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Invited Review Articles

Immunologic evaluation and genetic defects of apoptosis in patients with autoimmune lymphoproliferative syndrome (ALPS)

ORCID Icon, ORCID Icon, ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 253-274 | Received 03 Jul 2020, Accepted 22 Nov 2020, Published online: 23 Dec 2020

References

  • Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239–257.
  • Cory S. Regulation of lymphocyte survival by the BCL-2 gene family. Annu Rev Immunol. 1995;13:513–543.
  • Hengartner H, Odermat B, Schneider R, et al. Deletion of self-reactive T cells before entry into the thymus medulla. Nature. 1988;336(6197):388–390.
  • Kisielow P, Blüthmann H, Staerz UD, et al. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4 + 8+ thymocytes. Nature. 1988;333(6175):742–746.
  • Palmer E. Negative selection-clearing out the bad apples from the T-cell repertoire. Nat Rev Immunol. 2003;3(5):383–391.
  • Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045.
  • Schwartz RH. A cell culture model for T lymphocyte clonal anergy. Science. 1990;248(4961):1349–1356.
  • Steinman RM, Turley S, Mellman I, et al. The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med. 2000;191(3):411–416.
  • Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–787.
  • Lenardo M, Chan FKM, Hornung F, et al. Mature T lymphocyte apoptosis-immune regulation in a dynamic and unpredictable antigenic environment. Annu Rev Immunol. 1999;17:221–253.
  • Tanchot C, Rosado MM, Agenes F, et al. Lymphocyte homeostasis. Semin Immunol. 1997;9(6):331–337.
  • Anel A, Gallego-Lleyda A, de Miguel D, et al. Role of exosomes in the regulation of T-cell mediated immune responses and in autoimmune disease. Cells. 2019;8(2):154.
  • Bosque A, Pardo J, Martínez-Lorenzo MJ, et al. Down-regulation of normal human T cell blast activation: roles of APO2L/TRAIL, FasL, and c- FLIP, Bim, or Bcl-x isoform expression. J Leukoc Biol. 2005;77(4):568–578.
  • Bosque A, Marzo I, Naval J, et al. Apoptosis by IL-2 deprivation in human CD8+ T cell blasts predominates over death receptor ligation, requires Bim expression and is associated with Mcl-1 loss. Mol Immunol. 2007;44(6):1446–1453.
  • Cory S, Adams JM. The BCL2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002;2(9):647–656.
  • Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2020;21(2):85–100.
  • Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science. 1998;281(5381):1305–1308.
  • Krammer PH. CD95(APO-1/Fas)-mediated apoptosis: live and let die. Adv Immunol. 1999;71:163–210.
  • Nagata S. Apoptosis by death factor. Cell. 1997;88(3):355–365.
  • Cho SG, Choi EJ. Apoptotic signaling pathways: caspases and stress-activated protein kinases. J Biochem Mol Biol. 2002;35(1):24–27.
  • Nagata S. Apoptosis and clearance of apoptotic cells. Annu Rev Immunol. 2018;36:489–517.
  • Li KP, Shanmuganad S, Carroll K, et al. Dying to protect: cell death and the control of T-cell homeostasis. Immunol Rev. 2017;277(1):21–43.
  • Watanabe-Fukunaga R, Brannan CI, Copeland NG, et al. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992;356(6367):314–317.
  • Takahashi T, Tanaka M, Brannan CI, et al. Generalized lymphoproliferative disease in mice, caused by a point mutation in the fas ligand. Cell. 1994;76(6):969–976.
  • Nagata S, Golstein P. The Fas death factor. Science. 1995;267(5203):1449–1456.
  • Nagata S, Suda T. Fas and Fas ligand: lpr and gld mutations. Immunol Today. 1995;16(1):39–43.
  • Wilber A, O'Connor TP, Lu ML, et al. Dnase1l3 deficiency in lupus-prone MRL and NZB/W F1 mice. Clin Exp Immunol. 2003;134(1):46–52.
