Autoimmune lymphoproliferative syndrome caused by a homozygous FasL mutation that disrupts FasL assembly Ali Sobh, MD, Elena Crestani, MD, Brittney Cangemi,

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Presentation transcript:

Autoimmune lymphoproliferative syndrome caused by a homozygous FasL mutation that disrupts FasL assembly Ali Sobh, MD, Elena Crestani, MD, Brittney Cangemi, BA, Jennifer Kane, BA, Janet Chou, MD, Sung-Yun Pai, MD, Luigi D. Notarangelo, MD, Waleed Al-Herz, MD, Raif S. Geha, MD, Michel J. Massaad, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 1, Pages 324-327.e2 (January 2016) DOI: 10.1016/j.jaci.2015.08.025 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 FasL mutation in the patients. A, Family tree. B, Multiple protein alignment showing the position of the conserved glycine 277 residue in different species. C, FasL mRNA expression determined by RT-PCR. D, Immunoblotting of FasL from lysates of total PBMCs stimulated for 72 hours with PHA+IL-2. E and F, FasL surface expression on CD3+ cells in activated PBMCs, as determined by flow cytometry using anti-FasL mAbs (Fig 1, E), or Fas-huFc chimera (Fig 1, F). Ctrl, Control; Pt, patient; WB, Western blot. Journal of Allergy and Clinical Immunology 2016 137, 324-327.e2DOI: (10.1016/j.jaci.2015.08.025) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 The FasL G277S mutation results in disordered FasL assembly and abolishes function. A, Decreased apoptosis of PHA blasts restimulated for 12 hours with PHA+IL-2. (N = 3 controls and 2 patients). B, Increased proliferation of PHA blasts stimulated for 64 hours with PHA (N = 3 controls and 2 patients). C, Killing of Jurkat A1 target cells by CHO-K1 cells transfected with empty plasmid, or plasmids expressing WT or mutant FasL (N = 3). D and E, Immunoblot analysis of WT or mutant FasL extracted under nondenaturing conditions and resolved on a native gel (Fig 2, D), or extracted under denaturing conditions and resolved on a denaturing gel (Fig 2, E). Representative of 3 independent experiments. Actin was used as loading control. Statistical analyses were done using the Student t test (Fig 2, A and B), or 2-way ANOVA (Fig 2, C). **P < .01. cpm, Counts per minute; Ctrl, control; 3H-TdR, tritiated thymidine; Pt, patient; WB, Western blot. Journal of Allergy and Clinical Immunology 2016 137, 324-327.e2DOI: (10.1016/j.jaci.2015.08.025) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions