Rheumatoid Arthritis Prevention & Recovery
Research & Studies

Hydroxyl radical modification of collagen type II increases its arthritogenicity and immunogenicity

 

“Convincing evidence has been presented on the role of oxygen free radicals in the pathogenesis of rheumatoid arthritis. Superoxide produced in synovial fluid could generate •OH radical via Fenton reaction at the inflammation site. This •OH can damage cellular elements in the cartilage and extra cellular matrix components, including proteoglycan and collagen type II. Since the rat CIA model shares many features with human RA, our results may help in explaining certain aspects of the human RA, especially the role of free radicals.”

 

Shahab, U., Ahmad, S., M., Dixit, K., Habib, S., Alam, K., & Ali, A. (2012). Hydroxyl radical modification of collagen type II increases its arthritogenicity and immunogenicity. PLOS ONE, 7(2), 1-7. doi: 10.1371/journal.pone.0031199

 

Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: An open-label pilot study

 

“Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of bone and cartilage. Although its etiology is unknown, the hydroxyl radical has been suggested to be involved in the pathogenesis of RA. The results suggest that the hydroxyl radical scavenger H2 effectively reduces oxidative stress in patients with this condition. The symptoms of RA were significantly improved with high H2 water.”

 

Ishibashi, T., Sato, B., Rikitake, M., Seo, T., Kurokawa, R., Hara, Y., . . . Nagao, T. (2012). Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: An open-label pilot study. Medical Gas Research, 2(27), 1-8. doi: 10.1186/2045-9912-2-27

 

Hydroxyl radical damaged immunoglobulin G in patients with rheumatoid arthritis: Biochemical and immunological studies

 

“The OH modification of IgG causes perturbations, resulting in the generation of neo-epitopes, and making it a potential immunogen. The IgG modified with the .OH may be one of the factors for the induction of circulating RA autoantibodies.”

 

Rasheed, Z. (2008). Hydroxyl radical damaged Immunoglobulin G in patients with rheumatoid arthritis: Biochemical and immunological studies. Clinical Biochemistry, 41(9), 663-669. doi: 10.1016/j.clinbiochem.2008.02.013

 

Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals

“Hydrogen selectively reduces the hydroxyl radical, the most toxic free radical, and effectively protects cells. It does not react with free radicals that have physiological benefits, making it an incredibly effective therapy to neutralize acute oxidative stress.”

 

Ohsawa, I., Ishikawa, M., Takahashi, K., Watanabe, M., Nishimaki, K., Yamagata, K., . . . Ohta, S. (2007). Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nature Medicine, 13(6), 688-694. doi: 10.1038/nm1577

 

Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: A randomized, double-blind, placebo-controlled pilot study

 

“The aim of this study was to demonstrate the safety and efficacy of H2-saline infusion for treatment of rheumatoid arthritis (RA). We conducted a randomized, double-blind, placebo-controlled investigation of the infusion of 1 ppm H2-dissolved saline (H2-saline) in 24 RA patients. Drop infusion of H2 safely and effectively reduced RA disease activity.”

 

Ishibashi, T., Sato, B., Shibata, S., Sakai, T., Hara, Y., Naritomi, Y., . . . Nagao, T. (2014). Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: A randomized, double-blind, placebo-controlled pilot study. International Immunopharmacology, 21(2), 468-473. doi: 10.1016/j.intimp.2014.06.001

 

Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases

 

“Psoriasis, a chronic inflammatory skin disease, is caused by infiltrating lymphocytes and associated cytokines, including tumor necrosis factor (TNF) α, interleukin (IL)-6, and IL-17. IL-6 levels decreased during H2 treatment in Case 1 and 2. IL-17, whose concentration was high in Case 1, was reduced following H2 treatment, and TNFα also decreased in Case 1. The psoriatic skin lesions almost disappeared at the end of the treatment. H2 administration reduced inflammation associated with psoriasis in the three cases examined and it may therefore be considered as a treatment strategy for psoriasis-associated skin lesions and arthritis.”

 

Ishibashi, T., Ichikawa, M., Sato, B., Shibata, S., Hara, Y., Naritomi, Y., . . . Nagao, T. (2015). Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases. Molecular Medicine Reports, 12, 2757-2764. doi: 10.3892/mmr.2015.3707

 

Impact of inflammation on the osteoblast in rheumatic diseases

 

“Normal bone remodeling depends upon a balance between the action of bone-resorbing cells, osteoclasts, and bone-forming cells, osteoblasts. When this balance is disrupted, as is seen in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS), abnormal bone loss or bone formation occurs. In RA, proinflammatory cytokines induce osteoclast differentiation and inhibit osteoblast maturation, leading to articular bone erosions.”

 

Baum, R., & Gravallese, E. M. (2013). Impact of inflammation on the osteoblast in rheumatic diseases. Current Osteoporosis Reports, 12(1), 9-16. doi: 10.1007/s11914-013-0183-y

 

Treatment with hydrogen molecule alleviates TNFα-induced cell injury in osteoblast

 

“Tumor necrosis factor-alpha (TNFα) plays a crucial role in inflammatory diseases such as rheumatoid arthritis and postmenopausal osteoporosis. Recently, it has been demonstrated that hydrogen gas, known as a novel antioxidant, can exert therapeutic anti-inflammatory effect in many diseases. Treatment with H(2) alleviates TNFα-induced cell injury in osteoblast through abating oxidative stress, preserving mitochondrial function, suppressing inflammation, and enhancing NO bioavailability.”

 

Cai, W.,-W., Zhang, M., -H., Yu, Y., -S., & Cai, J., -H. (20132). Treatment with hydrogen molecule alleviates TNFα-induced cell injury in osteoblast. Molecular and Cellular Biochemistry, 373(1-2), 1-9. doi: 10.1007/s11010-012-1450-4

 

RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis

 

“The pattern of RANKL and OPG expression and the presence of RANK-expressing osteoclast precursor cells at sites of bone erosion in RA contributes to the generation of a local microenvironment that favours osteoclast differentiation and activity. These data provide further evidence implicating RANKL in the pathogenesis of arthritis-induced joint destruction.”

 

Pettit, A. R. (2006). RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis. Rheumatology, 45(9), 1068-1076. doi: 10.1093/rheumatology/kel045

 

Treatment with hydrogen molecules prevents RANKL-induced osteoclast differentiation associated with inhibition of ROS formation and inactivation of MAPK, AKT and NF-kappa B pathways in murine RAW264.7 cells

 

“The bone protective effects of the hydrogen molecule (H2) have been demonstrated in several osteoporosis models. Hydrogen molecules prevented RANKL-induced osteoclast differentiation associated with inhibition of reactive oxygen species formation and inactivation of NF-κB, mitogen-activated protein kinase and AKT pathways.”

 

Li, D., Zhang, Q., Dong, X., Li, H., & Ma, X. (2013). Treatment with hydrogen molecules prevents RANKL-induced osteoclast differentiation associated with inhibition of ROS formation and inactivation of MAPK, AKT and NF-kappa B pathways in murine RAW264.7 cells. Journal of Bone and Mineral Metabolism, 32(5), 494-504. doi: 10.1007/s00774-013-0530-1

 

Reactive oxygen and nitrogen species in patients with rheumatoid arthritis as potential biomarkers for disease activity and the role of antioxidants

 

“The results have shown significant higher serum levels of individual ROS and RNS in RA patients compared with healthy subjects. Moreover, this study might be the first to report strong positive correlations between most of the reactive species and the clinical and biochemical markers of RA. Interestingly, the addition of ascorbic acid had significantly reduced the levels of all ROS and RNS in RA patients. In conclusion, the role of oxidative and nitrative stress in the pathogenesis of RA has been confirmed by this study.”

