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    • br Conclusion In conclusion rats in this model

    2021-11-22


    Conclusion In conclusion, rats in this model of HELLP syndrome demonstrated increased placental and circulating FasL and increased placental Fas when compared to NP rats. Administration of an ETA receptor antagonist to HELLP rats tended to decrease circulating FasL and placental Fas, while not affecting placental FasL levels. These results suggest, that there is an additional source of FasL besides the placenta that can be contributing to the increase in circulating FasL and that the endothelin system is not involved in the regulation of FasL in the placenta. In the current study we did not investigate all of the potential sources of FasL, however studies by other labs have indicated that the placenta along with circulating immune KPT-185 mg can potentially serve as a source of FasL [10], [20], [32]. As such future studies, in addition to a closer look at hypertension and vascular function in relation to Fas/FasL will also include examining the role of these immune cells (both circulating and placental) to contribute to the pathogenesis of HELLP syndrome. As the Fas/FasL system can initiate not only apoptosis but also inflammation via immune cell activation, it is important to continue to study the role of this system in contributing to HELLP syndrome where both apoptosis and inflammation are increased.
    Funding
    Conflict of interest
    Introduction Programmed cell death, more commonly called apoptosis, is a crucial process required for immune homeostasis [1] and also helps maintain immunologic tolerance [2]. Apoptosis is efficiently induced by the Fas-Fas ligand (FasL) pathway. The interaction of Fas and FasL, two homotrimeric transmembrane counter-receptors, results in the association of the adaptor protein FADD (Fas associated death domain) and the recruitment of procaspases 8 and 10. This leads to the formation of a signaling multimolecular complex called DISC (death-inducing signaling complex) which is a critical step in delivering a successful death signal [3], [4], [5]. The importance of this orchestrated Fas-FasL apoptotic pathway was illustrated by the discovery of human genetic defects leading to autoimmune lymphoproliferative syndrome (ALPS) [6], [7], [8]. ALPS is a genetic disorder of immune regulation characterized by chronic lymphoproliferation leading to enlargement of the lymph nodes, spleen and/or liver, associated with autoimmune manifestations primarily directed against the hematopoietic system. A hallmark of ALPS is the expansion of TCRαβ+CD4−CD8− T cells, called double-negative T (DNT) cells, that typically does not exceed 1% in healthy adults. Other reliable biomarkers able to predict ALPS include polyclonal hypergammaglobulinemia as well as high serum or plasma levels of either IL-10, IL-18, soluble Fas ligand (sFasL) or vitamin B12 [9]. Approximately 70% of patients have molecular defects in genes associated with the apoptotic pathway [10]. Mutations in the gene encoding FasL (ALPS-FASLG) or caspase-10 (ALPS-CASP10) have been identified in a minority of patients. Deleterious heterozygous germline mutations in the FAS (CD95) gene inherited in an autosomal dominant pattern and associated with preserved protein expression, are the most common cause of ALPS (ALPS-FAS). Somatic FAS mutations, detected primarily in DNT cells, are the second most common genetic etiology of this disease (ALPS-sFAS) [11]. Autosomal recessive (AR) form of ALPS caused by homozygous germline FAS mutations is very rare [6], [12], [13], [14]. Indeed, only four mutations have been previously described: i) a 290-base pair deletion and ii) a 20-nucleotide duplication in exon 9 encoding the death domain [6], [13], both resulting in either an unstable protein or defective trafficking to the cell surface, iii) a splice acceptor site mutation of intron 3 resulting in the skipping of exon 4 [12], and finally iv) a missense extracellular mutation that induces a protein retention at the endoplasmic reticulum [14]. This AR form is associated with a complete defect of Fas expression (previously classified as ALPS Type 0) that leads to an early onset and a more severe ALPS phenotype. It represents the human homologue of the Fas null mouse.