  • Canale VC, Smith CH. Chronic lymphadenopathy simulating malignant lymphoma. J Pediatr. 1967;70(6):891–899.
  • Sneller MC, Straus SE, Jaffe ES, et al. A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Invest. 1992;90(2):334–341.
  • Rieux-Laucat F, Le Deist F, Hivroz C, et al. Mutations in fas associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995;268(5215):1347–1349.
  • Fisher GH, Rosenberg FJ, Straus SE, et al. Dominant interfering fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995;81(6):935–946.
  • Drappa J, Vaishnaw AK, Sullivan KE, et al. Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med. 1996;335(22):1643–1649.
  • Neven B, Magerus-Chatinet A, Florkin B, et al. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood. 2011;118(18):4798–4807.
  • Price S, Shaw PA, Seitz A, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood. 2014;123(13):1989–1999.
  • Bosque A, Pardo J, Martínez-Lorenzo MJ, et al. Human CD8+ T cell blasts are more sensitive than CD4+ T cell blasts to regulation by APO2L/TRAIL. Eur J Immunol. 2005;35(6):1812–1821.
  • Bosque A, Aguiló JI, del Rey M, et al. Cell cycle regulation by FasL and Apo2L/TRAIL in human T-cell blasts. Implications for autoimmune lymphoproliferative syndromes. J Leukoc Biol. 2008;84(2):488–498.
  • Daszkiewicz L, Vázquez-Mateo C, Rackov G, et al. Distinct p21 requirements for regulating normal and self-reactive T cells through IFN-γ production. Sci Rep. 2015;5(1):7691–7614.
  • Balomenos D, Shokri R, Daszkiewicz L, et al. On how fas apoptosis-independent pathways drive T cell hyperproliferation and lymphadenopathy in lpr mice. Front Immunol. 2017. DOI:https://doi.org/10.3389/fimmu.2017.00237
  • Bosque A, Aguiló JI, Alava MA, et al. The induction of Bim expression in human T-cell blasts is dependent on nonapoptotic Fas/CD95 signaling. Blood. 2007;109(4):1627–1635.
  • Rossin A, Miloro G, Hueber AO. TRAIL and FasL functions in cancer and autoimmune diseases: towards an increasing complexity. Cancers. 2019;11(5):639.
  • Bleesing JJH, Brown MR, Novicio C, et al. A composite picture of TcR alpha/beta(+) CD4(-)CD8(-) T Cells (alpha/beta-DNTCs) in humans with autoimmune lymphoproliferative syndrome. Clin Immunol. 2002;104(1):21–30.
  • Bristeau-Leprince A, Mateo V, Lim A, et al. Human TCR alpha/beta + CD4-CD8- double-negative T cells in patients with autoimmune lymphoproliferative syndrome express restricted Vbeta TCR diversity and are clonally related to CD8+ T cells. J Immunol. 2008;181(1):440–448.
  • Ibegbu CC, Xu Y-X, Harris W, et al. Expression of killer cell lectin-like receptor G1 on antigen-specific human CD8+ T lymphocytes during active, latent, and resolved infection and its relation with CD57. J Immunol. 2005;174(10):6088–6094.
  • Völkl S, Rensing-Ehl A, Allgäuer A, et al. Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome. Blood. 2016;128(2):227–238.
  • Rensing-Ehl A, Völkl S, Speckmann C, et al. Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency. Blood. 2014;124(6):851–860.
  • Teachey DT, Obzut DA, Axsom K, Choi JK, et al. Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS). Blood. 2006;108(6):1965–1971.
  • Bride KL, Vincent T, Smith-Whitley K, Lambert MP, et al. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-Institutional trial. Blood. 2016;127(1):17–28.
  • Teachey D, Bride K. Autoimmune lymphoproliferative syndrome: more than a FAScinating disease. F1000Res. 2017;6:1928.
