title: Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis.
abstract: Programmed cell death (or apoptosis) is a physiological process essential to the normal development and homeostatic maintenance of the immune system. The Fas/Apo-1 receptor plays a crucial role in the regulation of apoptosis, as demonstrated by lymphoproliferation in MRL-lpr/lpr mice and by the recently described autoimmune lymphoproliferative syndrome (ALPS) in humans, both of which are due to mutations in the Fas gene. We describe a novel family with ALPS in which three affected siblings carry two distinct missense mutations on both the Fas gene alleles and show lack of Fas-induced apoptosis. The children share common clinical features including splenomegaly and lymphadenopathy, but only one developed severe autoimmune manifestations. In all three siblings, we demonstrated the presence of anergic CD3+CD4-CD8- (double negative, [DN]) T cells; moreover, a chronic lymphocyte activation was found, as demonstrated by the presence of high levels of HLA-DR expression on peripheral CD3+ cells and by the presence of high levels of serum activation markers such as soluble interleukin-2 receptor (slL-2R) and soluble CD30 (sCD30).
authors.affiliation: Consorzio per le Biotecnologie, Servizio di Immunologia Clinica, Spedali Civili di Brescia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bettinardi
authors.forename: D
authors.initials: D
authors.lastname: Brugnoni
authors.forename: E
authors.initials: E
authors.lastname: Quiròs-Roldan
authors.forename: A
authors.initials: A
authors.lastname: Malagoli
authors.forename: S
authors.initials: S
authors.lastname: La Grutta
authors.forename: A
authors.initials: A
authors.lastname: Correra
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
mesh_terms: D000293:Adolescent; D000945:Antigens, Differentiation, T-Lymphocyte / Q000097:blood; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology*; D008297:Male; D009154:Mutation; D010375:Pedigree; D012995:Solubility; D013577:Syndrome; D013601:T-Lymphocytes / Q000145:classification / Q000276:immunology; D019014:fas Receptor / Q000235:genetics*
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D015415:Biomarkers; D019014:fas Receptor