. The excessive autoimmune responses cause an imbalance in bone metabolism, promoting bone resorption and inhibiting bone formation. Preliminary studies have revealed [...] Read more.

Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by multiple-joint synovitis with subsequent destruction of bone and cartilage. The excessive autoimmune responses cause an imbalance in bone metabolism, promoting bone resorption and inhibiting bone formation. Preliminary studies have revealed that receptor activator of NF-κB ligand (RANKL)-mediated osteoclast induction is an important component of bone destruction in RA. Synovial fibroblasts are the crucial producers of RANKL in the RA synovium; novel analytical techniques, primarily, single-cell RNA sequencing, have confirmed that synovial fibroblasts include heterogeneous subsets of both pro-inflammatory and tissue-destructive cell types. The heterogeneity of immune cells in the RA synovium and the interaction of synovial fibroblasts with immune cells have recently received considerable attention. The current review focused on the latest findings regarding the crosstalk between synovial fibroblasts and immune cells, and the pivotal role played by synovial fibroblasts in joint destruction in RA. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)

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38 pages, 3334 KiB

Open AccessReview

Organokines in Rheumatoid Arthritis: A Critical Review

by Lucas Fornari Laurindo, Mariana Canevari de Maio, Sandra Maria Barbalho, Elen Landgraf Guiguer, Adriano Cressoni Araújo, Ricardo de Alvares Goulart, Uri Adrian Prync Flato, Edgar Baldi Júnior, Cláudia Rucco Penteado Detregiachi, Jesselina Francisco dos Santos Haber, Patrícia C. Santos Bueno, Raul S. J. Girio, Rachel Gomes Eleutério and Marcelo Dib Bechara

Int. J. Mol. Sci. 2022, 23(11), 6193; https://doi.org/10.3390/ijms23116193 - 31 May 2022

Cited by 17 | Viewed by 3706

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily affects the joints. Organokines can produce beneficial or harmful effects in this condition. Among RA patients, organokines have been associated with increased inflammation and cartilage degradation due to augmented cytokines and metalloproteinases production, [...] Read more.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily affects the joints. Organokines can produce beneficial or harmful effects in this condition. Among RA patients, organokines have been associated with increased inflammation and cartilage degradation due to augmented cytokines and metalloproteinases production, respectively. This study aimed to perform a review to investigate the role of adipokines, osteokines, myokines, and hepatokines on RA progression. PubMed, Embase, Google Scholar, and Cochrane were searched, and 18 studies were selected, comprising more than 17,000 RA patients. Changes in the pattern of organokines secretion were identified, and these could directly or indirectly contribute to aggravating RA, promoting articular alterations, and predicting the disease activity. In addition, organokines have been implicated in higher radiographic damage, immune dysregulation, and angiogenesis. These can also act as RA potent regulators of cells proliferation, differentiation, and apoptosis, controlling osteoclasts, chondrocytes, and fibroblasts as well as immune cells chemotaxis to RA sites. Although much is already known, much more is still unknown, principally about the roles of organokines in the occurrence of RA extra-articular manifestations. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)

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