title: Impaired apoptosis of lymphocytes derived from patient with decreased expression of caspase-8 results in Alps-like phenotype.
abstract: Human autoimmune lymphoproliferative syndrome has been described as a result of various mutations concerning genes encoding receptor CD95 and/or its ligand - CD178. However, recently, several cases with identical clinical manifestation, despite a normal structure of CD95 or CD178 have also been reported. In this study we analyzed PBMC obtained from patient with clinically overt lymphoproliferative disorder. Using in vitro assays as well as molecular methods we tested expression and biological activity of CD95 and CD178 molecules. We found that analyzed patient's lymphocytes displayed normal cytotoxic activity against CD95-bearing targets. However, CD95-dependent induction of apoptosis in analyzed lymphocytes was diminished, as compared to healthy control. Surprisingly, the molecular studies did not reveal any abnormalities in structure of patient-derived CD95 receptor molecule. Therefore, expression of other factors involved in CD95-mediated signaling pathway was estimated using RNase protection assay. The expression of FADD was comparable to that of healthy control. However, it has been found that patient-derived lymphocytes expressed reduced amount of caspase-8 mRNA, as compared to control subject cells. This report confirms previous observations that lymphoproliferative disorder could be associated not only with CD95 and/or CD178 mutations, but also with dysfunction of other components of apoptosis induction pathway. However, the detailed molecular mechanism of observed abnormalities in caspase-8 expression remains to be elucidated.
authors.affiliation: Department of Histology and Embryology, Warsaw Medical University, PL 02 004 Warsaw, Poland. tgrzela@ib.amwaw.edu.pl.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Grzela
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Krauze
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Grzela
authors.forename: Maciej
authors.initials: M
authors.lastname: Lazarczyk
authors.forename: Justyna
authors.initials: J
authors.lastname: Niderla
authors.forename: Robert
authors.initials: R
authors.lastname: Brawura-Biskupski-Samaha
authors.forename: Piotr
authors.initials: P
authors.lastname: Dziunycz
authors.forename: Lukasz
authors.initials: L
authors.lastname: Milewski
authors.forename: Grazyna
authors.initials: G
authors.lastname: Korczak-Kowalska
authors.forename: Marek
authors.initials: M
authors.lastname: Kulus
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001327:Autoimmune Diseases / Q000276:immunology*; D053181:Caspase 8; D020169:Caspases / Q000172:deficiency / Q000235:genetics*; D002470:Cell Survival / Q000276:immunology; D002675:Child, Preschool; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology*; D008232:Lymphoproliferative Disorders / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019014:fas Receptor / Q000235:genetics*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases