Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: Implications for autoimmunity in rheumatoid arthritis
TL;DR: It is shown that P gingivalis rapidly generates citrullinated host peptides by proteolytic cleavage at Arg-X peptide bonds by arginine gingipains, followed bycitrullination of carboxy-terminal arginines by bacterial PAD.
Abstract: Objectives
To investigate protein citrullination by the periodontal pathogen Porphyromonas gingivalis (P. gingivalis) as a potential mechanism for breaking tolerance to citrullinated proteins in rheumatoid arthritis (RA).
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TL;DR: The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.
Abstract: The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.
3,975 citations
TL;DR: The mechanisms of microbial immune subversion that tip the balance from homeostasis to disease in oral or extra-oral sites are discussed.
Abstract: Periodontitis is a dysbiotic inflammatory disease with an adverse impact on systemic health. Recent studies have provided insights into the emergence and persistence of dysbiotic oral microbial communities that can mediate inflammatory pathology at local as well as distant sites. This Review discusses the mechanisms of microbial immune subversion that tip the balance from homeostasis to disease in oral or extra-oral sites.
1,621 citations
TL;DR: A treat-to-target strategy aimed at reducing disease activity by at least 50% within 3 months and achieving remission or low disease activity within 6 months, with sequential drug treatment if needed, can prevent RA-related disability.
Abstract: Importance Rheumatoid arthritis (RA) occurs in about 5 per 1000 people and can lead to severe joint damage and disability. Significant progress has been made over the past 2 decades regarding understanding of disease pathophysiology, optimal outcome measures, and effective treatment strategies, including the recognition of the importance of diagnosing and treating RA early. Observations Early diagnosis and treatment of RA can avert or substantially slow progression of joint damage in up to 90% of patients, thereby preventing irreversible disability. The development of novel instruments to measure disease activity and identify the presence or absence of remission have facilitated new treatment strategies to arrest RA before joints are damaged irreversibly. Outcomes have been improved by recognizing the benefits of early diagnosis and early therapy with disease-modifying antirheumatic drugs (DMARDs). The treatment target is remission or a state of at least low disease activity, which should be attained within 6 months. Methotrexate is first-line therapy and should be prescribed at an optimal dose of 25 mg weekly and in combination with glucocorticoids; 40% to 50% of patients reach remission or at least low disease activity with this regimen. If this treatment fails, sequential application of targeted therapies, such as biologic agents (eg, tumor necrosis factor [TNF] inhibitors) or Janus kinase inhibitors in combination with methotrexate, have allowed up to 75% of these patients to reach the treatment target over time. New therapies have been developed in response to new pathogenetic findings. The costs of some therapies are considerable, but these costs are decreasing with the advent of biosimilar drugs (drugs essentially identical to the original biologic drugs but usually available at lower cost). Conclusions and relevance Scientific advances have improved therapies that prevent progression of irreversible joint damage in up to 90% of patients with RA. Early treatment with methotrexate plus glucocorticoids and subsequently with other DMARDs, such as inhibitors of TNF, IL-6, or Janus kinases, improves outcomes and prevents RA-related disability. A treat-to-target strategy aimed at reducing disease activity by at least 50% within 3 months and achieving remission or low disease activity within 6 months, with sequential drug treatment if needed, can prevent RA-related disability.
1,042 citations
TL;DR: Current treatment strategies for rheumatoid arthritis are reviewed and how such insights could ultimately lead to the earlier diagnosis of RA - as well as providing new opportunities for drug treatment and prevention through behavioral changes in high-risk individuals.
Abstract: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages: (i) triggering, (ii) maturation, (iii) targeting, and (iv) fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies (including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs) remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA.
867 citations
TL;DR: Recent data that support intriguing models of disease pathogenesis allude to the possibility of restoration of immunologic homeostasis and thus a state of tolerance associated with drug-free remission of RA, and represents a bold vision for the future of RA therapeutics.
685 citations
Cites background from "Peptidylarginine deiminase from Por..."
...gingivalis could potentially citrullinate peptides in the oral mucosa that, in the context of inflammation, could promote ACPA generation (Wegner et al., 2010)....
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...P. gingivalis could potentially citrullinate peptides in the oral mucosa that, in the context of inflammation, could promote ACPA generation (Wegner et al., 2010)....
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References
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TL;DR: A new approach to rapid sequence comparison, basic local alignment search tool (BLAST), directly approximates alignments that optimize a measure of local similarity, the maximal segment pair (MSP) score.
88,255 citations
TL;DR: An etiology involving a specific genotype, an environmental provocation, and the induction of specific autoimmunity are suggested, all restricted to a distinct subset of RA.
Abstract: A new model for an etiology of rheumatoid arthritis : smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination.
1,425 citations
TL;DR: Results show that deiminated forms of fibrin deposited in the rheumatoid synovial membranes are the major target of AFA, and suggest that autoimmunization against deimination fibrIn is a critical step in RA pathogenesis.
Abstract: IgG antifilaggrin autoantibodies (AFA) are the most specific serological markers of rheumatoid arthritis In epithelial tissues, they recognize citrulline-bearing epitopes present on various molecular forms of (pro)filaggrin Histological analysis of rheumatoid synovial membranes with an Ab to citrulline showed labeling of interstitial amorphous deposits and mononuclear cells of various types Immunochemical analysis of exhaustive sequential extracts of the same tissues showed that they contain several deiminated (citrulline containing) proteins Among them, two proteins, p64--78 and p55--61, present in urea-DTT and guanidine extracts, were shown by immunoblotting to be specifically targeted by AFA By amino-terminal sequencing the proteins were identified as deiminated forms of the alpha- and beta-chains of fibrin, respectively Their identity was confirmed using several Abs specific for the A alpha- and/or to the B beta-chain of fibrin(ogen) Moreover, AFA-positive rheumatoid arthritis (RA) sera and purified AFA were highly reactive to the A alpha- and B beta-chains of human fibrinogen only after deimination of the molecules by a peptidylarginine deiminase Autoantibodies affinity purified from a pool of RA sera onto deiminated fibrinogen were reactive toward all of the epithelial and synovial targets of AFA This confirmed that the autoantibodies to the deiminated A alpha-and B beta-chains of fibrinogen, the autoantibodies to the synovial proteins p64--78 and p55--61, and, lastly, AFA, constitute largely overlapping autoantibody populations These results show that deiminated forms of fibrin deposited in the rheumatoid synovial membranes are the major target of AFA They suggest that autoimmunization against deiminated fibrin is a critical step in RA pathogenesis
664 citations
TL;DR: Key findings are summarized that attempt to delineate the mechanisms by which immune factors can lead to the loss of connective tissue attachment and alveolar bone in periodontal disease.
Abstract: Although periodontal diseases are initiated by bacteria that colonize the tooth surface and gingival sulcus, the host response is believed to play an essential role in the breakdown of connective tissue and bone, key features of the disease process. An intermediate mechanism that lies between bacterial stimulation and tissue destruction is the production of cytokines, which stimulates inflammatory events that activate effector mechanisms. These cytokines can be organized as chemokines, innate immune cytokines, and acquired immune cytokines. Although they were historically identified as leukocyte products, many are also produced by a number of cell types, including keratinocytes, resident mesenchymal cells (such as fibroblasts and osteoblasts) or their precursors, dendritic cells, and endothelial cells. Chemokines are chemotactic cytokines that play an important role in leukocyte recruitment and may directly or indirectly modulate osteoclast formation. This article focuses on aspects of osteoimmunology that affect periodontal diseases by examining the role of cytokines, chemokines, and immune cell mediators. It summarizes some of the key findings that attempt to delineate the mechanisms by which immune factors can lead to the loss of connective tissue attachment and alveolar bone. In addition, a discussion is presented on the importance of clarifying the process of uncoupling, a process whereby insufficient bone formation occurs following resorption, which is likely to contribute to net bone loss in periodontal disease.
569 citations
TL;DR: These findings, showing both the protected protease activity of SEN-bound plasmin and SEN-specific immune responses, provide evidence for an important role of SEN in the disease process and post-streptococcal autoimmune diseases.
548 citations