Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS)

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of T cell dysregulation caused by defective Fas‐mediated apoptosis. Patients with ALPS can develop a myriad of clinical manifestations including lymphadenopathy, hepatosplenomegaly, autoimmunity and increased rates of malignancy. ALPS may be more common that originally thought, and testing for ALPS should be considered in patients with unexplained lymphadenopathy, hepatosplenomegaly, and/or autoimmunity. As the pathophysiology of ALPS is better characterized, a number of targeted therapies are in preclinical development and clinical trials with promising early results. This review describes the clinical and laboratory manifestations found in ALPS patients, as well as the molecular basis for the disease and new advances in treatment.

[1]  J. Carew,et al.  Mammalian target of rapamycin as a target in hematological malignancies , 2011, Targeted Oncology.

[2]  K. Nada,et al.  Rapid regression of lymphadenopathy upon rapamycin treatment in a child with autoimmune lymphoproliferative syndrome , 2009 .

[3]  Yuan Shen,et al.  Deacetylase inhibition increases regulatory T cell function and decreases incidence and severity of collagen-induced arthritis. , 2009, Experimental and molecular pathology.

[4]  P. Newburger,et al.  Use of rituximab for refractory cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS) , 2009, Pediatric blood & cancer.

[5]  A. Thrasher,et al.  Repeated courses of rituximab for autoimmune cytopenias may precipitate profound hypogammaglobulinaemia requiring replacement intravenous immunoglobulin , 2009, British journal of haematology.

[6]  V Koneti Rao,et al.  Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, diminishes lymphoproliferation in the Fas -deficient MRL/lpr(-/-) murine model of autoimmune lymphoproliferative syndrome (ALPS). , 2009, Experimental hematology.

[7]  D. Wechsler,et al.  Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome , 2009, British journal of haematology.

[8]  F. Rieux-Laucat,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. , 2009, Blood.

[9]  R. González-Amaro,et al.  Effect of Arsenic on Regulatory T Cells , 2009, Journal of Clinical Immunology.

[10]  K. Debatin,et al.  Residual CD95-Pathway Function in Children With Autoimmune Lymphoproliferative Syndrome Is Independent From Clinical State and Genotype of CD95 Mutation , 2009, Pediatric Research.

[11]  E. Neufeld,et al.  Response to mercaptopurine for refractory autoimmune cytopenias in children , 2009, Pediatric blood & cancer.

[12]  G. Hortin,et al.  Significantly Elevated Vitamin B12 Levels in Autoimmune Lymphoproliferative Syndrome (ALPS), a Rare Lymphoproliferative Disorder with Apoptosis Defect , 2008 .

[13]  J. Bluestone,et al.  Human regulatory T cells: role in autoimmune disease and therapeutic opportunities , 2008, Immunological reviews.

[14]  D. Teachey,et al.  Targeting Notch signaling in autoimmune and lymphoproliferative disease. , 2008, Blood.

[15]  J. Puck,et al.  Pyrimethamine treatment does not ameliorate lymphoproliferation or autoimmune disease in MRL/lpr−/− mice or in patients with autoimmune lymphoproliferative syndrome , 2007, American journal of hematology.

[16]  P. Tak,et al.  Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study , 2007, Annals of the rheumatic diseases.

[17]  A. Wei,et al.  Rituximab responsive immune thrombocytopenic purpura in an adult with underlying autoimmune lymphoproliferative syndrome due to a splice-site mutation (IVS7+2 T>C) affecting the Fas gene , 2007, European journal of haematology.

[18]  M. Ratain,et al.  Rapamycin: Something Old, Something New, Sometimes Borrowed and Now Renewed , 2007, Clinical pharmacology and therapeutics.

[19]  N. Sebire,et al.  Successful treatment of lymphoproliferative disease complicating primary immunodeficiency/immunodysregulatory disorders with reduced-intensity allogeneic stem-cell transplantation. , 2007, Blood.

[20]  S. Qualman,et al.  Autoimmune Lymphoproliferative Syndrome (ALPS): A Case with Congenital Onset , 2007, Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society.

[21]  Peter J. Munson,et al.  NRAS mutation causes a human autoimmune lymphoproliferative syndrome , 2007, Proceedings of the National Academy of Sciences.

[22]  Sonali M. Smith.  Clinical development of mTOR inhibitors: a focus on lymphoma. , 2007, Reviews on recent clinical trials.

[23]  W. V. van Son,et al.  Presentation and early detection of post‐transplant lymphoproliferative disorder after solid organ transplantation , 2007, Transplant international : official journal of the European Society for Organ Transplantation.

[24]  M. Herrmann,et al.  The expanded double negative T cell populations of a patient with ALPS are not clonally related to CD4+ or to CD8+ T cells , 2007, Autoimmunity.

[25]  P. Opolon,et al.  Arsenic trioxide: A promising novel therapeutic agent for lymphoproliferative and autoimmune syndromes in MRL/lpr mice. , 2006, Blood.

[26]  F. Rieux-Laucat,et al.  Mycophenolate mofetil as an alternate immunosuppressor for autoimmune lymphoproliferative syndrome. , 2006, Journal of pediatric hematology/oncology.

[27]  K. Sullivan,et al.  Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS). , 2006, Blood.

[28]  A. Perl,et al.  Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. , 2006, Arthritis and rheumatism.

[29]  H. Bobby Gaspar,et al.  Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype , 2006, British journal of haematology.

[30]  D. Teachey,et al.  The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. , 2006, Blood.

[31]  W. Wilson,et al.  Fluorodeoxyglucose positron emission tomography (FDG‐PET) for monitoring lymphadenopathy in the autoimmune lymphoproliferative syndrome (ALPS) , 2006, American journal of hematology.

[32]  A. Zanella,et al.  Primary and secondary autoimmune neutropenia , 2005, Arthritis research & therapy.

[33]  A. Chiocchetti,et al.  Cutaneous Manifestations as Presenting Sign of Autoimmune Lymphoproliferative Syndrome in Childhood , 2005, Dermatology.

[34]  J. Puck,et al.  Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome , 2005, British journal of haematology.

[35]  Andreas Mackensen,et al.  Isolation and characterization of human antigen-specific TCRαβ+ CD4-CD8- double-negative regulatory T cells , 2005 .

[36]  R. Martín-Vivaldi,et al.  Mycophenolate mofetil-induced neutropenia in liver transplantation. , 2005, Transplantation proceedings.

[37]  L. Gesualdo,et al.  Sirolimus for Kaposi's sarcoma in renal-transplant recipients. , 2005, The New England journal of medicine.

[38]  T. Rath,et al.  Mutagenic and cytotoxic effects of immunosuppressive drugs on human lymphocyte cultures. , 2004, Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation.

[39]  J. B. Oliveira,et al.  Autoimmune lymphoproliferative syndrome , 2004, Current opinion in allergy and clinical immunology.

[40]  K. Sullivan,et al.  Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). , 2004, Blood.

[41]  F. Rieux-Laucat,et al.  Autoimmune lymphoproliferative syndrome with somatic Fas mutations. , 2004, The New England journal of medicine.

[42]  A. van den Berg,et al.  Development of Lymphoma in Autoimmune Lymphoproliferative Syndrome (ALPS) and its Relationship to Fas Gene Mutations , 2004, Leukemia & lymphoma.

[43]  V. Brown,et al.  Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Y. Natkunam,et al.  Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas. , 2003, Cancer research.

[45]  H. Takada,et al.  Dominant expression of interleukin 10 but not interferon γ in CD4–CD8–αβT cells of autoimmune lymphoproliferative syndrome , 2002 .

[46]  J. Puck,et al.  Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency , 2002, Nature.

[47]  A. Mehta,et al.  Effect of anti‐CD20 (rituximab) on resistant thrombocytopenia in autoimmune lymphoproliferative syndrome , 2002, British journal of haematology.

[48]  D. Isenberg,et al.  Characterization of CD3+CD4-CD8- (double negative) T cells in patients with systemic lupus erythematosus: production of IL-4 , 2002, Lupus.

[49]  T. Fleisher,et al.  A composite picture of TcRα/β+ CD4-CD8- T cells (α/β-DNTCs) in humans with autoimmune lymphoproliferative syndrome , 2002 .

[50]  J. Bleesing.  Autoimmune lymphoproliferative syndrome A genetic disorder of abnormal lymphocyte apoptosis , 2002 .

[51]  R. Beyaert,et al.  Reversion of autoimmune lymphoproliferative syndrome with an antimalarial drug: preliminary results of a clinical cohort study and molecular observations , 2002, British journal of haematology.

[52]  J. Puck,et al.  Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome. , 2001, Blood.

[53]  J. Puck,et al.  TcR-alpha/beta(+) CD4(-)CD8(-) T cells in humans with the autoimmune lymphoproliferative syndrome express a novel CD45 isoform that is analogous to murine B220 and represents a marker of altered O-glycan biosynthesis. , 2001, Clinical immunology.

[54]  A. Marx,et al.  The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. , 2001, Blood.

[55]  K. Izeradjene,et al.  Mycophenolate mofetil interferes with interferon γ production in T-cell activation models , 2001 .

[56]  F. Cadario,et al.  Defective function of Fas in patients with type 1 diabetes associated with other autoimmune diseases. , 2001, Diabetes.

[57]  T. Fleisher,et al.  Autoimmune lymphoproliferative syndrome. A human disorder of abnormal lymphocyte survival. , 2000, Pediatric clinics of North America.

[58]  A. Chiocchetti,et al.  Defective T cell Fas function in patients with multiple sclerosis , 2000, Neurology.

[59]  J. Puck,et al.  Autoimmune lymphoproliferative syndrome, a disorder of apoptosis. , 1999, Current opinion in pediatrics.

[60]  J. Puck,et al.  An Inherited Disorder of Lymphocyte Apoptosis: The Autoimmune Lymphoproliferative Syndrome , 1999, Annals of Internal Medicine.

[61]  J. Puck,et al.  Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. , 1999, American journal of human genetics.

[62]  P. Krammer,et al.  The molecular basis for apoptotic defects in patients with CD95 (Fas/Apo-1) mutations. , 1999, The Journal of clinical investigation.

[63]  J. V. Bosch,et al.  Autoimmune Lymphoproliferative Syndrome , 2003, Paediatric drugs.

[64]  E. Jaffe,et al.  Pathological findings in human autoimmune lymphoproliferative syndrome. , 1998, The American journal of pathology.

[65]  R. Arceci,et al.  Correction of autoimmune lymphoproliferative syndrome by bone marrow transplantation , 1998, Bone Marrow Transplantation.

[66]  U. Dianzani,et al.  Deficiency of the Fas apoptosis pathway without Fas gene mutations in pediatric patients with autoimmunity/lymphoproliferation. , 1997, Blood.

[67]  E. Jaffe,et al.  Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. , 1997, Blood.

[68]  K. Sullivan,et al.  Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. , 1996, The New England journal of medicine.

[69]  Warren Strober,et al.  Dominant interfering fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome , 1995, Cell.

[70]  F. Rieux-Laucat,et al.  Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. , 1995, Science.

[71]  S. Nagata,et al.  The Fas death factor , 1995, Science.

[72]  N. Jenkins,et al.  Generalized lymphoproliferative disease in mice, caused by a point mutation in the fas ligand , 1994, Cell.

[73]  Matthew J. Brauer,et al.  Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. , 1994, Science.

[74]  E. Jaffe,et al.  A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. , 1992, The Journal of clinical investigation.

[75]  N. Copeland,et al.  Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis , 1992, Nature.

[76]  J. Janković,et al.  Rapid regression of lymphadenopathy upon rapamycin treatment in a child with autoimmune lymphoproliferative syndrome , 2009, Pediatric blood & cancer.

[77]  A. Chiocchetti,et al.  The broad spectrum of autoimmune lymphoproliferative disease: molecular bases, clinical features and long-term follow-up in 31 patients. , 2006, Haematologica.

[78]  Andreas Mackensen,et al.  Isolation and characterization of human antigen-specific TCR alpha beta+ CD4(-)CD8- double-negative regulatory T cells. , 2005, Blood.

[79]  J. Bleesing.  Autoimmune lymphoproliferative syndrome (ALPS). , 2003, Current pharmaceutical design.

[80]  F Le Deist,et al.  Autoimmune lymphoproliferative syndromes: genetic defects of apoptosis pathways , 2003, Cell Death and Differentiation.

[81]  J. van der Werff Ten Bosch.  Autoimmune lymphoproliferative syndrome: etiology, diagnosis, and management. , 2003, Paediatric drugs.

[82]  T. Fleisher,et al.  A composite picture of TcR alpha/beta(+) CD4(-)CD8(-) T Cells (alpha/beta-DNTCs) in humans with autoimmune lymphoproliferative syndrome. , 2002, Clinical immunology.

[83]  H. Takada,et al.  Dominant expression of interleukin 10 but not interferon gamma in CD4(-)CD8(-)alphabetaT cells of autoimmune lymphoproliferative syndrome. , 2002, British journal of haematology.

[84]  K. Izeradjene,et al.  Mycophenolate mofetil interferes with interferon gamma production in T-cell activation models. , 2001, Transplantation proceedings.

[85]  K. Takahashi,et al.  Primary thrombocytopenic purpura and acquired hemolytic anemia; evidence for a common etiology. , 1951, A.M.A. archives of internal medicine.

[86]  F. Rieux-Laucat,et al.  CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Lymphoproliferative Syndrome With Autoimmunity: A Possible Genetic Basis for Dominant Expression of the Clinical Manifestations , 2022 .