J Rheum Dis.  2016 Dec;23(6):340-347. 10.4078/jrd.2016.23.6.340.

Roles of Reactive Oxygen Species in Rheumatoid Arthritis Pathogenesis

• Yoo SJ
• Go E
• Kim YE
• Lee S
• Kwon J

• KMID: 2364687
• DOI: http://doi.org/10.4078/jrd.2016.23.6.340

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease that starts with decreased tolerance to modified self-antigens and eventually leads to synovitis and destruction of bone and cartilage. Age is a risk factor for developing RA. Major changes in the immune system come with age due to chronic oxidative stress on the deoxyribonucleic acid (DNA) damage pathway, somatic mutation, modifications of auto-antigens, T cell tolerance and activation of fibroblast-like synoviocytes (FLS). Reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2) suppress T cell receptor signaling. Sirtuin 1 (SIRT1) is a critical immune suppressor of T cell activation and a key regulator of oxidative stress. When oxidative stress reduces activity of SIRT1, the breakdown of tolerance to modified self-antigens is expected. Generation of ROS can be perpetuated by enhanced DNA damage and dysfunctional mitochondria in a feedback loop during the development of RA. Through major T cell loss and selective proliferation of peripheral T cells, pro-inflammatory T cell pools with abnormal features are established in the T cell compartment. Hypoxic and inflammatory condition in synovium perpetuates ROS generation, which leads to the activation of FLS. In both T cell and synovium compartment, oxidative stress reshapes the immune system into the development of pre-clinical RA.

Keyword

Rheumatoid arthritis; Reactive oxygen species; NADPH oxidase; Sirtuin 1; Oxidative stress

MeSH Terms

Arthritis, Rheumatoid*
Autoantigens
Autoimmune Diseases
Cartilage
DNA
DNA Damage
Immune System
Mitochondria
NADP
NADPH Oxidase
Oxidative Stress
Oxidoreductases
Reactive Oxygen Species*
Receptors, Antigen, T-Cell
Risk Factors
Sirtuin 1
Synovial Membrane
Synovitis
T-Lymphocytes
Autoantigens
DNA
NADP
NADPH Oxidase
Oxidoreductases
Reactive Oxygen Species
Receptors, Antigen, T-Cell
Sirtuin 1

Figure

• 

  Figure 1. Role of oxidative stress in the pathogenesis of rheumatoid arthritis (RA). (A) With advancing age, oxidative stress plays critical roles in the generation of pre-clinical RA in the process of the immune-aging. (B) Important pathways regulated by the oxidative stress in the immune-aging process re-shape the immune systems to lead breakdown of T cell tolerance, activation of fibroblast-like synoviocytes (FLS) and the generation of the inflammatory networks for pathogenesis of RA. Oxidative stress could contribute to development of RA in several ways. Enhanced generation of reactive oxygen species (ROS), oxidative modification of self-antigens, generation of danger-associated molecular patterns (DAMPs), mutagenesis of genomic deoxyribonucleic acid (DNA) and mitochondrial DNA, dysfunctional mitochondria, reduced autophagy, DNA damage, defects in DNA damage pathways, reduced activity of sirtuin 1 (SIRT1), p53, forkhead box O (FoxOs), and antioxidants, enhanced activity of AKT, activation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF) pathway and inhibition of phosphatase and tensin homo-log (PTEN).

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