  • Klemann C, Esquivel M, Magerus-Chatinet A, et al. Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome. Haematologica. 2017;102(2):e52–e56.
  • Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4 + CD25 + FoxP3+ regulatory T cells . Blood. 2005;105(12):4743–4748.
  • Mazerolles F, Stolzenberg MC, Pelle O, et al. Autoimmune lymphoproliferative syndrome-fas patients have an abnormal regulatory T cell (Treg) phenotype but display normal natural Treg-suppressive function on T cell proliferation. Front Immunol. 2018. DOI:https://doi.org/10.3389/fimmu.2018.00718
  • Lopatin U, Yao X, Williams RK, et al. Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression. Blood. 2001;97(10):3161–3170.
  • Neven B, Bruneau J, Stolzenberg MC, et al. Defective anti-polysaccharide response and splenic marginal zone disorganization in ALPS patients. Blood. 2014;124(10):1597–1609.
  • Janda A, Schwarz K, Van Der Burg M, et al. Disturbed B-lymphocyte selection in autoimmune lymphoproliferative syndrome. Blood. 2016;127(18):2193–2202.
  • Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors of immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40(1):24–64.
  • Bousfiha A, Jeddane L, Picard C, et al. Human inborn errors of immunity: 2019 Update of the IUIS Phenotypical Classification. J Clin Immunol. 2020;40(1):66–81.
  • Van Der Burg M, De Groot R, Comans-Bitter WM, et al. Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease? Pediatr Res. 2000;47(3):336–343.
  • Holzelova E, Vonarbourg C, Stolzenberg MC, et al. Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med. 2004;351(14):1409–1418.
  • Martínez-Feito A, Melero J, Mora-Díaz S, et al. Autoimmune lymphoproliferative syndrome due to somatic FAS mutation (ALPS-sFAS) combined with a germline caspase-10 (CASP10) variation. Immunobiology. 2016;221(1):40–47.
  • Del-Rey M, Ruiz-Contreras J, Bosque A, et al. A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome. Blood. 2006;108(4):1306–1312.
  • Magerus-Chatinet A, Stolzenberg MC, Lanzarotti N, et al. Autoimmune lymphoproliferative syndrome caused by a homozygous null FAS ligand (FASLG) mutation. J Allergy Clin Immunol. 2013;131(2):486–490.
  • Ruiz-Garcia R, Mora S, Lozano-Sanchez G, et al. Decreased activation-induced cell death by EBV-transformed B-cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation. Pediatr Res. 2015;78(6):603–608.
  • Wang J, Zheng L, Lobito A, et al. Inherited human caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell. 1999;98(1):47–58.
  • Zhu S, Hsu AP, Vacek MM, et al. Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome. Hum Genet. 2006;119(3):284–294.
  • Rieux-Laucat F, Magérus-Chatinet A, Neven B. The autoimmune lymphoproliferative syndrome with defective FAS or FAS-ligand functions. J Clin Immunol. 2018;38(5):558–568.
  • Miano M, Cappelli E, Pezzulla A, et al. FAS-mediated apoptosis impairment in patients with ALPS/ALPS-like phenotype carrying variants on CASP10 gene. Br J Haematol. 2019;187(4):502–508.
  • Chun HJ, Zheng L, Ahmad M, et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature. 2002;419(6905):395–399.
  • Niemela J, Kuehn HS, Kelly C, et al. Caspase-8 Deficiency presenting as late-onset multi-organ lymphocytic infiltration with granulomas in two adult siblings. J Clin Immunol. 2015;35(4):348–355.
  • Lehle AS, Farin HF, Marquardt B, et al. Intestinal inflammation and dysregulated immunity in patients with inherited caspase-8 deficiency. Gastroenterology. 2019;156(1):275–278.
  • Bolze A, Byun M, McDonald D, et al. Whole-exome-sequencing-based discovery of human FADD deficiency. Am J Hum Genet. 2010;87(6):873–881.