 

Khojah, H., M., Ahmed, S., Abdel-Rahman, M., S., & Hamza, A. (2016). Reactive oxygen and nitrogen species in patients with rheumatoid arthritis as potential biomarkers for disease activity and the role of antioxidants. Free Radical Biology and Medicine, 97, 285-291. doi: 10.1016/j.freeradbiomed.2016.06.020

 

Molecular hydrogen decelerates rheumatoid arthritis progression through inhibition of oxidative stress

 

“Rheumatoid arthritis (RA) is a chronic inflammatory disease which results in progressive destruction of the joint. Our data suggested that H2 can directly neutralize OH and ONOO- to reduce oxidative stress. Moreover, MAPK and NF-κB pathway also play roles in oxidative damage caused by H2O2in RA-FLSs. H2 can provide protection to cells against inflammation, which may be related to inhibition of the activation of MAPK and NF-κB.”

 

Meng, J., Yu, P., Jiang, H., Yuan, T., Liu, N., Tong, J., . . . Zhao, J. (2016). Molecular hydrogen decelerates rheumatoid arthritis progression through inhibition of oxidative stress. American Journal of Translational Research, 8(10), 4472-4477. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095341/

 

Oxidative stress in rheumatoid arthritis patients: Relationship to diseases activity

 

“Patients had significantly higher levels of pro-oxidants (O₂(-), H₂O₂, and TBARS) compared to controls, despite significantly higher levels of SOD. Significant differences were also observed in serum levels of NO in patients with high-diseases activity. Our findings support an association between oxidative/nitrosative stress and RA. Stronger response in samples with higher diseases activity suggests that oxidative/nitrosative stress markers may be useful in evaluating the progression of RA as well as in elucidating the mechanisms of disease pathogenesis.”

 

Veselinovic, M., Barudzic, N., Vuletic, M., Zivkovic, V., Tomic-Lucic, A., Djuric, D., & Jakovljevic, V. (2014). Oxidative stress in rheumatoid arthritis patients: Relationship to diseases activity. Molecular and Cellular Biochemistry, 391(1-2), 225-232. doi: 10.1007/s11010-014-2006-6

 

Molecular hydrogen: New antioxidant and anti-inflammatory therapy for rheumatoid arthritis and related diseases

 

“H2 showed significant therapeutic potential, which also seemed to assist diagnosis and treatment decisions of RA. The possible expectations regarding the potential benefits of H2 by reducing the oxidative stress, resulting from inflammatory factors, are raised and discussed here. They include prevention of RA and related atherosclerosis, as well as therapeutic validity for RA.”

 

Ishibashi, T. (2013). Molecular hydrogen: New antioxidant and anti-inflammatory therapy for rheumatoid arthritis and related diseases. Current Pharmaceutical Design, 19(35), 6375-6381. doi: 10.2174/13816128113199990507

 

Increased reactive oxygen species formation and oxidative stress in rheumatoid arthritis

 

“RA patients showed a marked increase in ROS formation, lipid peroxidation, protein oxidation, DNA damage and decrease in the activity of antioxidant defence system leading to oxidative stress which may contribute to tissue damage and hence to the chronicity of the disease.”

 

Mateen, S., Moin, S., Khan, A. Q., Zafar, A., & Fatima, N. (2016). Increased reactive oxygen species formation and oxidative stress in rheumatoid arthritis. PLOS One, 11(4), 1-15. doi: 10.1371/journal.pone.0152925

 

Hydrogen as a selective antioxidant: A review of clinical and experimental studies

“H2 is emerging as a novel and safe therapeutic antioxidant. It has selective antioxidant properties, giving it anti-inflammatory properties.”

 

Hong, Y., Chen, S., & Zhang, J. (2010). Hydrogen as a selective antioxidant: A review of clinical and experimental studies. Journal of International Medical Research, 38(6), 1893-1903. doi: 10.1177/147323001003800602

 

Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis

 

“Abnormal cellular metabolism and mitochondrial dysfunction thus ensue and, in turn, through the increased production of reactive oxygen species, actively induce inflammation. The reprogramming of hypoxia-mediated pathways in synovial cells, such as fibroblasts, dendritic cells, macrophages and T cells, is implicated in the pathogenesis of rheumatoid arthritis and other inflammatory conditions, and might therefore provide an opportunity for therapeutic intervention.”

