Increased expression of CD40 on bone marrow CD34+ hematopoietic progenitor cells in patients with systemic lupus erythematosus: contribution to Fas-mediated apoptosis.
OBJECTIVE
Patients with systemic lupus erythematosus (SLE) display increased apoptosis of bone marrow (BM) CD34+ hematopoietic progenitor cells. This study was undertaken to evaluate the expression of CD40 and CD40L in the BM of SLE patients, and to explore the possible involvement of these molecules in apoptosis of CD34+ cells.


METHODS
The proportion and survival characteristics of CD40+ cells within the BM CD34+ fraction from SLE patients and healthy controls were evaluated by flow cytometry. The production of CD40L by BM stromal cells was assessed using long-term BM cultures, and the effect of CD40L on the survival characteristics and clonogenic potential of CD34+ cells was evaluated ex vivo by flow cytometry and clonogenic assays.


RESULTS
SLE patients displayed an increased proportion of CD40+ cells within the CD34+ fraction as compared with controls. The CD34+CD40+ subpopulation contained an increased proportion of apoptotic cells compared with the CD34+CD40- fraction in patients and controls, suggesting that CD40 is involved in the apoptosis of CD34+ cells. Stimulation of patients' CD34+ cells with CD40L increased the proportion of apoptotic cells and decreased the proportion of colony-forming cells as compared with untreated cultures. The CD40L-mediated effects were amplified following treatment with recombinant Fas ligand, suggesting that the effects of these ligands are synergistic. CD40L levels were significantly increased in long-term BM culture supernatants and adherent layers of BM cells from SLE patients as compared with controls.


CONCLUSIONS
These data reveal a novel role for the CD40/CD40L dyad in SLE by demonstrating that up-regulation and induction of CD40 on BM CD34+ cells from patients with SLE contribute to the amplification of Fas-mediated apoptosis of progenitor cells.
Pyrovolaki
Katerina
K
University of Crete School of Medicine, Heraklion, Crete, Greece.
Mavroudi
Irene
I
Sidiropoulos
Prodromos
P
Eliopoulos
Aristides G
AG
Boumpas
Dimitrios T
DT
Papadaki
Helen A
HA
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000276:immunology / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D002999:Clone Cells; D053222:Fas Ligand Protein / Q000494:pharmacology; D005260:Female; D006304:Health Status; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D055815:Young Adult; D019014:fas Receptor / Q000378:metabolism
D018952:Antigens, CD34; D015415:Biomarkers; D019013:CD40 Antigens; D053222:Fas Ligand Protein; D019014:fas Receptor