  • Singh A, Jindal AK, Joshi V, et al. An updated review on phenocopies of primary immunodeficiency diseases. Genes Dis. 2020;7(1):12–25.
  • Magerus-Chatinet A, Neven B, Stolzenberg MC, et al. Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation. J Clin Invest. 2011;121(1):106–112.
  • Del-Rey MJ, Manzanares J, Bosque A, et al. Autoimmune lymphoproliferative syndrome (ALPS) in a patient with a new germline Fas gene mutation. Immunobiology. 2007;212(2):73–83.
  • Boggio E, Aricò M, Melensi M, et al. Mutation of FAS, XIAP, and UNC13D genes in a patient with a complex lymphoproliferative phenotype. Pediatrics. 2013;132(4):e1052–e1058.
  • Clementi R, Dagna L, Dianzani U, et al. Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma. N Engl J Med. 2004;351(14):1419–1424.
  • Calvo KR, Price S, Braylan RC, et al. JMML and RALD (Ras-associated autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities. Blood. 2015;125(18):2753–2758.
  • Meynier S, Rieux-Laucat F. After 95 years, it's time to eRASe JMML. Blood Rev. 2020;(43):100652
  • Rieux-Laucat F. What's up in the ALPS. Curr Opin Immunol. 2017;49:79–86.
  • Kuehn HS, Niemela JE, Rangel-Santos A, et al. Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans. Blood. 2013;121(16):3117–3125.
  • Patiroglu T, Haluk Akar H, Gilmour K, et al. A case of XMEN syndrome presented with severe auto-immune disorders mimicking autoimmune lymphoproliferative disease. Clin Immunol. 2015;159(1):58–62.
  • Milner JD, Vogel TP, Forbes L, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015;125(4):591–599.
  • Nabhani S, Schipp C, Miskin H, et al. STAT3 gain-of-function mutations associated with autoimmune lymphoproliferative syndrome like disease deregulate lymphocyte apoptosis and can be targeted by BH3 mimetic compounds. Clin Immunol. 2017;181:32–42.
  • Fabre A, Marchal S, Barlogis V, et al. Clinical aspects of STAT3 gain-of-function germline mutations: a systematic review. J Allergy Clin Immunol Pract. 2019;7(6):1958–1969.
  • Kuehn HS, Ouyang W, Lo B, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204):1623–1627.
  • Schubert D, Bode C, Kenefeck R, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410–1416.
  • Fernández KS, Antony R, Kumar A. Patients with “ALPS-like phenotype” diagnosed with immune dysregulation due to LRBA deficiency. Pediatr Blood Cancer. 2019;66(3):e27558.
  • Wallace JG, Alosaimi MF, Khayat CD, et al. ITK deficiency presenting as autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol. 2020. DOI:https://doi.org/10.1016/j.jaci.2020.06.019
  • Schipp C, Schlütermann D, Hönscheid A, et al. EBV negative lymphoma and autoimmune lymphoproliferative syndrome like phenotype extend the clinical spectrum of primary immunodeficiency caused by STK4 deficiency. Front Immunol. 2018;9:2400.
  • Olbrich P, Freeman AF. STAT1 and STAT3 mutations: important lessons for clinical immunologists. Expert Rev Clin Immunol. 2018;14(12):1029–1041.
  • Fieschi C, Dupuis S, Catherinot E, et al. Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications. J Exp Med. 2003;197(4):527–535.
  • Nabhani S, Ginzel S, Miskin H, et al. Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease. Haematologica. 2015;100(9):1189–1198.
  • Barzaghi F, Minniti F, Mauro M, et al. ALPS-like phenotype caused by ADA2 deficiency rescued by allogeneic hematopoietic stem cell transplantation. Front Immunol. 2018;9:2767.