 

“Fearon, U., Canavan, M., Biniecka, M., & Veale, D. J. (2016). Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. Nature Reviews Rheumatology, 12(7), 385-397. doi: 10.1038/nrrheum.2016.69

 

Recent progress toward hydrogen medicine: Potential of molecular hydrogen for preventative and therapeutic applications

“H2 shows not only effects against oxidative stress, but also various anti-inflammatory and anti-allergic effects. H2 prevented the decline of the mitochondrial membrane potential. This suggested that H2 protected mitochondria from OH. Along with this protective effect, H2 also prevented a decrease in the cellular level of ATP synthesized in mitochondria. The fact that H2 protected mitochondria and nuclear DNA provided evidence that H2 penetrated most membranes and diffused into organelles.”

 

Ohta, S. (2011). Recent progress toward hydrogen medicine: Potential of molecular hydrogen for preventative and therapeutic applications. Current Pharmaceutical Design, 17(22), 2241-2252. doi: 10.2174/138161211797052664

 

Mitochondrial dysfunction promotes and aggravates the inflammatory response in normal human synoviocytes

 

“In RA, synoviocytes cause increased oxidative stress, leading to mitochondrial alterations that may participate in the pathogenesis of RA. These data suggest that mitochondrial dysfunction could induce an inflammatory response in normal human synoviocytes and sensitize these cells, causing a significant amplification of the inflammatory response induced by IL-1β.”

 

Valcarcel-Ares, M., N., Riveiro-Naveira, R., R., Vaamonde-Garcia, C., Loureiro, J., Hermida-Carballo, L., Blanco, F., J., & Lopez-Armada, M., J. (2014). Mitochondrial dysfunction promotes and aggravates the inflammatory response in normal human synoviocytes. Rheumatology, 53(7), 1332-1343. doi: 10.1093/rheumatology/keu016

 

Molecular hydrogen is a novel antioxidant to efficiently reduce oxidative stress with potential for the improvement of mitochondrial diseases

 

“Hydrogen has many advantages for therapeutic and preventive applications, and shows not only anti-oxidative stress effects, but also has various anti-inflammatory and anti-allergic effects. Preliminary clinical trials show that drinking hydrogen-dissolved water seems to improve the pathology of mitochondrial disorders.”

 

Ohta, S. (2012). Molecular hydrogen is a novel antioxidant to efficiently reduce oxidative stress with potential for the improvement of mitochondrial diseases. Biochimica et Biophysica Acta, 1820(5), 586-594. doi: 10.1016/j.bbagen.2011.05.006

 

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

 

“These findings demonstrate that hypoxia-induced mitochondrial dysfunction drives mitochondrial genome mutagenesis, and antioxidants significantly rescue these events.”

 

Biniecka, M., Fox, E., Gao, W., Ng, C., T., Veale, D., J., Fearon, U., & O'Ssullivan, J. (2011). Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis. Arthritis & Rheumatism, 63(8), 2172-2182. doi: 10.1002/art.30395

 

Molecular hydrogen and its potential application in therapy of brain disorders

 

“A possible cause for the neuroprotective effect of hydrogen may be related to its high diffusibility. Hydrogen molecules can readily cross the blood-brain barrier and penetrate biomembranes smoothly to diffuse into the cytosol, nucleus and mitochondria. This is particularly important, as mitochondria is the major source of ROS and notoriously difficult to target. The protective effect of molecular hydrogen on the mitochondria have also been found in our study.”

 

Ma, F. X. (2015). Molecular hydrogen and its potential application in therapy of brain disorders. Brain Disorders & Therapy, 4(1), 1-2. doi: 10.4172/2168-975x.1000154

 

Risk of rheumatoid arthritis in patients with type 2 diabetes: A nationwide population-based case-control studyThis large nationwide, population-based, case-control study showed an elevated risk of RA in female Taiwanese patients with type 2 diabetes. Our findings were consistent with the hypothesis that chronic low-grade inflammation in type 2 diabetes may elicit the development of RA in genetically susceptible individuals.

