Early ReportClinical, immunological, and pathological consequences of Fas-deficient conditions
Introduction
The Fas/CD 95/Apo-1 molecule, originally described with two monoclonal antibodies (anti-Fas, anti-APO-1) that were found to be cytolytic for various human cell lines,1, 2 is a cell surface protein belonging to the family of receptors for tumour necrosis factor (TNF). Its expression on lymphocytes is triggered by cell activation. Prolonged activation makes Fas-expressing cells sensitive to death by apoptosis once the Fas ligand (Fas-L), also expressed by activated T-lymphocytes, has interacted with Fas.1, 3 Fas/Fas-L interaction can occur in a cis or trans cell mechanism inducing suicide or cell killing, respectively,2, 4 through the activation of proteases of the interleukin converting enzyme (ICE) family.1 Fas-L/Fas interactions control the peripheral lymphocyte life span and thereby participate in peripheral elimination of autoreactive lymphocytes.5 The latter conclusion was mainly drawn from observations of Murphy/Roth (MRL) mouse strains with Fas-encoding lymphoproliferation gene mutations (1pr and 1prc-g that develop a syndrome associated with variable autoimmune manifestations (including a lupus-like syndrome and glomerulonephritis).6 We reported that homozygous and heterozygous mutations of the human Fas-encoding gene, located on chromosome 10, also cause lymphoproliferation.7 Similar findings in the case of heterozygous mutations were independently reported in five patients8 following an earlier description of children with a phenotype of lymphoproliferation resembling that of 1pr mice.9 Here we provide an in-depth description of the clinical, immunological and pathological manifestations associated with homozygous or heterozygous fas mutations in one and two patients, respectively. The outcome of treatment for lymphoproliferation and autoimmunity is also reported.
Section snippets
Patients and methods
We have previously reported fas gene mutations in three patients.7 Fas deficiency was related to a homozygous deletion in the Fas-encoding gene, resulting in loss of the last 29 aminoacid residues and the presence of six additional residues in the Fas protein in patient 1, while a heterozygous two-base pair (bp) nucleotide deletion was found at genomic position 1005 in two siblings (patients 2 and 3), and in their healthy mother. This deletion resulted in a reading frame shift which generated a
Complete Fas expression deficiency
Lymphoproliferation–Patient 1 was born, at 34–35 weeks of gestation, to second-cousin parents originating from the Middle East, from a polyhydramniotic uterine environment. Two older brothers were healthy. Hydrops and hepatosplenomegaly were noted at birth, with anaemia (9 g/dL) and thrombocytopoenia (50 000/μL). Splenectomy was done at age 3 months for persistent massive splenomegaly with hypersplenism. At age 5 months she developed tachypnoea with widespread pulmonary infiltrates, mild
Discussion
We describe the clinical, pathological and immunological manifestations associated with complete and partial Fas protein deficiencies in three patients from two families, together with responses to treatment of lymphoproliferation and autoimmunity. Complete absence of Fas expression resulted in prenatal onset of a major lymphocyte proliferative syndrome. There were no extra-lymphocyte manifestations, despite the known expression of Fas by liver cells and some heart cells.13 Absence of
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