TY - JOUR
T1 - Rejuvenating the immune system in rheumatoid arthritis
AU - Weyand, Cornelia M.
AU - Fujii, Hiroshi
AU - Shao, Lan
AU - Goronzy, Jörg J.
N1 - Funding Information:
The authors wish to thank Linda Arneson and Tamela Yeargin for their editorial support. This work was funded in part by grants from the NIH (AR 42527, AR 41974, AI 44142, AI 57266, AG 15043) and the “Within Our Reach” campaign of the American College of Rheumatology Research and Education Foundation.
PY - 2009
Y1 - 2009
N2 - In rheumatoid arthritis (RA), the aging process of the immune system is accelerated. Formerly, this phenomenon was suspected to be a consequence of chronic inflammatory activity. However, newer data strongly suggest that deficiencies in maintaining telomeres and overall DNA stability cause excessive apoptosis of RA T cells, imposing proliferative pressure and premature aging on the system. Already during the early stages of their life cycle, and long before they participate in the inflammatory process, RA T cells are lost owing to increased apoptotic susceptibility. A search for underlying mechanisms has led to the discovery of defective pathways of repairing broken DNA and elongating and protecting telomeric sequences at the chromosomal ends. Two enzymatic machineries devoted to DNA repair and maintenance have been implicated. RA T cells fail to induce sufficient amounts of the telomeric repair enzyme telomerase, leaving telomeric ends uncapped and thus susceptible to damage. Of equal importance, RA T cells produce low levels of the DNA repair enzyme ataxia telangiectasia mutated and the complex of nucleoproteins that sense and fix DNA double-strand breaks. The inability to repair damaged DNA renders naive T cells vulnerable to apoptosis, exhausts T-cell regeneration and reshapes the T cell repertoire. Therapeutic attempts to reset the immune systems of patients with RA and prevent premature immunosenescence should include restoration of DNA repair capability.
AB - In rheumatoid arthritis (RA), the aging process of the immune system is accelerated. Formerly, this phenomenon was suspected to be a consequence of chronic inflammatory activity. However, newer data strongly suggest that deficiencies in maintaining telomeres and overall DNA stability cause excessive apoptosis of RA T cells, imposing proliferative pressure and premature aging on the system. Already during the early stages of their life cycle, and long before they participate in the inflammatory process, RA T cells are lost owing to increased apoptotic susceptibility. A search for underlying mechanisms has led to the discovery of defective pathways of repairing broken DNA and elongating and protecting telomeric sequences at the chromosomal ends. Two enzymatic machineries devoted to DNA repair and maintenance have been implicated. RA T cells fail to induce sufficient amounts of the telomeric repair enzyme telomerase, leaving telomeric ends uncapped and thus susceptible to damage. Of equal importance, RA T cells produce low levels of the DNA repair enzyme ataxia telangiectasia mutated and the complex of nucleoproteins that sense and fix DNA double-strand breaks. The inability to repair damaged DNA renders naive T cells vulnerable to apoptosis, exhausts T-cell regeneration and reshapes the T cell repertoire. Therapeutic attempts to reset the immune systems of patients with RA and prevent premature immunosenescence should include restoration of DNA repair capability.
UR - http://www.scopus.com/inward/record.url?scp=70349962909&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70349962909&partnerID=8YFLogxK
U2 - 10.1038/nrrheum.2009.180
DO - 10.1038/nrrheum.2009.180
M3 - Review article
C2 - 19798035
AN - SCOPUS:70349962909
SN - 1759-4790
VL - 5
SP - 583
EP - 588
JO - Nature Reviews Rheumatology
JF - Nature Reviews Rheumatology
IS - 10
ER -