Rare splicing defects of FAS underly severe recessive autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is a prototypic disorder of impaired apoptosis characterized by autoimmune features and lymphoproliferation. Heterozygous germline or somatic FAS mutations associated with preserved protein expression have been described. Very rare cases of homozygous germline FAS mutations causing severe autosomal recessive form of ALPS with a complete defect of Fas expression have been reported. We report two unrelated patients from highly inbred North African population showing a severe ALPS phenotype and an undetectable Fas surface expression. Two novel homozygous mutations have been identified underlying rare splicing defects mechanisms. The first mutation breaks a branch point sequence and the second alters a regulatory exonic splicing site. These splicing defects induce the skipping of exon 6 encoding the transmembrane domain of CD95. Our findings highlight the requirement of tight regulation of FAS exon 6 splicing for balanced alternative splicing and illustrate the importance of such studies in highly consanguineous populations.

[Prevalence of Pneumocystis jiroveci pneumonia in Tunisian primary immunodeficient patients]. / Prévalence de la pneumopathie à Pneumocystis Jiroveci au cours des déficits immunitaires héréditaires observés en Tunisie.

UNLABELLED: Pneumocystis Jiroveci pneumonia (PJP) is a rare opportunistic infection in immunodeficient patients in Tunisia, as well as in other Africain countries including those with a high prevalence of AIDS. In the literature, PJP has been reported in primary immunodeficiency diseases (PID) namely SCID T-B- or T-B+ or X-linked hyper-IgM syndrome. OBJECTIVE: To evaluate the prevalence of PJP in the different PID observed in Tunisia. PATIENTS AND METHODS: This retrospective study concerned 290 cases of PID confirmed by immunological investigation including the study of specific and/or non-pecific humoral and cellular immunity. The identification of P. Jiroveci in patients suspected of pneumocystosis was achieved by parasitological investigation in bronchoalveolar lavages. RESULTS: A PID associated to a parasitologically confirmed pneumocystic infection was found in 9 out of 290 patients (3%) among whom the majority (7 patients) had an HLA class II combined immunodeficiency. The latter is an autosomic recessive disease which has been reported mainly in North African families. Indeed, this population is characterized by a high rate of consanguinity. Interestingly, no PJP has been observed neither in SCID T-B- or T-B+ nor in X-linked hyper-IgM syndrome. DISCUSSION AND CONCLUSION: PJP seems to be particularly frequent in HLA class II deficiency patients, since 7 out of 22 patients with this deficiency had a PJP (31%). Due to this defect, antigen presenting cells are unable to present the antigen to T lymphocytes demonstrating the critical role of CD4+ T lymphocytes responses in the immune response to this pathogen.

[Primary immunologic deficiency by deficiency of HLA class II antigens: nine new Tunisian cases]. / Déficit immunitaire primitif par défaut d'expression des antigènes HLA de classe II: neuf observations tunisiennes.

BACKGROUND: Bare lymphocyte syndrome is a rare inherited primary immunodeficiency. The majority of the patients reported to date are from North Africa. We report nine new Tunisian cases. POPULATION AND METHODS: Over a period of 5 years, we have established the diagnosis of bare lymphocyte syndrome in nine patients who belong to seven different families. Class II HLA antigen expression was studied on resting peripheral mononuclear cells and PHA blasts. RESULTS: The clinical symptoms started at the mean age of 4.5 months (2-10 months) with chronic diarrhea. The evolution was characterized by appearance of other recurrent infections: pneumopathies (seven cases), thrush (seven cases), otitis (five cases) and septicemia (four cases). Allergic manifestations were observed in four cases. Six patients died at the mean age of 30 months from severe denutrition. Class II HLA antigens were not expressed on resting and activated lymphocytes. The absolute count of TCD4+ lymphocytes was decreased in seven patients. Lymphoproliferative response to specific antigens was absent. Four patients had panhypogammaglobulinemia. CONCLUSION: This study confirms the frequency of this disease among the North African population. The severity of the recurrent infection suggests the diagnosis of bare lymphocyte syndrome. This disease is fatal in the absence of bone marrow transplantation.