scholarly journals Pathogenic Role of Circulating Citrullinated Antigens and Anti-Cyclic Monoclonal Citrullinated Peptide Antibodies in Rheumatoid Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Pureun Won ◽  
Youngkyun Kim ◽  
Hyerin Jung ◽  
Yeri Alice Rim ◽  
Dong Hyun Sohn ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Monoclonal Antibody ◽  
Lupus Erythematosus ◽  
Sandwich Elisa ◽  
Immunohistochemical Analysis ◽  
Target Tissue ◽  
Citrullinated Proteins ◽  
Citrullinated Peptide

We examined whether it is possible to directly detect citrullinated antigens in the serum of rheumatoid arthritis (RA) patients using a monoclonal antibody (mAb) designed to be specific for citrullinated peptides. In order to confirm the potential of the mAb as a direct arthritis-inducing substance through experimental model of RA, a monoclonal antibody (mAb) 12G1 was generated using by immunization of mice with a challenging cyclic citrullinated peptide. Immunohistochemical analysis of RA-affected synovial tissue showed that our mAb 12G1 could indeed detect citrullinated proteins in target tissues. Subsequently, serum levels of citrullinated type II collagen and filaggrin were measured in healthy volunteers, patients with RA, ankylosing spondylitis (AS), and systemic lupus erythematosus (SLE) using a 12G1-based sandwich ELISA. This showed that citrullinated filaggrin showed 78.9% sensitivity and 85.9% specificity for RA diagnosis with a cutoff optical density (OD) value of 1.013, comparable with the results from a second-generation anti-citrullinated protein antibody (ACPA) test. Circulating citrullinated collagen and filaggrin were detected even in sera of RA patients who were negative for both rheumatoid factor (RF) and ACPA. ELISA results also showed that RF and ACPA titers showed significantly positive correlation with both citrullinated collagen and filaggrin OD values in sera of RA patients. 12G1 challenging aggravated the severity of murine arthritis. In summary, mAb 12G1 can directly detect citrullinated proteins in RA target tissue and in sera of RA patients and 12G1 showed direct arthritogenic potential in vivo. This, 12G1 might be useful for diagnosis of RA including seronegative RA and may help to elucidate the pathophysiological role of citrullination in RA.

scholarly journals Antihomocitrullinated Fibrinogen Antibodies are Specific to Rheumatoid Arthritis and Frequently Bind Citrullinated Proteins/peptides

2014 ◽  
Vol 41 (2) ◽  
pp. 270-279 ◽  
Author(s):  
Mathias Scinocca ◽  
David A. Bell ◽  
Maud Racapé ◽  
Radha Joseph ◽  
Gary Shaw ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mass Spectrometry ◽  
Computer Modeling ◽  
Lupus Erythematosus ◽  
Shared Epitope ◽  
Affinity Purification ◽  
Peptide Antibody ◽  
Citrullinated Proteins ◽  
Peptide Interaction ◽  
Citrullinated Peptide

Objective.Anticitrullinated protein/peptide antibodies (ACPA) are implicated in rheumatoid arthritis (RA) pathogenesis and linked to the shared epitope (SE). Citrulline modification is very similar to a different modified amino acid, homocitrulline. We investigated antihomocitrullinated protein/ peptide antibody (AHCPA) specificity for RA, whether ACPA were also able to bind homocitrullinated targets, and whether the SE could accommodate homocitrullinated peptide.Methods.Homocitrullinated fibrinogen was used to screen sera from patients with RA, psoriatic arthritis, and systemic lupus erythematosus, and healthy subjects for AHCPA using ELISA. Homocitrullination sites on fibrinogen were identified by mass spectrometry. ACPA were affinity-purified using a synthetic citrullinated peptide and tested for binding to homocitrullinated protein/peptide. Inhibition of antihomocitrullinated fibrinogen antibody binding was examined. Homocitrullinated peptide interaction with the SE was studied using computer modeling.Results.IgG antihomocitrullinated fibrinogen antibodies were found specifically in 49% of patients with RA. Enrichment of ACPA by affinity purification from 5 patients with RA also enriched AHCPA. Serum AHCPA was inhibited by citrullinated fibrinogen and more significantly by homocitrullinated fibrinogen. Computer modeling indicated that the SE could accommodate a homocitrullinated peptide without steric hindrance. Mass spectrometry identified that 89/103 lysines of fibrinogen could be homocitrullinated, and 5 peptides that could be both citrullinated and homocitrullinated and are predicted to bind the SE.Conclusion.Antihomocitrullinated fibrinogen antibodies are specific to RA. The presence of AHCPA coincides with ACPA, and AHCPA copurifies with ACPA in affinity purification and is inhibited by citrullinated and homocitrullinated antigens. Thus AHCPA and ACPA are frequently cross-reactive and homocitrullinated proteins/peptides may bind the SE.

scholarly journals Secreted KIAA1199 promotes the progression of rheumatoid arthritis by mediating hyaluronic acid degradation in an ANXA1-dependent manner

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wei Zhang ◽  
Guoyu Yin ◽  
Heping Zhao ◽  
Hanzhi Ling ◽  
Zhen Xie ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Hyaluronic Acid ◽  
Dependent Manner ◽  
Collagen Induced Arthritis ◽  
Intracellular Degradation ◽  
Main Pathway ◽  
First Time

AbstractIn inflamed joints, enhanced hyaluronic acid (HA) degradation is closely related to the pathogenesis of rheumatoid arthritis (RA). KIAA1199 has been identified as a hyaladherin that mediates the intracellular degradation of HA, but its extracellular function remains unclear. In this study, we found that the serum and synovial levels of secreted KIAA1199 (sKIAA1199) and low-molecular-weight HA (LMW-HA, MW < 100 kDa) in RA patients were significantly increased, and the positive correlation between them was shown for the first time. Of note, treatment with anti-KIAA1199 mAb effectively alleviated the severity of arthritis and reduced serum LMW-HA levels and cytokine secretion in collagen-induced arthritis (CIA) mice. In vitro, sKIAA1199 was shown to mediate exogenous HA degradation by attaching to the cell membrane of RA fibroblast-like synoviosytes (RA FLS). Furthermore, the HA-degrading activity of sKIAA1199 depended largely on its adhesion to the membrane, which was achieved by its G8 domain binding to ANXA1. In vivo, kiaa1199-KO mice exhibited greater resistance to collagen-induced arthritis. Interestingly, this resistance could be partially reversed by intra-articular injection of vectors encoding full-length KIAA1199 instead of G8-deleted KIAA119 mutant, which further confirmed the indispensable role of G8 domain in KIAA1199 involvement in RA pathological processes. Mechanically, the activation of NF-κB by interleukin-6 (IL-6) through PI3K/Akt signaling is suggested to be the main pathway to induce KIAA1199 expression in RA FLS. In conclusion, our study supported the contribution of sKIAA1199 to RA pathogenesis, providing a new therapeutic target for RA by blocking sKIAA1199-mediated HA degradation.

scholarly journals Low Intensity Shockwave Treatment Modulates Macrophage Functions Beneficial to Healing Chronic Wounds

2021 ◽  
Vol 22 (15) ◽  
pp. 7844
Author(s):  
Jason S. Holsapple ◽  
Ben Cooper ◽  
Susan H. Berry ◽  
Aleksandra Staniszewska ◽  
Bruce M. Dickson ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Molecular Mechanisms ◽  
Chronic Wounds ◽  
Immunohistochemical Analysis ◽  
Therapeutic Effects ◽  
Gene Expressions ◽  
Extracorporeal Shock Wave

Extracorporeal Shock Wave Therapy (ESWT) is used clinically in various disorders including chronic wounds for its pro-angiogenic, proliferative, and anti-inflammatory effects. However, the underlying cellular and molecular mechanisms driving therapeutic effects are not well characterized. Macrophages play a key role in all aspects of healing and their dysfunction results in failure to resolve chronic wounds. We investigated the role of ESWT on macrophage activity in chronic wound punch biopsies from patients with non-healing venous ulcers prior to, and two weeks post-ESWT, and in macrophage cultures treated with clinical shockwave intensities (150–500 impulses, 5 Hz, 0.1 mJ/mm2). Using wound area measurements and histological/immunohistochemical analysis of wound biopsies, we show ESWT enhanced healing of chronic ulcers associated with improved wound angiogenesis (CD31 staining), significantly decreased CD68-positive macrophages per biopsy area and generally increased macrophage activation. Shockwave treatment of macrophages in culture significantly boosted uptake of apoptotic cells, healing-associated cytokine and growth factor gene expressions and modulated macrophage morphology suggestive of macrophage activation, all of which contribute to wound resolution. Macrophage ERK activity was enhanced, suggesting one mechanotransduction pathway driving events. Collectively, these in vitro and in vivo findings reveal shockwaves as important regulators of macrophage functions linked with wound healing. This immunomodulation represents an underappreciated role of clinically applied shockwaves, which could be exploited for other macrophage-mediated disorders.

scholarly journals Role of Fluorophore Charge on the In Vivo Optical Imaging Properties of Near-Infrared Cyanine Dye/Monoclonal Antibody Conjugates

2015 ◽  
Vol 27 (2) ◽  
pp. 404-413 ◽  
Author(s):  
Kazuhide Sato ◽  
Alexander P. Gorka ◽  
Tadanobu Nagaya ◽  
Megan S. Michie ◽  
Roger R. Nani ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Optical Imaging ◽  
Near Infrared ◽  
Cyanine Dye ◽  
Antibody Conjugates ◽  
Imaging Properties ◽  
In Vivo Optical Imaging

scholarly journals Diet in Rheumatoid Arthritis versus Systemic Lupus Erythematosus: Any Differences?

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 772
Author(s):  
Alessia Alunno ◽  
Francesco Carubbi ◽  
Elena Bartoloni ◽  
Davide Grassi ◽  
Claudio Ferri ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Musculoskeletal Diseases ◽  
Normal Subjects ◽  
Experimental Models ◽  
Systemic Lupus ◽  
History Of ◽  
Indirect Action

In recent years, an increasing interest in the influence of diet in rheumatic and musculoskeletal diseases (RMDs) led to the publication of several articles exploring the role of food/nutrients in both the risk of developing these conditions in normal subjects and the natural history of the disease in patients with established RMDs. Diet may be a possible facilitator of RMDs due to both the direct pro-inflammatory properties of some nutrients and the indirect action on insulin resistance, obesity and associated co-morbidities. A consistent body of research has been conducted in rheumatoid arthritis (RA), while studies in systemic lupus erythematosus (SLE) are scarce and have been conducted mainly on experimental models of the disease. This review article aims to outline similarities and differences between RA and SLE based on the existing literature.

Markers of the early stage of rheumatoid arthritis

2016 ◽  
Vol 51 (4) ◽  
pp. 305-314
Author(s):  
Beata Polińska ◽  
Joanna Matowicka-Karna ◽  
Halina Kemona
Keyword(s):  
Rheumatoid Arthritis ◽  
Human Population ◽  
Early Stage ◽  
Clinical Signs ◽  
High Sensitivity ◽  
Unknown Etiology ◽  
Serological Tests ◽  
Citrullinated Peptide ◽  
Peptide Antibodies

Rheumatoid arthritis (RA) is a chronic, autoimmune connective tissue disease of unknown etiology. RA affects about 1% of the human population, women suffer three times more often than men, with the peak incidence between the age of 40 to 50. The up-to-date criteria from 2010 for the diagnosis of RA include: occurrence and duration of clinical signs, indicators of inflammation and serological tests. Neopterin, a protein released by macrophages, is a sensitive indicator of inflammation and the severity of RA. Regarding the serological tests, anti-cyclic citrullinated peptide antibodies represent a well-known marker with the specificity for RA of about 98%. The antibodies may be present in the serum of patients even a few years before the first clinical signs of the disease, heralding erosive changes in the joints and more severe course of RA. The literature also contains reports about autoantibodies anti-CarP and anti-Sa/ anti-MCV, which may occur in people with pain and swelling of joints and precede full-blown development of RA as well as reflect disease activity. Serological diagnosis of RA may be supported by some genetic tests based on PCR for detecting mutations e.g. C1858T in the PNPN22 gene. In turn, the quantitative analysis of different classes of miRNAs seems justified in order to better classify patients showing symptoms of RA. Further studies are needed that take into account the role of different markers in the development of RA, and confirm the high sensitivity and specificity of these markers in the diagnosis of the disease.

scholarly journals Role of Biological Response Modifiers in the Treatment of Rheumatoid Arthritis - A Review

1970 ◽  
Vol 18 (1) ◽  
pp. 60-65
Author(s):  
Md Azizul Haque ◽  
ARM Saifuddin Ekram ◽  
Quazi Tarikul Islam
Keyword(s):  
Rheumatoid Arthritis ◽  
Monoclonal Antibody ◽  
Chronic Disease ◽  
Receptor Antagonist ◽  
Disease Progression ◽  
Joint Damage ◽  
Biological Response ◽  
The Past ◽  
Conventional Dmards

