Reduced p53 in peripheral blood mononuclear cells from patients with rheumatoid arthritis is associated with loss of radiation-induced apoptosis.
OBJECTIVE
Patients with autoimmune disorders exhibit highly reproducible gene expression profiles in their peripheral blood mononuclear cells. This profile includes, at least in part, a collection of underexpressed genes that encode proteins that inhibit cell cycle progression and stimulate apoptosis. We aimed to determine whether this gene expression profile confers functional liability on lymphocytes from patients with rheumatoid arthritis (RA).


METHODS
Viability studies in response to a panel of proapoptotic stimuli revealed that T lymphocytes from patients with RA were resistant to gamma radiation-induced apoptosis, a process known to be dependent on p53. To assess p53 function in RA peripheral blood mononuclear cells, baseline levels of p53 protein and TP53 transcript were measured in patients with RA and controls. The cellular p53 response to gamma radiation was also assessed by immunoblotting.


RESULTS
Lymphocytes from patients with RA had lower baseline levels of TP53 messenger RNA (mRNA) and p53 protein than did those from control subjects and were deficient in their ability to increase p53 after exposure to gamma radiation. A subgroup of patients with RA had a second biochemical defect characterized by expression of very low baseline levels of checkpoint kinase 2 mRNA and protein.


CONCLUSIONS
We conclude that defects in the expression of TP53 mRNA and, in a subgroup, defects in expression of CHK2 mRNA, lead to severe defects in apoptosis in patients with RA. We hypothesize that this liability may contribute to autoimmunity.
Maas
Kevin
K
Vanderbilt University, Nashville, Tennessee, USA.
Westfall
Matthew
M
Pietenpol
Jennifer
J
Olsen
Nancy J
NJ
Aune
Thomas
T
D000328:Adult; D017209:Apoptosis / Q000528:radiation effects*; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000473:pathology; D002470:Cell Survival / Q000528:radiation effects; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D005260:Female; D005720:Gamma Rays; D016158:Genes, p53 / Q000528:radiation effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D012333:RNA, Messenger / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects*
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases