Abstract
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by immune dysregulation due to a defect in lymphocyte apoptosis. The clinical manifestations may be noted in multiple family members and include lymphadenopathy, splenomegaly, increased risk of lymphoma, and autoimmune disease, which typically involves hematopoietic cell lines manifesting as multilineage cytopenias. Since the disease was first characterized in the early 1990s, there have been many advances in the diagnosis and management of this syndrome. The inherited genetic defect of many ALPS patients has involved (FAS) pathway signaling proteins, but there remain those patients who carry undefined genetic defects. Despite ALPS having historically been considered a primary immune defect presenting in early childhood, adult onset presentation is increasingly becoming recognized and more so in genetically undefined patients and those with somatic FAS mutations. Thus, future research may identify novel pathways and/or regulatory proteins important in lymphocyte activation and apoptosis.
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References
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Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood. 2011;118(22):5741–51. Discusses management of various complications related to ALPS based on study of a large cohort of ALPS patients.
Fisher GH et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995;81(6):935–46.
Straus SE 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.
Hauck F 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):61–8.
Del-Rey M et al. A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome. Blood. 2006;108(4):1306–12.
Zhu S et al. Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome. Hum Genet. 2006;119(3):284–94.
Wang J 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.
Lambotte O et al. Diagnosis of autoimmune lymphoproliferative syndrome caused by FAS deficiency in adults. Haematologica. 2013;98(3):389–92.
Deutsch M, Tsopanou E, Dourakis SP. The autoimmune lymphoproliferative syndrome (Canale-Smith) in adulthood. Clin Rheumatol. 2004;23(1):43–4.
Rudman Spergel A et al. Autoimmune lymphoproliferative syndrome misdiagnosed as hemophagocytic lymphohistiocytosis. Pediatrics. 2013;132(5):e1440–4.
Magerus-Chatinet A et al. Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation. J Clin Investig. 2011;121(1):106–12.
Neven B et al. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood. 2011;118(18):4798–807.
Kim YJ et al. Eosinophilia is associated with a higher mortality rate among patients with autoimmune lymphoproliferative syndrome. Am J Hematol. 2007;82(7):615–24.
Caminha I 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):946–9.e6.
Bowen RA et al. Elevated vitamin B(1)(2) levels in autoimmune lymphoproliferative syndrome attributable to elevated haptocorrin in lymphocytes. Clin Biochem. 2012;45(6):490–2.
Oliveira JB et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010;116(14):e35–40. Discusses current diagnostic criteria for ALPS.
Desai NK et al. Autoimmune lymphoproliferative disorder in an adult patient. J Postgrad Med. 2011;57(2):131–3.
Rao VK et al. Use of rituximab for refractory cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS). Pediatr Blood Cancer. 2009;52(7):847–52.
Wei A, Cowie T. Rituximab responsive immune thrombocytopenic purpura in an adult with underlying autoimmune lymphoproliferative syndrome due to a splice-site mutation (IVS7 + 2T > C) affecting the Fas gene. Eur J Haematol. 2007;79(4):363–6.
Arora S et al. Autoimmune lymphoproliferative syndrome: response to mycophenolate mofetil and pyrimethamine/sulfadoxine in a 5-year-old child. Indian J Hematol Blood Transfus. 2011;27(2):101–3.
Teachey DT et al. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br J Haematol. 2009;145(1):101–6.
Teachey DT et al. Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS). Blood. 2006;108(6):1965–71.
Bajwa R, Savelli S, Gross T. Pentostatin for treatment of refractory autoimmune lymphoproliferative syndrome. Pediatr Blood Cancer. 2011;57(2):336–7.
Kotb R et al. Efficacy of mycophenolate mofetil in adult refractory auto-immune cytopenias: a single center preliminary study. Eur J Haematol. 2005;75(1):60–4.
Farruggia P et al. Effectiveness of cyclosporine and mycophenolate mofetil in a child with refractory evans syndrome. Pediatr Rep. 2011;3(2):e15.
Liang Y et al. Rituximab for children with immune thrombocytopenia: a systematic review. PLoS One. 2012;7(5):e36698.
Price S et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood. 2014;123(13):1989–99. Discusses long term follow-up, including morbidity and mortality, of a large cohort of ALPS patients.
Price S, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood. 2014.
Boggio E, et al. IL-17 protects T cells from apoptosis and contributes to development of ALPS-like phenotypes. Blood. 2013.
Benkerrou M et al. Correction of Fas (CD95) deficiency by haploidentical bone marrow transplantation. Eur J Immunol. 1997;27(8):2043–7.
Dimopoulou MN et al. Successful treatment of autoimmune lymphoproliferative syndrome and refractory autoimmune thrombocytopenic purpura with a reduced intensity conditioning stem cell transplantation followed by donor lymphocyte infusion. Bone Marrow Transplant. 2007;40(6):605–6.
Sleight BJ et al. Correction of autoimmune lymphoproliferative syndrome by bone marrow transplantation. Bone Marrow Transplant. 1998;22(4):375–80.
Venkataraman G et al. Development of disseminated histiocytic sarcoma in a patient with autoimmune lymphoproliferative syndrome and associated Rosai-Dorfman disease. Am J Surg Pathol. 2010;34(4):589–94.
Acknowledgments
This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and 1R03AR059286.
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Shaili Shah, Eveline Wu, V. Koneti Rao, and Teresa K. Tarrant declare no conflict of interest.
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Shah, S., Wu, E., Rao, V.K. et al. Autoimmune Lymphoproliferative Syndrome: an Update and Review of the Literature. Curr Allergy Asthma Rep 14, 462 (2014). https://doi.org/10.1007/s11882-014-0462-4
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DOI: https://doi.org/10.1007/s11882-014-0462-4