Biologically active CD40 ligand is elevated in sickle cell anemia: potential role for platelet-mediated inflammation.
OBJECTIVE
After activation, platelets expose CD40 ligand (CD40L) on their surface, then subsequently release the inflammatory mediator as a soluble fragment (sCD40L). Because sickle cell anemia (SCA) is noted for both platelet activation and chronic inflammation, we asked whether platelet-released CD40L potentially plays a role in SCA.


RESULTS
ELISAs demonstrate that SCA patient plasma contains 30-fold more sCD40L than control plasma. Correspondingly, platelets from these patients contain less than half the CD40L found in control platelets. Platelets from patients in painful crises are further depleted of CD40L, with even higher plasma levels, suggesting a correlation to the patient's clinical state. In addition, elevated sCD40L correlates with increased tissue factor in SCA plasma. Blockage of the CD40L receptor CD40 reduces SCA plasma-induced production of tissue factor and endothelial intercellular adhesion molecule-1 (ICAM-1). Finally, sCD40L activity in SCA plasma is confirmed by its induction of B-cell proliferation.


CONCLUSIONS
Platelet-derived sCD40L is elevated in SCA, further elevated in crises, and biologically active. The participation of sCD40L in SCA plasma-induced production of B cells, tissue factor, and ICAM-1 suggests that CD40L may contribute to the chronic inflammation and increased thrombotic activity known to occur in SCA.
Lee
Sheritha P
SP
Department of Pharmacology, University of North Carolina, CB#7365, Chapel Hill, NC 27599-7365, USA.
Ataga
Kenneth I
KI
Orringer
Eugene P
EP
Phillips
David R
DR
Parise
Leslie V
LV
D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000150:complications*; D001402:B-Lymphocytes / Q000473:pathology; D001792:Blood Platelets / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000097:blood* / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D006451:Hemoglobin, Sickle / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000209:etiology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D013925:Thromboplastin / Q000096:biosynthesis / Q000378:metabolism
D019013:CD40 Antigens; D006451:Hemoglobin, Sickle; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand; D013925:Thromboplastin