Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Pediatric Drugs
Published in: Pediatric Drugs 3/2003

01-03-2003 | Review Article

Autoimmune Lymphoproliferative Syndrome

Etiology, Diagnosis, and Management

Author: Dr Jutte van der Werff ten Bosch

Published in: Pediatric Drugs | Issue 3/2003

Login to get access

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a childhood disorder characterized by chronic, nonmalignant lymphoproliferation and autoimmunity, most commonly involving cells of hematopoietic origin. Mutations of the tumor necrosis factor receptor super family member 6 (TNFRSF6) gene, coding for the apoptosis-inducing protein Fas (Apo-1, CD95) are involved in the physiopathology of the syndrome, although the complete mechanism by which the syndrome is caused has not yet been unraveled. Although the syndrome has a benign nature, life-threatening complications can demand treatment. Treatment schedules, including corticosteroids, low doses of chemotherapy, granulocyte colony stimulating factor, or splenectomy, have varying results. Treatment with the antimalarial drug pyrimethamine/sulfadoxine (25/500mg per tablet) seems to be a new, well tolerated, and efficient approach, although larger studies will have to demonstrate the true value of this drug in patients with ALPS.
Literature
1.
Trauth BC, Klas C, Peters AM, et al. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 1989; 245: 301–5PubMedCrossRef
2.
Kerr J, Wyllie A, Currie A. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239–57PubMedCrossRef
3.
Jenkins M, Keir M, McCune JM. Fas is expressed early in human thymocyte development but does not transmit an apoptotic signal. J Immunol 1999; 163: 1195–204PubMed
4.
Lowin B, Hahne M, Mattmann C, et al. Cytolytic T-cell cytotoxicity is mediated through perform and Fas lytic pathways. Nature 1994; 370: 650–2PubMedCrossRef
5.
Mogil RJ, Radvanyi L, Gonzalez-Quintial R, et al. Fas (CD95) participates in peripheral T cell deletion and associated apoptosis in vivo. Int Immunol 1995; 7: 1451–8PubMedCrossRef
6.
Dhein J, Walzac H, Baumler C, et al. Autocrine T-cell suicide mediated by APO-l(Fas/CD95). Nature 1995; 373: 438–41PubMedCrossRef
7.
Oehm A, Behrmann I, Falk W, et al. Purification and molecular cloning of the APO-1 cell surface antigen, a member of the TNF/NGF receptor superfamily. J Biol Chem 1992; 15: 10709–15
8.
Ju S, Panka D, Cui H, et al. Fas (CD95)/FasL interaction required for programmed cell death after T cell activation. Nature 1995; 373: 444–8PubMedCrossRef
9.
Garonne P, Neidhardt E, Garcia E, et al. Fas ligation induces apoptosis in CD40-activated human B lymphocytes. J Exp Med 1995; 182: 1265–73CrossRef
10.
Dhein J, Daniel P, Trauth B, et al. Induction of apoptosis by monoclonal antibody anti-APO-1 class switch variants is dependent on cross-linking of APO-1 cell surface antigens. J Immunol 1992; 149: 3166–73PubMed
11.
Kischkel F, Hellbardt S, Behrmann I, et al. Cytotoxicity-dependent APO-1 (FAS/CD95) associated proteins form a death-inducing signal complex (DISC) with the receptor. EMBO J 1995; 4: 5579–88
12.
Itoh N, Nagata S. A novel protein domain required for apoptosis-mutational analysis of human Fas antigen. J Biol Chem 1993; 268: 10932–7PubMed
13.
Wang J, Chun HJ, Wong W, et al. Caspase-10 is an initiator caspase in death receptor signaling. Proc Natl Acad Sci USA 2001; 98: 13884–8PubMedCrossRef
14.
15.
Zheng T, Schlosser S, Dao T, et al. Caspase-3 controls both cytoplasmatic and nuclear events associated with Fas-mediated apoptosis in vivo. Proc Natl Acad Sci USA 1998; 95: 13618–23PubMedCrossRef
16.
Andrews B, Eisenberg R, Theofilopoulos A, et al. Spontanous murine lupus-like syndromes: clinical and immunopathological manifestations in several strains. J Exp Med 1978; 166: 1198–203CrossRef
17.
Watanabe-Fukunaga R, Brannan C, Copeland N, et al. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 1992; 356: 314–7PubMedCrossRef
18.
Takahashi T, Tanaka M, Brannan C, et al. Generalized lymphoproliferative disease in mice caused by a point mutation in the Fas ligand. Cell 1994; 76: 969–76PubMedCrossRef
19.
Sneller C, Straus S, Jaffe E, et al. A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Invest 1992; 90: 334–41PubMedCrossRef
20.
Fisher G, Rosenberg F, Straus S, et al. Dominant interfering fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995; 81: 935–46PubMedCrossRef
21.
Rieux-Laucat F, Le Deist F, Hivroz C, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 1995; 268: 1347–9PubMedCrossRef
22.
Canale VC, Smith CH. Chronic lymphadenopathy simulating malignant lymphoma. J Pediatrics 1967; 70: 891–9CrossRef
23.
Weisdorf SA, Krivit W. Paucity of splenic germinal centers: a new and unique splenomegaly syndrome including dysfunctional immune system. Clin Immunol Immunopathol 1982; 23: 492–500PubMedCrossRef
24.
Horowitz SD, Borcherding W, Hong R. Autoimmune hemolytic anemia as a manifestation of T-suppressor-cell deficiency. Clin Immunol Immunopathol 1984; 33: 313–23PubMedCrossRef
25.
McKinley RA, Kwan YL, Lam-Po-Tang PR. Familial splenomegaly syndrome with reduced circulating T helper cells and splenic germinal centre hypoplasia. Br J Haematol 1987; 67: 393–6PubMedCrossRef
26.
Drappa J, Vaishnaw AK, Sullivan KE, et al. Fas gene mutation in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med 1996; 335: 1643–9PubMedCrossRef
27.
Straus SE, Sneller M, Lenardo MJ, et al. An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med 1999; 130: 591–601PubMed
28.
Dianzani U, Bragardo M, DiFranco D, et al. Deficiency of Fas apoptosis pathway without fas gene mutations in pediatric patients with autoimmunity/lymphoproliferation. Blood 1997; 89: 2871–9PubMed
29.
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: 47–58PubMedCrossRef
30.
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: 395–9PubMedCrossRef
31.
Wu J, Wilson J, He J, et al. Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J Clin Invest 1996; 98: 1107–13PubMedCrossRef
32.
Jackson P, Puck J. Autoimmune lymphoproliferative syndrome, a disorder of apoptosis. Curr Opin Pediatr 1999; 11: 521–7PubMedCrossRef
33.
Pensati L, Costanzo A, Ianni A, et al. Fas/Apol mutations and autoimmune lymphoproliferative syndrome in a patient with type 2 autoimmune hepatitis. Gastroenterology 1997; 113: 1384–9PubMedCrossRef
34.
Sneller M, Wang Y, Dale J, et al. Clinical, immunologic and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood 1997; 89: 1341–8PubMed
35.
Bettinardi A, Brugnoni D, Quiros-Roldan E, et al. Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. Blood 1997; 89: 902–9PubMed
36.
Kasahara Y, Wada T, Niida Y, et al. Novel Fas (CD95/APO-1) mutations in infants with a lymphoproliferative disorder. Int Immunol 1998; 10: 195–202PubMedCrossRef
37.
van der Werff ten Bosch J, Demanet C, Balduck N, et al. The use of the anti malaria drug Fansidar (pyrimethamine and sulfadoxine) in the treatment of a patient with autoimmune lymphoproliferative syndrome and Fas deficiency. Br J Haematol 1998; 102: 578–81PubMedCrossRef
38.
Sleight B, Prasad V, DeLaat C, et al. Correction of autoimmune lymphoproliferative syndrome by bone marrow transplantation. Bone Marrow Transplant 1998; 22: 375–80PubMedCrossRef
39.
Peters A, Kohfink B, Martin H, et al. Defective apoptosis due to a point mutation in the death domain of CD95 associated with autoimmune lymphoproliferative syndrome, T-cell lymphoma, and Hodgkin’s disease. Exp Hematol 1999; 27: 868–74PubMedCrossRef
40.
Rieux-Laucat F, Blachere S, Danielan S, et al. Lymphoproliferative syndrome with autoimmunity: a possible genetic basis for dominant interfering expression of the clinical phenotype. Blood 1999; 94: 2575–82PubMed
41.
Aspinall Al, Pinto A, Auer IA, et al. Identification of new Fas mutations in a patient with autoimmune lymphoproliferative syndrome (ALPS) and eosinophilia. Blood Cells Mol Dis 1999; 25: 227–38PubMedCrossRef
42.
Shenoy S, Arnold S, Chatila T. Response to steroid therapy in autism secondary to autoimmune lymphoproliferative syndrome. J Pediatr 2000; 136: 682–7PubMedCrossRef
43.
Bader-Meunier B, Rieux-Laucat F, Croisille L, et al. Dyserythropoiesis associated with a Fas-deficient condition in childhood. Br J Haematol 2000; 108: 300–4PubMedCrossRef
44.