  • Stremenova Spegarova J, Lawless D, Mohamad SMB, et al. Germline TET2 loss of function causes childhood immunodeficiency and lymphoma. Blood. 2020;136(9):1055–1066.
  • Teachey DT, Manno CS, Axsom KM, et al. Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). Blood. 2005;105(6):2443–2448.
  • Straus SE, Jaffe ES, Puck JM, et al. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood. 2001;98(1):194–200.
  • Dowdell KC, Niemela JE, Price S, et al. Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome. Blood. 2010;115(25):5164–5169.
  • Bleesing JJH. Sorting out the causes of ALPS. J Pediatr. 2005;147(5):571–574.
  • Dale JK, Price S, Tretler J, et al. Use of rituximab for refractory immune cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS). Blood. 2007;110(11):1319–1319.
  • Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood. 2011;118(22):5741–5751.
  • Cooper N, Davies EG, Thrasher AJ. Repeated courses of rituximab for autoimmune cytopenias may precipitate profound hypogammaglobulinaemia requiring replacement intravenous immunoglobulin. Br J Haematol. 2009;146(1):120–122.
  • Teachey DT, Grupp SA, Brown VI. Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies. Br J Haematol. 2009;145(5):569–580.
  • Barrett D, Brown VI, Grupp SA, et al. Targeting the PI3KAKTmTOR signaling axis in children with hematologic malignancies. Paediatr Drugs. 2012;14:299–316.
  • Teachey DT, Jubelirer T, Baluarte HJ, et al. Treatment with sirolimus ameliorates tacrolimus-induced autoimmune cytopenias after solid organ transplant. Pediatr Blood Cancer. 2009;53(6):1114–1116.
  • Teachey DT, Greiner R, Seif A, et al. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br J Haematol. 2009;145(1):101–106.
  • Rao VK. Approaches to managing autoimmune cytopenias in novel immunological disorders with genetic underpinnings like autoimmune lymphoproliferative syndrome. Front Pediatr. 2015;3:65.
  • Vignesh P, Rawat A, Singh S. An update on the use of immunomodulators in primary immunodeficiencies. Clin Rev Allergy Immunol. 2017;52(2):287–303.
  • Oksenhendler E, Spaan AN, Neven B, et al. Autoimmune lymphoproliferative syndrome presenting with invasive Streptococcus pneumoniae infection. J Clin Immunol. 2020;40(3):543–546.
  • Forbes LR, Vogel TP, Cooper MA, et al. Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations. J Allergy Clin Immunol. 2018;142(5):1665–1669.
  • Lo B, Zhang K, Lu W, et al. Autoimmune disease. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436–440.
  • Delmonte OM, Castagnoli R, Calzoni E, et al. Inborn errors of immunity with immune dysregulation: from bench to bedside. Front Pediatr. 2019;(7):353.
  • Oliveira JB, Bleesing JJ, Dianzani U, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010;116(14):e35–e40.
  • Rensing-Ehl A, Janda A, Lorenz MR, et al. Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia. Haematologica. 2013;98(12):1948–1955.
  • Sriram S, Joshi AY, Rodriguez V, et al. Autoimmune lymphoproliferative syndrome: a rare cause of disappearing HDL syndrome. Case Reports Immunol. 2016;2016:7945953–7945954.
  • Moraitis AG, Freeman LA, Shamburek RD, et al. Elevated interleukin-10: a new cause of dyslipidemia leading to severe HDL deficiency. J Clin Lipidol. 2015;9(1):81–90.
  • Caminha I, Fleisher TA, Hornung RL, et al. Using biomarkers to predict the presence of FAS mutations in patients with features of the autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol. 2010;125(4):946–949.e6.
  • Rensing-Ehl A, Warnatz K, Fuchs S, et al. Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency. Clin Immunol. 2010;137(3):357–365.
  • Meyts I, Bosch B, Bolze A, et al. Exome and genome sequencing for inborn errors of immunity. J Allergy Clin Immunol. 2016;138(4):957–969.
