Defining the cooperation between molecular pathways within h
Defining the cooperation between molecular pathways within highly complex biological systems, such as those between immune cell networks and target tissues is certainly a hard task. Recently, there are many investigations in the pathogenesis of renal graft rejection, one of the most evident investigation is the protein molecules that participate in various stages of apoptosis. Fas/Fas Ligand (FasL) interaction seems to play a key role in AR and chronic allograft nephropathy (CAN) . Apo-1/Fas, (CD95 and TNFRSF6), is a trans-membrane protein and its major function might be the induction of apoptosis in Azaperone expressing it after ligation by its legend. Its natural ligand, FasL (TNFSF6, CD95L) is a type II membrane protein belonging to the TNF family , . Fas is mainly expressed on tubular cells and may be up-regulated in AR or with injury such as cold ischemia , , while FasL is expressed by graft infiltrating T cells and it has been reported to be a specific graft rejection marker .
Tubulitis and death of graft tubular epithelial cells are major components of acute rejection and both Fas and FasL polymorphisms are seemed to play an evident role in tubulitis . However, few previous studies have evaluated the role of the polymorphisms in both of these genes together. Therefore, our study tries to evaluate the role of the polymorphisms of Fas and FasL together in AR in children with renal transplantation.
The determination of polymorphisms on the 5′ flanking region on the human Fas gene has introduced useful markers for investigation of graft rejection and survival . The polymorphism may have a potential role in gene regulation as is located on a consensus sequence of the gamma-activated sequence (GAS) .
Fas gene had been evaluated by Huang et al. . One of these, a G to A nucleotide substitution at position −671 [Fas −670A/G]), is presented in a putative nuclear transcription element GAS binding site and could affect the expression of the FasL (T or C at position −843 [FasL −843C/T]) gene .
The purpose of the current retrospective (Case-control) study was to investigate distribution of Fas gene −670A/G and FasL gene −843C/T polymorphisms in pediatric renal transplant patients and to investigate the role of these polymorphisms on allograft nephropathy.
Discussion Cytokines and the molecules associated with cytolytic effector functions of T lymphocytes have long been studied as surrogates of AR and as possible candidates to the development of a non-invasive diagnostic tool , , , , , . Although with some good initial results, none of the proposed markers studied, until now, are being used routinely in the clinical practice or gained full acceptance. Most of the data reported a low degree of specificity, complicating its wide use in clinical practice. Few studies have revealed the role of immunomodulatory molecules in the pathogenesis of AR in humans, in contra balance of cytotoxic and pro-inflammatory ones. It is possible to think that both actors share in the immune response, and the end balance between them will be critical for graft outcome. Here, we investigated the role of Fas/FasL polymorphisms in children who had undergone renal transplantation and compare these polymorphisms in children with and without AR as well as healthy controls. In this study, frequency of C allele of FasL gene polymorphism in pediatric renal transplant recipients was significantly higher than that in the controls. Interaction of Fas and FasL induces a cytolytic pathway leading to caspase- mediated apoptosis . In this view it is a marker of renal damage initiation , . On the other hand, FasL in renal tubular cells induces removal of antigen- activated CD4 T lymphocytes . Therefore, the occurrence of AR depends on a balance between these mechanisms besides many other factors.