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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (25 August 2024) | Viewed by 11484

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Prof. Dr. Hajime Kono

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Department of Internal Medicine, Teikyo University School of Medicine, Tokyo 173-8606, Japan
Interests: systemic lupus erythematosus; vasculitis; atherosclerosis; cell death; inflammation; innate immunity
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Special Issue Information

Dear Colleagues,

We are pleased to announce a Special Issue of International Journal of Molecular Sciences focused on "Molecular Insights in Rheumatoid Arthritis". This Issue aims to bring together the latest research on the molecular mechanisms that lead to the development and progression of rheumatoid arthritis—a chronic autoimmune disease that affects approximately 1% of the world’s population. In the last 20 years, advances in molecular-targeted drugs have led to significant advances in the treatment of rheumatoid arthritis. However, a significant proportion of RA patients do not effectively respond to current therapies, and thus new drugs are urgently required.

We invite original research articles, review articles, and communications that provide new insights into the genetic and epigenetic factors that contribute to RA susceptibility and severity, the molecular pathways that regulate inflammation and tissue destruction, the role of immune cells in the pathogenesis of RA, and the molecular mechanisms of current and emerging therapies for RA. By bringing together cutting-edge research on the molecular insights of rheumatoid arthritis, we hope to deepen our understanding of this complex disease, and contribute to the development of more effective therapies for those affected.

We look forward to your contributions to this exciting Special Issue.

Prof. Dr. Hajime Kono
Guest Editor

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Published Papers (7 papers)

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Research

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11 pages, 619 KiB

Open AccessArticle

Are the Soluble Receptors sRAGE, sRANKL, and Osteoprotegerin Associated with Anemia in Rheumatoid Arthritis?

by Katya Stefanova, Ginka Delcheva and Teodora Stankova

Int. J. Mol. Sci. 2024, 25(23), 12729; https://doi.org/10.3390/ijms252312729 - 27 Nov 2024

Viewed by 812

Abstract

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with articular and systemic manifestations, and one of the most common is anemia. This study aims to investigate whether the levels of the soluble receptors sRAGE, sRANKL, and OPG are affected by the distribution of RA patients in subgroups according to soluble transferrin receptor/log ferritin (sTfR-F index) and hemoglobin (Hb) levels and to examine their correlation with indicators of iron metabolism, disease activity, and autoimmune and inflammatory changes. The levels of sRANKL and sRAGE were significantly higher in the subgroup of anemia of chronic disease combined with iron deficiency anemia (ACD/IDA) compared to the ACD group: p < 0.0001 and p < 0.0001. The level of OPG tended to decrease in ACD/IDA (p = 0.053). sRAGE was positively correlated with prohepcidin, RF and anti-CCP antibodies, sRANKL, CRP, and IL-6 only in the ACD group. A negative correlation was found between sRAGE, sRANKL, and serum iron only in the ACD/IDA group. sRANKL was positively correlated with OPG, prohepcidin, CRP, IL-6, RF, anti-CCP antibodies, and DAS28 only in the ACD group. Positive correlations were observed between OPG and ferritin, sTfR, CRP, IL-6, RF, and DAS28, and a negative correlation was observed with serum iron only in the ACD group. Therefore, the investigated soluble receptors may serve as reliable biomarkers involved in the pathogenesis of RA and may contribute to the identification of patients at risk of developing combined anemia. Full article

(This article belongs to the Special Issue Molecular Insights in Rheumatoid Arthritis)

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11 pages, 288 KiB

Open AccessCommunication

Effective Assessment of Rheumatoid Arthritis Disease Activity and Outcomes Using Monocyte Chemotactic Protein-1 (MCP-1) and Disease Activity Score 28-MCP-1

by Ping-Han Tsai and Lieh-Bang Liou

Int. J. Mol. Sci. 2024, 25(21), 11374; https://doi.org/10.3390/ijms252111374 - 23 Oct 2024

