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Review
. 2018 Dec 20:9:3055.
doi: 10.3389/fimmu.2018.03055. eCollection 2018.

DNA Damage Response Signals Transduce Stress From Rheumatoid Arthritis Risk Factors Into T Cell Dysfunction

Lan Shao  1
Affiliations
Review

DNA Damage Response Signals Transduce Stress From Rheumatoid Arthritis Risk Factors Into T Cell Dysfunction

Lan Shao. Front Immunol. .

Abstract

Rheumatoid arthritis (RA) is an autoimmune-mediated disease that is associated with significant cartilage damage and immunosenescence. Despite decades of research, the major signal pathways that initiate RA are still unclear. The DNA damage response (DDR) is a specific and hierarchical network that includes cell cycle checkpoints, DNA repair, and DNA-damage tolerance pathways. Recent studies suggest that this condition is associated with deficits in telomere maintenance and overall genomic instability in the T cells of RA patients. Analysis of the underlying mechanisms has revealed defects in DDR pathways. Particularly, the DNA repair enzyme, ataxia telangiectasia mutated (ATM), is downregulated, which leaves the damaged DNA breaks in RA-associated T cells unrepaired and pushes them to apoptosis, exhausts the T cell pool, and promotes the arthritogenesis effector function of T cells. This review discusses recent advancements and illustrates that risk factors for RA, such as viral infections, environmental events, and genetic risk loci are combat with DDR signals, and the impaired DDR response of RA-associated T cells, in turn, triggers disease-related phenotypes. Therefore, DDR is the dominant signal that converts genetic and environmental stress to RA-related immune dysfunction. Understanding the orchestration of RA pathogenesis by DDR signals would further our current knowledge of RA and provide novel avenues in RA therapy.

Keywords: DNA damage response; T cell dysfunction; ataxia telangiectasia mutated; high-risk factors; rheumatoid arthritis.

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Figures

Figure 1
Figure 1
Abnormalities in the DNA damage repair pathway in T cells of rheumatoid arthritis patients. DNA stability is critical for the function of T cells. Naïve T cells from RA patients have ATM deficiency, which impairs the cells' ability to detect and repair DNA lesions. T cells alternatively upregulate DNA-PKcs. The activated DNA-PKcs-JNK-Bim axis eventually forces naïve T cells into apoptosis. Moreover, there is insufficient activation of the ATM kinase, hTERT, and MRE11A in RA-associated T cells after T cell receptor stimulation, which accelerates the G2/M checkpoint bypass and hyperproliferation. Unrepaired DNA breaks and telomere erosion finally induce T cell death and senescence. To compensate for the T cell pool, naive cells are forced into homeostatic clonal expansion, which facilitates the section of autoreactive T cell.
Figure 2
Figure 2
A model depicting the DNA damage response pathway inducing disease-related phenotypes in T cells in rheumatoid arthritis. RA risk factors, including viral infection, environmental events, and genetic factors lead to defective DDR signals in T cells, and the inadequate DDR responsiveness subsequently alters T cell functionality in multiple aspects. First, deficiency in DNA repair influences T cell survival resulting in a lower apoptotic threshold. Second, DDR is implicated in the metabolic regulation of RA-associated T cells. Moreover, an impaired DDR response biases T cell differentiation to inflammatory effector T cells. Therefore, DDR deficiency in RA-associated T cells represents a key mechanism for the pathogenesis of RA with transitional genetic and environmental factors to RA pathogenesis-related T cell dysfunction.
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