Post-Translational Modifications of Proteins: Novel Insights in the Autoimmune Response in Rheumatoid Arthritis

Carubbi, Francesco; Alunno, Alessia; Gerli, Roberto; Giacomelli, Roberto

doi:10.3390/cells8070657

Cited by 40 publications

(29 citation statements)

References 93 publications

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“…In addition, a recent study showed that specific gene expression profiles could be associated with a higher chance of achieving sustained drugfree remission (18). Furthermore, inflammation induces post translational modifications of proteins, notably citrullination and carbamylation, as in ACPA (anti-citrullinated protein antibodies) and AMPA (anti-modified protein antibodies), with changes in antigenicity (19). All these parameters could explain the strong heterogeneity in treatment response.…”

Section: Discussionmentioning

confidence: 99%

Effects of Methotrexate Alone or Combined With Arthritis-Related Biotherapies in an in vitro Co-culture Model With Immune Cells and Synoviocytes

Noack

Miossec

2019

Front. Immunol.

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Background: Methotrexate (MTX) at low dose is a key drug for rheumatoid arthritis (RA). MTX is widely used alone or combined with biologics or steroids. The aim was to study its effects on cytokine production using an in vitro model with synoviocytes interacting with peripheral blood mononuclear cells (PBMC) to reproduce the interactions in RA synovium. Methods: Activated-PBMC were co-cultured with RA synoviocytes during 48 h. A dose-response of MTX was tested and different biotherapies (Infliximab, Tocilizumab, Abatacept and Rituximab) were added alone or in combination with MTX. Cytokine production (IL-17, IL-6, IL-1β, IFN-γ, and IL-10) was measured by ELISA. These results were compared with those obtained with steroids. Results: MTX alone had a modest inhibitory effect on cytokine production compared to steroids. The most effective concentration was one of the lowest, 0.01 µg/ml, as for steroids. Infliximab was the most active biotherapy (p ≤ 0.05 for all cytokines) followed by Tocilizumab (p ≤ 0.05 for all cytokines except IL-6). Abatacept and Rituximab had a more restricted effect on cytokines (p ≤ 0.05 for IL-1β and IFN-γ). The combination MTX/biotherapies did not increase significantly the inhibition of cytokine production but some specific inhibitory effects were observed with Infliximab on IL-17 and IL-6, and with Abatacept and Rituximab on IL-1β. Conclusion: Low dose of MTX was at least as effective as high dose. The effects of the combination with biotherapies showed an important level of heterogeneity between the levels of some specific cytokines and the degree of inhibition with drugs.

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Section: Discussionmentioning

confidence: 99%

Effects of Methotrexate Alone or Combined With Arthritis-Related Biotherapies in an in vitro Co-culture Model With Immune Cells and Synoviocytes

Noack

Miossec

2019

Front. Immunol.

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“…Specifically, the sensitivity of anti-CarP Ab is 18–26% and 27–46% prior to and after RA diagnosis, respectively, and its specificity is approximately 90% and above in RA [ 67 ]. Approximately 8–16% of ACPA-negative patients test positive for anti-CarP Ab [ 28 , 65 ].…”

Section: Characteristics Of Rf Acpa and Anti-carp Abmentioning

confidence: 99%

From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis

Yang

Luo

et al. 2021

IJMS

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Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease mainly involving synovial inflammation and articular bone destruction. RA is a heterogeneous disease with diverse clinical presentations, prognoses and therapeutic responses. Following the first discovery of rheumatoid factors (RFs) 80 years ago, the identification of both anti-citrullinated protein antibodies (ACPAs) and anti-carbamylated protein antibodies (anti-CarP Abs) has greatly facilitated approaches toward RA, especially in the fields of early diagnosis and prognosis prediction of the disease. Although these antibodies share many common features and can function synergistically to promote disease progression, they differ mechanistically and have unique clinical relevance. Specifically, these three RA associating auto-antibodies (autoAbs) all precede the development of RA by years. However, while the current evidence suggests a synergic effect of RF and ACPA in predicting the development of RA and an erosive phenotype, controversies exist regarding the additive value of anti-CarP Abs. In the present review, we critically summarize the characteristics of these autoantibodies and focus on their distinct clinical applications in the early identification, clinical manifestations and prognosis prediction of RA. With the advancement of treatment options in the era of biologics, we also discuss the relevance of these autoantibodies in association with RA patient response to therapy.

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“…Patients diagnosed with RA produce a specific set of autoantibodies, typically reactive against post-translational modifications of proteins (5)(6)(7). Such autoantibodies appear decades before clinically apparent disease (8).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis

Qiu

Goodman

et al. 2021

Front. Immunol.

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Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease.

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Post-Translational Modifications of Proteins: Novel Insights in the Autoimmune Response in Rheumatoid Arthritis

Cited by 40 publications

References 93 publications

Effects of Methotrexate Alone or Combined With Arthritis-Related Biotherapies in an in vitro Co-culture Model With Immune Cells and Synoviocytes

Effects of Methotrexate Alone or Combined With Arthritis-Related Biotherapies in an in vitro Co-culture Model With Immune Cells and Synoviocytes

From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis

Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis

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