 

“This large nationwide, population-based, case-control study showed an elevated risk of RA in female Taiwanese patients with type 2 diabetes. Our findings were consistent with the hypothesis that chronic low-grade inflammation in type 2 diabetes may elicit the development of RA in genetically susceptible individuals.”

 

Lu, M., Yan, S., Yin, W., Koo, M., & Lai, N. (2014). Risk of rheumatoid arthritis in patients with type 2 diabetes: A nationwide population-based case-control study. PLOS ONE, 9(7), 1-6. doi: 10.1371/journal.pone.0101528

 

Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance

 

“In 4 of 6 patients with impaired glucose tolerance, intake of hydrogen-rich water normalized the oral glucose tolerance test. In conclusion, these results suggest that supplementation with hydrogen-rich water may have a beneficial role in prevention of T2DM and insulin resistance.”

 

Kajiyama, S., Hasegawa, G., Asano, M., Hosoda, H., Fukui, M., Nakamura, N., . . . Yoshikawa, T. (2008). Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutrition Research, 28(3), 137-143. doi: 10.1016/j.nutres.2008.01.008 

 

Role of oxidative stress in rheumatoid arthritis: Insights from the Nrf2-knockout mice

 

“Increasing evidence suggests that oxidative stress may play a key role in joint destruction due to rheumatoid arthritis (RA). These results provide strong evidence that oxidative stress is significantly involved in cartilage degradation in experimental arthritis, and indicate that the presence of a functional Nrf2 gene is a major requirement for limiting cartilage destruction.”

 

Wruck, C. J., Fragoulis, A., Gurzynski, A., Brandenburg, L., Kan, Y. W., Chan, K., . . . Pufe, T. (2010). Role of oxidative stress in rheumatoid arthritis: Insights from the Nrf2-knockout mice. Annals of the Rheumatic Diseases, 70(5), 844-850. doi: 10.1136/ard.2010.132720

 

Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles

 

“The anti-oxidative stress effect of hydrogen was first reported to be conferred by direct elimination of hydroxyl radical and peroxynitrite. Subsequent studies indicate that hydrogen activates the Nrf2-Keap1 system. Hydrogen activates Nrf2 and its downstream heme oxygenase-1 (HO-1).”

 

Ichihara, M., Sobue, S., Ito, M., Ito, M., Hirayama, M., & Ohno, K. (2015). Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles -. Medical Gas Research, 5(12), 1-21. doi: 10.1186/s13618-015-0035-1

 

Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease

 

“In this study, we analyzed the relevance of the transcription factor Nrf2, master regulator of redox homeostasis, in the effector phase of an animal model of rheumatoid arthritis, using the transfer of serum from K/BxN transgenic mice to Nrf2(-/-) mice. Our results support a protective role of Nrf2 against joint inflammation and degeneration in arthritis.”

 

Maicas, N., Ferrándiz, M., L., Brines, R., Ibáñez, L., Cuadrado, A., Koenders, M. I., . . . Alcaraz, M., J. (2011). Deficiency of Nrf2 aAccelerates the eEffector pPhase of aArthritis and aAggravates jJoint dDisease. Antioxidants & Redox Signaling, 15(4), 889-901. doi: 10.1089/ars.2010.3835

 

Molecular hydrogen protects mice against polymicrobial sepsis by ameliorating endothelial dysfunction via an Nrf2/HO-1 signaling pathway

 

“H2 regulated endothelial injury and the inflammatory response via Nrf2-mediated HO-1 levels. These results suggest that H2 could suppress excessive inflammatory responses and endothelial injury via an Nrf2/HO-1 pathway.”

 

Chen, H., Xie, K., Han, H., Li, Y., Liu, L., Yang, T., & Yu, Y. (2015). Molecular hydrogen protects mice against polymicrobial sepsis by ameliorating endothelial dysfunction via an Nrf2/HO-1 signaling pathway. International Immunopharmacology, 28(1), 643-654. doi: 10.1016/j.intimp.2015.07.034

 

A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders

 

“Recent studies have demonstrated that Nrf2-ARE signaling is also involved in attenuating inflammation-associated pathogenesis, such as autoimmune diseases, rheumatoid arthritis, asthma, emphysema, gastritis, colitis and atherosclerosis. Thus, disruption or loss of Nrf2 signaling causes enhanced susceptibility not only to oxidative and electrophilic stresses but also to inflammatory tissue injuries.”

 

Kim, J., Cha, Y. N., & Surh, Y. J. (2009). A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutation Research, 690(1-2), 12-23. doi: 10.1016/j.mrfmmm.2009.09.007

 

Hydrogen-rich water intake accelerates oral palatal wound healing via activation of the Nrf2/antioxidant defense pathways in a rat model


“Hydrogen-rich water intake exhibited multiple beneficial effects through activation of the Nrf2/antioxidant defense pathway. The results of this study support the hypothesis that oral administration of hydrogen-rich water benefits the wound healing process by decreasing oxidative stress and inflammatory responses.”

 

Tamaki, N., Orihuela-Campos, R. C., Fukui, M., & Ito, H. (2016). Hydrogen-rich water intake accelerates oral palatal wound healing via activation of the Nrf2/antioxidant defense pathways in a rat model. Oxidative Medicine and Cellular Longevity, 2016(5679040), 1-13. doi: 10.1155/2016/5679040

 

Oxidative stress relevance in the pathogenesis of the rheumatoid arthritis: A systematic review

 

“Gathering our results, we conclude that oxidative stress is a dynamic and complex phenomenon occurring in RA and that is involved in the disease pathogenesis in a complex fashion…The results of the present study suggest the plausibility of several oxidative stress related compounds as potential biomarkers to assess the disease activity and probably prognosis.”

 

Quinonez-Flores, C., M., Gonzalez-Chavez, S., A., Del Rio Najera, D., & Pacheco-Tena, C. (2016). Oxidative stress relevance in the pathogenesis of the rheumatoid arthritis: A systematic review. BioMed Research International, 2016(6097417), 1-14. doi: 10.1155/2016/6097417

 

NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis

 

“Neutrophils isolated from patients with various autoimmune diseases display enhanced neutrophil extracellular trap (NET) formation, a phenomenon that exposes autoantigens in the context of immunostimulatory molecules…Enhanced NETosis was observed in circulating and RA synovial fluid neutrophils compared to neutrophils from healthy controls and from patients with osteoarthritis (OA)…NETs significantly augmented inflammatory responses in RA and OA synovial fibroblasts, including induction of IL-6, IL-8, chemokines, and adhesion molecules. These observations implicate accelerated NETosis in RA pathogenesis.”

 

Khandpur, R., Carmona-Rivera, C., Vivekanandan-Giri, A., Gizinski, A., Yalavarthi, S., Knight, J., S., . . . Kaplan, M., J. (2013). NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Science Translational Medicine, 5(178), 1-10. doi: 10.1126/scitranslmed.3005580

 

 

Autoimmune priming, tissue attack, and chronic inflammation – The three stages of rheumatoid arthritis

 

“First, yet unknown environmental challenges seem to activate innate immunity thereby providing an adjuvant signal for the induction of adaptive immune responses that lead to the production of autoantibodies and determine the subsequent disease development. Second, a joint-specific inflammatory reaction occurs. This inflammatory reaction may be clinically diagnosed as the earliest signs of the disease. Third, inflammation is converted to a chronic process leading to tissue destruction and remodeling.”

 

Holmdahl, R., Malmstrom, V., & Burkhardt, H. (2014). Autoimmune priming, tissue attack, and chronic inflammation – The three stages of rheumatoid arthritis. European Journal of Immunology, 44, 1593-1599. doi: 10.1002/eji.201444486

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