  • Jackson CE, Fischer RE, Hsu AP, et al. Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. Am J Hum Genet. 1999;64(4):1002–1014.
  • Siegel RM, Frederiksen JK, Zacharias DA, et al. Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science. 2000;288(5475):2354–2357.
  • Kuehn HS, Caminha I, Niemela JE, et al. FAS haploinsufficiency is a common disease mechanism in the human autoimmune lymphoproliferative syndrome. J Immunol. 2011;186(10):6035–6043.
  • Bousfiha A, Jeddane L, Al-Herz W, et al. The 2015 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol. 2015;35(8):727–738.
  • Nabhani S, Hönscheid A, Oommen PT, et al. A novel homozygous Fas ligand mutation leads to early protein truncation, abrogation of death receptor and reverse signaling and a severe form of the autoimmune lymphoproliferative syndrome. Clin Immunol. 2014;155(2):231–237.
  • Sobh A, Crestani E, Cangemi B, et al. Autoimmune lymphoproliferative syndrome caused by a homozygous FasL mutation that disrupts FasL assembly. J Allergy Clin Immunol. 2016;137(1):324–327.
  • Bisgin A, Boga I, Yilmaz M, et al. The utility of next-generation sequencing for primary immunodeficiency disorders: experience from a clinical diagnostic laboratory. Biomed Res Int. 2018;2018:9647253.
  • Magerus-Chatinet A, Rieux-Laucat F. In vitro evaluation of the apoptosis function in human activated T cells. Methods Mol Biol. 2017;1557:33–40.
  • Lo B, Ramaswamy M, Davis J, et al. A rapid ex vivo clinical diagnostic assay for Fas receptor-induced T lymphocyte apoptosis. J Clin Immunol. 2013;33(2):479–488.
  • Brenner D, Krammer PH, Arnold R. Concepts of activated T cell death. Crit Rev Oncol Hematol. 2008;66(1):52–64.
  • Mateo V, Ménager M, De Saint-Basile G, et al. Perforin-dependent apoptosis functionally compensates Fas deficiency in activation-induced cell death of human T lymphocytes. Blood. 2007;110(13):4285–4292.
  • Muppidi J, Porter M, Siegel RM. Measurement of apoptosis and other forms of cell death. Curr Protoc Immunol. 2004;59:3.17.1–3.17.36.
  • Magerus-Chatinet A, Stolzenberg MC, Loffredo MS, et al. FAS-L, IL-10, and double-negative CD4- CD8- TCR alpha/beta + T cells are reliable markers of autoimmune lymphoproliferative syndrome (ALPS) associated with FAS loss of function. Blood. 2009;113(13):3027–3030.
  • Cabral-Marques O, Schimke LF, de Oliveira EB, et al. Flow cytometry contributions for the diagnosis and immunopathological characterization of primary immunodeficiency diseases with immune dysregulation. Front Immunol. 2019;(10):2742.
  • Hsu AP, Dowdell KC, Davis J, et al. Autoimmune lymphoproliferative syndrome due to FAS mutations outside the signal-transducing death domain: molecular mechanisms and clinical penetrance. Genet Med. 2012;14(1):81–89.
  • Krammer PH, Weyd H. Life, death and tolerance. Biochem Biophys Res Commun. 2017;482(3):470–472.
  • Rieux-Laucat F, Fischer A, Le Deist F. Cell-death signaling and human disease. Curr Opin Immunol. 2003;15(3):325–331.
  • Hauck F, Magerus-Chatinet A, Vicca S, et al. Somatic loss of heterozygosity, but not haploinsufficiency alone, leads to full-blown autoimmune lymphoproliferative syndrome in 1 of 12 family members with FAS start codon mutation. Clin Immunol. 2013;147(1):61–68.
  • Rieux-Laucat F, Casamova JL. Immunology. Autoimmunity by haploinsufficiency. Science. 2014;345(6204):1560–1561.

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