Rheumatoid arthritis is a chronic disease with the potential to cause substantial joint damage and disability. During the past 10 years, improved understanding of the pathophysiology of rheumatoid arthritis has led to several key changes in the approach to therapy. Most important of that is the development of some biological agents interfering with the activity of several important cytokines. Infliximab, etanarcept, and adalimumab are TNF blockers, anakinra is IL-1 receptor antagonist, and rituximab is anti CD-20 monoclonal antibody. These newer agents proved to be useful for alleviating symptoms and slowing the disease progression in the patients with RA who have failed to respond to conventional DMARDs.   doi: 10.3329/taj.v18i1.3309 TAJ 2005; 18(1): 60-65

scholarly journals Decreased MiR-128-3p alleviates the progression of rheumatoid arthritis by up-regulating the expression of TNFAIP3

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Zhongbin Xia ◽  
Fanru Meng ◽  
Ying Liu ◽  
Yuxuan Fang ◽  
Xia Wu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Peripheral Blood ◽  
Potential Role ◽  
Enzyme Linked Immunosorbent Assay ◽  
Normal Person ◽  
Synovial Joint ◽  
Peripheral Blood Mononuclear

Background: Rheumatoid arthritis (RA) is a inflammatory disease that characterized with the destruction of synovial joint, which could induce disability. Inflammatory response mediated the RA. It has been reported that MiR-128-3p is significantly increased in RA, while the potential role was still unclear. Methods: T cells in peripheral blood mononuclear cell (PBMC) were isolated from the peripheral blood from people of RA and normal person were used. Real-time PCR was performed to detect the expression of MiR-128-3p, while the protein expression of tumor necrosis factor-α-induced protein 3 (TNFAIP3) was determined using Western blot. The levels of IL-6 and IL-17 were measured using enzyme-linked immunosorbent assay (ELISA). The expression of CD69 and CD25 was detected using flow cytometry. The RA mouse model was constructed for verification of the role of MiR-128-3p. Results: The expression of MiR-128-3p was significantly increased, while TNFAIP3 was decreased, the levels of IL-6 and IL-17 were also increased in the T cells of RA patients. Down-regulated MiR-128-3p significantly suppressed the expression of p-IkBα and CD69, and CD25in T cells. MiR-128-3p targets TNFAIP3 to regulate its expression. MiR-128-3p knockdown significantly suppressed the activity of nuclear factor κB (NF-κB) and T cells by up-regulating TNFAIP3, while cells co-transfected with si-TNFAIP3 abolished the effects of MiR-128-3p knockdown. The in vivo experiments verified the potential role of MiR-128-3p on RA. Conclusion: Down-regulated MiR-128-3p significantly suppressed the inflammation response of RA through suppressing the activity of NF-κB pathway, which was mediated by TNFAIP3.

Rheumatoid Arthritis: Etiology and Pathogenesis

2014 ◽  
Author(s):  
Gary S. Firestein ◽  
Anna-Karin H. Ekwall
Keyword(s):  
Rheumatoid Arthritis ◽  
Intracellular Signaling ◽  
Cartilage Damage ◽  
Signs And Symptoms ◽  
American College Of Rheumatology ◽  
European League Against Rheumatism ◽  
Citrullinated Proteins ◽  
Definition Of

Rheumatoid arthritis (RA) is among the most common forms of chronic inflammatory arthritis. It affects approximately 1% of adults and is two to three times more prevalent in women than in men. There are no specific laboratory tests for RA; diagnosis depends on a constellation of signs and symptoms that can be supported by serology and radiographs. The disease evolves over many years as a consequence of repeated environmental stress causing inflammation and immune activation followed by a breakdown of tolerance in individuals with a specific genetic background. This review describes the definition of RA; its etiology, including genetics, infections, the role of smoking and citrullination of proteins, and epigenetic mechanisms; and its pathogenesis, including synovial histopathology, bone and cartilage damage, adaptive and innate immunity, and the role of cytokines and intracellular signaling. Tables include the 1987 American Rheumatism Association criteria for the classification of RA and the 2010 American College of Rheumatology/European League Against Rheumatism classification for RA. Figures show citrullinated proteins in airway cells, a section of a proliferative synovium from a patient with a classic RA, and scalloped regions of erosion at the junction between a proliferative inflamed rheumatoid synovium and the bone. This review contains 3 highly rendered figures, 2 tables, and 71 references.

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