Muhtemel Otoimmün Lenfoproliferatif Sendrom (Alps) Tanısıyla Izlenen Hastaların Bilinen Moleküler Defektler Yönünden Araştırılması
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Apoptosis plays a crucial role in immune homeostasis. The interaction between Fas and FasL, essential molecules in an apoptosis pathway, play an important role in the termination of the immune response, regulation of lymphocyte survival, and immune tolerance. Defects in genes that have role in apoptosis pathways result in dysregulation of lymphocyte homeostasis and development of ALPS and ALPS related disorders which are characterized by chronic lymphadenopathy and/or splenomegaly, autoimmune features, most commonly autoimmune cytopenias, and susceptibility to development of lymphoma. Most cases of ALPS are associated with germline heterozygous mutations of the FAS gene. Somatic(s) FAS mutations constitute the second most common genetic defect. In a small number of patients FASL and CASP10 gene defects are responsible for ALPS; CASP8, NRAS and KRAS mutations, for ALPS related diseases. Patients who fulfill ALPS diagnostic criteria in whom no causative mutations can be identified are classified as ALPS-Unknown (ALPS-U) and comprise about one third of all cases. In addition to the Fas defects, clinical presentation of ALPS appears to be influenced by modifier genes. The FAS, FAS ligand (FASL), and CASP8 are key molecules in apoptosis and defects in related genes may create a susceptibility to cancer development and may effect its prognosis. Studies showed that nucleotide changes in Fas gene contribute to susceptibility to autoimmune diseases and cancer. We investigated biochemical markers (sFas-L, IL-10, IL-18, vitamine B12) that constitute the secondary accessory diagnostic criteria for ALPS, and performed sequence analysis to detect underlying FAS,FASL and CASP8 gene defects in 25 unrelated patients with the diagnosis of probable ALPS according to criteria revised in 2009. No mutation was found in the FAS, FASL or CASP8 genes. However, we found the frequencies of SNP rs 2234987 of FAS gene (homozygous minor T allele) and rs1045487 of CASP8 (heterozygous minor A allele) significantly increased in our patients comparing healthy controls (p=0.001 and p=0.004 respectively). sFAS mutation was studied in DNA sample extracted from DNT (double negative T) cells but not demonstrated in a patient whose biochemical markers’ levels were suggestive for Fas defect and without germline FAS mutation. Our results suggest that CASP8 and FAS gene polimorphisms in particular, may contribute to the susceptibility to ALPS phenotype. To determine the responsible mechanisms for the possible effect of these polymorphisms on the susceptibility to the disease, functional and gene expression studies; and to discover the mutations in yet unknown genes Whole Exome(WES) and Whole genom (WGS) studies should be done.