Viewed by 1041

Abstract

The effectiveness of monocyte chemotactic protein-1 (MCP-1) and Disease Activity Score 28 (DAS28)-MCP-1 (DAS28-MCP-1) in assessing rheumatoid arthritis (RA) disease activity is unclear, although some studies have demonstrated their potential usefulness. The present study investigated relationships between MCP-1 and different DAS28 measures, the occurrence of residual swollen joints in different DAS28 remission statuses, changes in medication dosage in relation to the 2005 modified American Rheumatism Association and 2011 American College of Rheumatology/European League against Rheumatism (ACR/EULAR) remission definitions, and the correlations between different DAS28-related scores and Health Assessment Questionnaire Disability Index (HAQ-DI) scores in two RA patient cohorts. The results revealed that the MCP-1 level was correlated with five disease activity measures (DAS28-erythrocyte sedimentation rate [DAS28-ESR], DAS28-C-reactive protein [CRP], Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), and DAS28-MCP-1) in multivariable regression analysis (all p < 0.05; ESR, CRP, and MCP-1 as independent variables). However, ESR was not significantly associated with SDAI and CDAI scores (p = 0.343 and 0.323, respectively). Residual swollen joints were more frequently observed in patients who met the DAS28-ESR remission criteria (<2.6) compared with those meeting the other four remission criteria, with a difference ranging from 71% to 94%. Among patients meeting the DAS28-ESR remission criteria (<2.6), medication changes (dose increase by ≥30% or new medications prescribed) were less frequent in those who also met the 2011 ACR/EULAR remission criteria than in those who did not meet them (p = 0.006). Moreover, the correlation coefficients for the relationship between DAS28-ESR and HAQ-DI scores were the lowest among the five disease activity measures. In conclusion, MCP-1 and DAS28-MCP-1 are effective in assessing RA disease activity, with less residual joint swelling and less frequent medication increases observed in the DAS28-MCP-1 remission < 2.2 subgroup. Full article

(This article belongs to the Special Issue Molecular Insights in Rheumatoid Arthritis)

19 pages, 1360 KiB

Open AccessArticle

Immunoregulatory Cells and Cytokines Discriminate Disease Activity Score 28-Remission Statuses and Ultrasound Grades in Rheumatoid Arthritis Patients with Non-High Disease Activity

by Lieh-Bang Liou, Yao-Fan Fang, Ping-Han Tsai, Yen-Fu Chen, Che-Tzu Chang, Chih-Chieh Chen and Wen-Yu Chiang

Int. J. Mol. Sci. 2024, 25(16), 8694; https://doi.org/10.3390/ijms25168694 - 9 Aug 2024

Cited by 1 | Viewed by 1301

Abstract

It is not clear whether immunoregulatory cytokines and cells are associated with Disease Activity Score 28 (DAS28) scores and ultrasound grades/scores. Here, we investigated the relationships between immunoregulatory cytokines or cells and different DAS28 scores or ultrasound grades/scores in patients with rheumatoid arthritis (RA). This study enrolled 50 RA patients (with 147 visits) who had remission/low/moderate DAS28-ESR scores (92% in remission and low disease activity) at baseline. Blood was collected and an ultrasound was performed three times in a year. Percentages of regulatory B cells and T regulatory type 1 cells and M2 macrophage numbers in the blood were examined. Plasma levels of 10 immunoregulatory cytokines IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-35, TGF-β1, sTNF-R1, and sTNF-R2 and monocyte chemotactic protein-1 (MCP-1) were assessed using ELISA assay. The correlations of cytokines and cells with different DAS28 scores and ultrasound grades were investigated, and cytokines and cells were compared between different categories of DAS28 scores and ultrasound grades. Plasma TGF-β1 levels were higher in the DAS28-ESR < 2.6 (remission) subgroup than in the DAS28-ESR ≥ 2.6 (nonremission) subgroup (p = 0.037). However, plasma TGF-β1 levels were higher in the high ultrasound grade subgroup than those in the low ultrasound grade subgroup (p = 0.007). The number of M2 macrophages was lower in the DAS28-MCP-1 < 2.2 subgroup than in the DAS28-MCP-1 ≥ 2.2 subgroup (p = 0.036). The levels of TGF-β1, sTNF-R2, IL-10, and IL-27 were higher in patients with high ultrasound grades than in those with low ultrasound grades. IL-27 was also higher in the nonremission DAS28-ESR subgroup than the remission one (p = 0.025). Moreover, sTNF-R1 levels in the 2011 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission subgroup were significantly lower than in the 2011 ACR/EULAR nonremission subgroup (p = 0.007). This trend was reflected in that lower sTNF-R1 levels correlated with low DAS28-MCP-1 scores (rho = 0.222, p = 0.007). We conclude that high plasma TGF-β1 levels indicate the DAS28-ESR remission (<2.6) subgroup and the high ultrasound grade subgroup. IL-27 probably connects the nonremission DAS28-ESR to high ultrasound grades. Low sTNF-R1 levels probably link low DAS28-MCP-1 scores with the 2011 ACR/EULAR remission subgroup. It suggests that incongruent immuno-inflammatory abnormalities exist between DAS28 scores and ultrasound grades, and are also dissimilar among various DAS28-formula categories. Therefore, this study may provide a basis for further research into individual cytokines and immunoregulatory cells behind each DAS28 formula and ultrasound grades/scores. Full article

(This article belongs to the Special Issue Molecular Insights in Rheumatoid Arthritis)

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16 pages, 1899 KiB

Open AccessArticle

Complete Description of the Three Pathways of the Complement System in a Series of 430 Patients with Rheumatoid Arthritis

by Dara Rodríguez-González, María García-González, Fuensanta Gómez-Bernal, Juan C. Quevedo-Abeledo, Agustín F. González-Rivero, Yolanda Fernández-Cladera, Elena González-López, J. Gonzalo Ocejo-Vinyals, Alejandro Jiménez-Sosa, Beatriz González-Toledo, Miguel Á. González-Gay and Iván Ferraz-Amaro

Int. J. Mol. Sci. 2024, 25(15), 8360; https://doi.org/10.3390/ijms25158360 - 31 Jul 2024

Cited by 1 | Viewed by 1463

Abstract

The complement (C) system is implicated in the etiopathogenesis of rheumatoid arthritis (RA). However, there is a lack of studies characterizing all three C pathways in RA patients. This study aimed to evaluate the association between an in-depth examination of the C system and RA patient characteristics, focusing on disease activity and the presence of rheumatoid factor and anti-citrullinated protein autoantibodies (ACPA). In a cohort of 430 RA patients, functional assays of the three C pathways (classical, alternative, and lectin) and serum levels of their components were assessed. Components included C1q (classical); factor D and properdin (alternative); lectin (lectin); C1-inhibitor; C2, C4, and C4b (classical and lectin); C3, C3a, and C4b (common); and C5, C5a, and C9 (terminal). A multivariable linear regression analysis showed significant positive correlations between C-reactive protein and C system proteins and functional assays, especially in the terminal and common pathways. Disease activity, measured by scores with or without acute phase reactants, positively correlated with the classical pathway functional test and terminal pathway products. Conversely, rheumatoid factor or ACPA presence was associated with lower classical pathway values and decreased C3a and C4b levels, suggesting complement depletion. In conclusion, RA disease activity increases C molecules and functional complement assays, while rheumatoid factor or ACPA positivity is linked to C consumption. Our study offers a detailed analysis of the complement system’s role in RA, potentially guiding the development of more targeted and effective treatment strategies. Full article

(This article belongs to the Special Issue Molecular Insights in Rheumatoid Arthritis)

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16 pages, 3977 KiB

Open AccessArticle

Free Fatty Acid 4 Receptor Activation Attenuates Collagen-Induced Arthritis by Rebalancing Th1/Th17 and Treg Cells

by Jung-Eun Lee, Ju-Hyun Lee, Jung-Min Koh and Dong-Soon Im

Int. J. Mol. Sci. 2024, 25(11), 5866; https://doi.org/10.3390/ijms25115866 - 28 May 2024

Cited by 2 | Viewed by 1763

Abstract

Dietary supplementation with n-3 polyunsaturated fatty acids (PUFA) has been found to be beneficial in rodent rheumatoid arthritis models and human trials. However, the molecular targets of n-3 PUFAs and their beneficial effects on rheumatoid arthritis are under-researched. Free fatty acid receptor 4 (FFA4, also known as GPR120) is a receptor for n-3 PUFA. We aim to investigate whether FFA4 activation reduces collagen-induced rheumatoid arthritis (CIA) by using an FFA4 agonist, compound A (CpdA), in combination with DBA-1J Ffa4 gene wild-type (WT) and Ffa4 gene knock-out (KO) mice. CIA induced an increase in the arthritis score, foot edema, synovial hyperplasia, pannus formation, proteoglycan loss, cartilage damage, and bone erosion, whereas the administration of CpdA significantly suppressed those increases in Ffa4 WT mice but not Ffa4 gene KO mice. CIA increased mRNA expression levels of pro-inflammatory Th1/Th17 cytokines, whereas CpdA significantly suppressed those increases in Ffa4 WT mice but not Ffa4 gene KO mice. CIA induced an imbalance between Th1/Th17 and Treg cells, whereas CpdA rebalanced them in spleens from Ffa4 WT mice but not Ffa4 gene KO mice. In SW982 synovial cells, CpdA reduced the LPS-induced increase in pro-inflammatory cytokine levels. In summary, the present results suggest that the activation of FFA4 in immune and synovial cells could suppress the characteristics of rheumatoid arthritis and be an adjuvant therapy. Full article

