Fas and Fas Ligand in young patients with sickle cell disease

Abstract

SUMMARY S ickle cell disease (SCD) is one of the most common severe monogenic disorders in the world. Increased expression of adhesion molecules on erythrocytes and endothelial cells, interactions with leukocytes, increased levels of circulating inflammatory cytokines, enhanced microvascular thrombosis, and endothelial damage are all thought to contribute to obstruction of the arterioles by sickled erythrocytes. Vascular dysfunction is the end result, due to complex and multifactorial interactions that ultimately manifest as the clinical phenotypes of SCD. The relevance of neutrophil death to the pathogenesis of inflammatory disease is now recognized, since alterations in the apoptotic processes of leukocytes may affect their cellular function and inflammatory processes. Fas and its ligand are typical members of the tumor necrosis factor (TNF) receptor superfamily. Similar to other members of this family, FasL induces apoptosis or programmed cell death when bound to its receptor Fas. However, depending on the conditions, Fas/FasL interactions may be related to augmentation of inflammatory response. In this sense, signals initiated by regulated Fas-associated death domain protein overexpression in the carotid artery induce expression of monocyte-chemoattractant protein-1 and interleukin (IL)-8, and cause massive migration of macrophages in vivo, indicating that Fas and Fas ligand act also as proinflammatory proteins. Therefore, we determined the levels of the levels of sFas, sFasL and sFas/sFasL ratio in young SCD patients and assess their relation to markers of hemolysis, iron overload, sickle vasculopathy including kidney disease. This study included 35 SCD patients (23 males and 12 females) recruited from the regular attendants of the Pediatric Hematology Clinic, Pediatric Hospital, Ain Shams University. Patients were compared with 35 age- and sex-matched healthy subjects (16 males and 19 females) enrolled as controls. The mean age of SCD patients was 8.4 ± 3.69 years (range: 3-15 years) while that of controls was 9.1 ± 3.2 years (range: 4-16 years). All included patients were subjected to detailed medical history and thorough clinical examination with special emphasis on anthropometric measures, disease duration, evidence of renal, hepatic or cardiac disease, history of sickling crisis or splenectomy, transfusion history and chelation/ hydroxyurea therapy. sFas and sFasL levels were measured by enzyme linked immunosorbent assay (ELISA). All patients were in steady state. In the current work, sFas and sFas/sFasL ratio were significantly higher in SCD patients compared with control group while sFasL was significantly lower in patients. Analysis of sFas and sFasL in relation to the clinical characteristics of patients with SCD revealed that patients with pulmonary hypertension or nephropathy had significantly higher levels of sFas and lower levels of sFasL than those without (p<0.05).