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. 2014 Apr;89(4):563-75.
doi: 10.1016/j.mayocp.2014.01.020.

Targets of Immune Regeneration in Rheumatoid Arthritis

Free PMC article

Targets of Immune Regeneration in Rheumatoid Arthritis

Philipp J Hohensinner et al. Mayo Clin Proc. .
Free PMC article


Many of the aging-related morbidities, including cancer, cardiovascular disease, neurodegenerative disease, and infectious susceptibility, are linked to a decline in immune competence with a concomitant rise in proinflammatory immunity, placing the process of immune aging at the center of aging biology. Immune aging affects individuals older than 50 years and is accelerated in patients with the autoimmune disease rheumatoid arthritis. Immune aging results in a marked decline in protective immune responses and a parallel increase in tissue inflammatory responses. By studying immune cells in patients with rheumatoid arthritis, several of the molecular underpinnings of the immune aging process have been delineated, such as the loss of telomeres and inefficiencies in the repair of damaged DNA. Aging T cells display a series of abnormalities, including the unopposed up-regulation of cytoplasmic phosphatases and the loss of glycolytic competence, that alter their response to stimulating signals and undermine their longevity. Understanding the connection between accelerated immune aging and autoimmunity remains an area of active research. With increasing knowledge of the molecular pathways that cause immunosenescence, therapeutic interventions can be designed to slow or halt the seemingly inevitable deterioration of protective immunity with aging.

Conflict of interest statement

Competing Financial Interests

The authors declare no competing financial interests.


Figure 1
Figure 1. Effects of aging on the immune system
Aging reduces immune competence, naïve T cell numbers, CD28 expression and DNA double strand repair, resulting in immune cells with increased DNA damage and a proinflammatory signature. DUSP = Dual Specificity Phosphatase
Figure 2
Figure 2. Senescence-associated cellular phenotype
Senescence in cells is induced by multiple factors, including repeated cell divisions, mitogenic signals and DNA damage. Senescent cells are characterized by an increased cell size, shortened telomeres, activated Chk2, p53 and p16INK4A and expression of proinflammatory proteins including TNF, MCP1, PAI1 and MMPs. ATM = Ataxia telangiectasia mutated; Chk2 = Checkpoint kinase 2; CDKN2A = cyclin dependent kinase inhibitor 2A; MCP1 = Monocyte chemotactic protein 1; MMP = Matrix metallopeptidase; NBS = Nijmegen breakage syndrome; PAI = Plasminogen activator inhibitor type 1; TNF = Tumor necrosis factor
Figure 3
Figure 3. Deficits in DNA damage repair and immune aging
(A) In healthy CD4 T cells, DNA damage rapidly induces the recruitment of the MRN complex, consisting of RAD50, Mre11 and NBS1 to the damage site. Complex formation facilitates the activation of the kinase ATM. The signaling cascade activated by ATM consists of numerous proteins including phosphorylation of H2AX, activation of BRCA1, activation of Chk2 and p53. Overall, ATM signaling leads to triggering of the cell cycle checkpoint with slowing of cell cycle progression and DNA damage repair. In contrast, CD4 T cells from RA patients fail to recruit sufficient MRN complexes, have reduced ATM activation and lack behind in p53 activation, causing cell cycle prolongation and reduced DNA damage repair in affected T cells. (B) Besides activating ATM, the MRN complex is also involved in activating DNA-PKcs. In healthy T cells, binding of Ku70/80 facilitates activation of DNA-PKcs at the double strand break resulting in phosphorylation of H2AX, DNA ligase IV recruitment and p53 activation. In RA T cells, DNA-PKcs is upregulated and the concentrations of phosphorylated DNA-PKcs are increased, while Ku70/80 is reduced. This imbalance triggers the stress kinase JNK and with persisting DNA damage mediates apoptosis via the Bim/Bmf pathway. ATM = Ataxia telangiectasia mutated; DNA-PKc = DNA-activated protein kinase catalytic polypeptide; NBS = Nijmegen breakage syndrome; Mre11 = Meiotic recombination 11
Figure 4
Figure 4. Metabolic abnormalities in T cells in patients with RA
Naïve CD4 T cells in patients with RA are characterized by metabolic reprogramming, including a reduction of glycolysis, diminished ATP production and insufficient autophagy. These defects in energy generation are caused by a failure of inducing the major regulatory enzyme of the glycolytic pathway, PFKFB3. Consequences of this metabolic reprogramming include an increase in NADPH levels, reduced availability of cellular ROS, and increased apoptotic susceptibility.

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