(This article belongs to the Special Issue Molecular Insights in Rheumatoid Arthritis)

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17 pages, 3324 KiB

Open AccessArticle

Exploring the Link between Hydrodynamic Size and Immunoglobulins of Circulating Immune Complexes in Rheumatoid Arthritis Patients

by Tamara Djukić, Ivana Drvenica, Marijana Kovačić, Sladjan Milanović, Dragana Majerič, Mirjana Šefik-Bukilica, Maja Miletić, Branko Bugarski and Vesna Ilić

Int. J. Mol. Sci. 2024, 25(6), 3138; https://doi.org/10.3390/ijms25063138 - 8 Mar 2024

Cited by 1 | Viewed by 1541

Abstract

The function of immune complexes in rheumatoid arthritis (RA) is related to their composition and size. Using dynamic light scattering (DLS), we investigated the link between the RA circulating immune complex (CIC) particles’ size and the CIC immunoglobulin level. In this study, 30 RA patients and 30 healthy individuals were included. IgA, IgG, and IgM were found in all analyzed CICs, but more IgA and IgG were found in RA than in control CICs. In both control and RA CICs, DLS detected 50 particles that differed in size and clustered around two size groups: with a 7.5–164 nm radius and with a 342–1718 nm radius. An increased level of IgA in RA CICs, compared to control ones, was associated with more than 50% of CIC particles. In RA, compared to the control, a higher number of CICs with 28.2 nm, 531 nm, 712 nm, and 1718 nm particles and a lower number of CICs with 78.8 nm particles were detected. This particle distribution pattern did not reflect the changes in the CIC immunoglobulin level. Thus, RA elevated CIC IgA was linked with all these particles (except the 1718 nm particle), the IgM increase was linked with 43.8 nm and 712 nm particles, and the IgG increase was linked with the 712 nm particle only. This study provides the very first data on the association between CIC particles’ size, CIC immunoglobulin level, and RA. It opens the possibility that the size of CICs determined by DLS can be used as a criterion in RA diagnosis or monitoring after a large-scale study confirmation. Full article

(This article belongs to the Special Issue Molecular Insights in Rheumatoid Arthritis)

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17 pages, 1265 KiB

Open AccessReview

The Role of Autophagy as a Trigger of Post-Translational Modifications of Proteins and Extracellular Vesicles in the Pathogenesis of Rheumatoid Arthritis

by Gloria Riitano, Serena Recalchi, Antonella Capozzi, Valeria Manganelli, Roberta Misasi, Tina Garofalo, Maurizio Sorice and Agostina Longo

Int. J. Mol. Sci. 2023, 24(16), 12764; https://doi.org/10.3390/ijms241612764 - 14 Aug 2023

Cited by 6 | Viewed by 2525

Abstract

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, characterized by persistent joint inflammation, leading to cartilage and bone destruction. Autoantibody production is directed to post-translational modified (PTM) proteins, i.e., citrullinated or carbamylated. Autophagy may be the common feature in several types of stress (smoking, joint injury, and infections) and may be involved in post-translational modifications (PTMs) in proteins and the generation of citrullinated and carbamylated peptides recognized by the immune system in RA patients, with a consequent breakage of tolerance. Interestingly, autophagy actively provides information to neighboring cells via a process called secretory autophagy. Secretory autophagy combines the autophagy machinery with the secretion of cellular content via extracellular vesicles (EVs). A role for exosomes in RA pathogenesis has been recently demonstrated. Exosomes are involved in intercellular communications, and upregulated proteins and RNAs may contribute to the development of inflammatory arthritis and the progression of RA. In RA, most of the exosomes are produced by leukocytes and synoviocytes, which are loaded with PTM proteins, mainly citrullinated proteins, inflammatory molecules, and enzymes that are implicated in RA pathogenesis. Microvesicles derived from cell plasma membrane may also be loaded with PTM proteins, playing a role in the immunopathogenesis of RA. An analysis of changes in EV profiles, including PTM proteins, could be a useful tool for the prevention of inflammation in RA patients and help in the discovery of personalized medicine. Full article

(This article belongs to the Special Issue Molecular Insights in Rheumatoid Arthritis)

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