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Review
. 2015;8(2):131-46.
doi: 10.2174/1874609808666150727110744.

Rheumatoid Arthritis, Immunosenescence and the Hallmarks of Aging

Paulina Chalan, Anke van den Berg, Bart-Jan Kroesen, Liesbeth Brouwer, Annemieke Boots  1
Affiliations
Review

Rheumatoid Arthritis, Immunosenescence and the Hallmarks of Aging

Paulina Chalan et al. Curr Aging Sci. 2015.

Abstract

Age is the most important risk factor for the development of infectious diseases, cancer and chronic inflammatory diseases including rheumatoid arthritis (RA). The very act of living causes damage to cells. A network of molecular, cellular and physiological maintenance and repair systems creates a buffering capacity against these damages. Aging leads to progressive shrinkage of the buffering capacity and increases vulnerability. In order to better understand the complex mammalian aging processes, nine hallmarks of aging and their interrelatedness were recently put forward. RA is a chronic autoimmune disease affecting the joints. Although RA may develop at a young age, the incidence of RA increases with age. It has been suggested that RA may develop as a consequence of premature aging (immunosenescence) of the immune system. Alternatively, premature aging may be the consequence of the inflammatory state in RA. In an effort to answer this chicken and egg conundrum, we here outline and discuss the nine hallmarks of aging, their contribution to the pre-aged phenotype and the effects of treatment on the reversibility of immunosenescence in RA.

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Figures

Fig. (1)
Fig. (1)
Depiction of senescence-associated alterations reported within A) hematopoietic stem cells (HSC) in bone marrow and peripheral blood, B) naive CD4+ T-cells in peripheral blood, C) senescent (CD28-) CD4+ T-cells in peripheral blood and D) senescent (CD28-) CD4+ T-cells in the inflamed joint of RA patients. A) In RA, bone marrow-derived hematopoietic stem cells (defined as CD34+) show impaired proliferative capacity and increased expression of Fas, rendering them apoptosis-sensitive. Consequently, RA patients show reduced HSC numbers at the level of the bone marrow. Peripheral blood-derived CD34+ HSC show similar defects in proliferation and increased susceptibility to apoptosis. Increased apoptosis sensitivity is via impaired ERK pathway signaling and/or age-inappropriate telomere erosion of CD34+ HSC in peripheral blood. B) Reduced thymic output in RA was evidenced by reductions of circulating recent thymic emigrants (defined as CD31+ or T-cell receptor excision circle (TREC)+ T-cells). This is explained by inadequate supply of HSC from the bone marrow and/or age-inappropriate enhanced thymic atrophy. Peripheral blood naive T-cells (defined as CD31+CD28+) are characterized by telomere shortening, increased levels of oxidized lesions and double-strand DNA breaks, decreased telomerase activity, deficiency of proteins involved in the DNA damage response (phosphorylated forms of ATM and downstream p53), overactivation of DNA-PKCs-JNK pathway, overexpression of proapoptotic proteins Bim, Bmf and downregulation of antiapoptotic protein Bcl-2. Defects of naive CD4+ T-cells may facilitate their accelerated differentiation towards the senescent state, when subjected to proliferative stress and enhance apoptosis. C) Compensatory hyperproliferation of the naive CD4+ T-cell pool leads to the expansion of senescent cells (characterized by the loss of CD28, de novo expression of NK receptors [KIR/KAR, CD56, NKG2D], upregulation of CD57, CD70, CX3CR1, expression of IFN-γ, TNF-α and cytotoxic molecules). Senescent CD4+ T-cells show further increase of DNA damage (double-strand breaks, oxidized DNA lesions and diminished levels of ATM and p53 phosphorylation) relative to naive CD4+ T-cells. Diminished activity of JNK and ERK pathways is associated with the increased expression of anti-apoptotic protein Bcl-2 and concomitant resistance to apoptosis of senescent CD4+ T-cells. D) Expression of CX3CR1 facilitates migration of senescent CD4+ T-cells towards soluble Fractalkine (FKN) abundant at the level of synovium. Interaction with FKN expressed on the surface of fibroblast-like synoviocytes (FLS) augments expression of IFN-γ, TNF-α and stimulates release of cytotoxic granules by senescent T-cells and enhances proliferation and FKN expression by FLS. IFN-γ production is also promoted by the interaction of NKG2D with FLS-expressed MIC. IL-12 increased at the level of inflamed joints, may restore CD28 expression by senescent T-cells.
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