Fang BS, Sneller MC, Straus SE, et al. Report of a factor VIII inhibitor in a patient with autoimmune lymphoproliferative syndrome. Am J Hematol 2000; 64: 214–7PubMedCrossRef
45.
van der Burg M, de Groot R, Comans-Bitter W, et al. Autoimmune lymphoproliferative syndrome (ALPS) in a child from cosanguineous parents: a dominant or recessive disease. Pediatr Res 2000; 47: 336–43PubMedCrossRef
46.
Hanlon MG, Gacis ML, Kakakios AM, et al. Investigation of suspected deficient Fas-mediated apoptosis in a father and son. Cytometry 2001; 43: 195–8PubMedCrossRef
47.
van den Berg A, Maggio E, Diepstra A, et al. Germline FAS gene mutation in a case of ALPS and NLP Hodgkin lymphoma. Blood 2002; 99: 1492–4PubMedCrossRef
48.
van der Werff ten Bosch J, Schotte P, Ferster A, et al. Reversion of autoimmune lymphoproliferative syndrome with an antimalarial drug: preliminary results of a clinical cohort study and molecular observations. Br J Haematol 2002; 117: 176–88PubMedCrossRef
49.
Strobel P, Nanan R, Gattenlohner S, et al. Reversible monoclonal lymphadenopathy in autoimmune lymphoproliferative syndrome with functional FAS (CD95/APO-1) deficiency. Am J Surg Pathol 1999; 23: 829–37PubMedCrossRef
50.
Ramenghi U, Bonissoni S, Migliaretti G, et al. Deficiency of the fas apoptosis pathway without fas gene mutations is a familial trait predisposing to development of autoimmune diseases and cancer. Blood 2000; 95: 3176–82PubMed
51.
van der Werff ten Bosch J, Otten J, Thielemans K. Autoimmune lymphoproliferative syndrome type III: an indefinite disorder. Leuk Lymphoma 2001; 41: 55–65CrossRef
52.
Boehler T, Posovszky C, Fulda S, et al. Defective CD95-induced apoptosis in children with autoimmune lymphoproliferative syndrome (ALPS)/Canale-Smith syndrome (CSS) in the absence of CD95 mutations [abstract]. Blood 1999; 94 (Suppl. 1 Pt 2): 50B
53.
Posovszky C, Scheuerpflug C, Fuchs H, et al. CD95-death-inducing signaling complex formation in autoimmune lymphoproliferative syndrome/Canale-Smith syndrome (ALPS/CSS). Eur J Pediatr 2001; 160: R17–28CrossRef
54.
Le Deist F, Emile J, Rieux-Laucat F, et al. Clinical, immunological and pathological consequenses of Fas-deficient condition. Lancet 1996; 348: 719–23PubMedCrossRef
55.
van der Werff ten Bosch J, Delabie J, Bohler T, et al. Revision of the diagnosis of T-zone lymphoma in the father of a patient with autoimmune lymphoproliferative syndrome type II. Br J Haematol 1999; 106: 1045–8PubMedCrossRef
56.
Bleesing JJ, Straus SE, Fleisher TA. Autoimmune lymphoproliferative syndrome: a human disorder of abnormal lymphocyte survival. Pediatr Clin North Am 2000; 47: 1291–310PubMedCrossRef
57.
Carter LB, Procter JL, Dale JK, et al. Description of serologic features in autoimmune lymphoproliferative syndrome. Transfusion 2000; 40: 943–8PubMedCrossRef
58.
Fuss I, Strober W, Dale J, et al. Characteristic T helper 2 cell cytokine abnormalities in autoimmune lymphoproliferative syndrome, a syndrome marked by defective apoptosis and humoral autoimmunity. J Immunol 1997; 158: 1912–8PubMed
59.
Lim M, Straus S, Dale J, et al. Pathological findings in human autoimmune lymphoproliferative syndrome. Am J Pathol 1998; 153: 1541–50PubMedCrossRef
60.
Infante A, Britton H, DeNapoli T, et al. The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs apoptosis. J Pediatr 1998; 133: 629–33PubMedCrossRef
61.
Bleesing JJ, Brown MR, Straus SE, et al. Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome. Blood 2001; 98: 2466–73PubMedCrossRef
62.
Boulanger E, Rieux-Laucat F, Picard C, et al. Diffuse large B-cell non-Hodgkin’s lymphoma in a patient with autoimmune lymphoproliferative syndrome. Br J Haematol 2001; 113: 432–4PubMedCrossRef
63.
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: 194–200PubMedCrossRef
64.
65.
Jackson CE, Fischer RE, Hsu AP, et al. Autoimmune lymphoproliferative syndrome with defective Fas:genotype influence penetrance. Am J Hum Genet 1999; 64: 1002–14PubMedCrossRef
66.
Benkerrou M, Le Deist F, Villartay J, et al. Correction of Fas (CD95) deficiency by haploidentical bone marrow transplantation. Eur J Immunol 1997; 27: 2043–7PubMedCrossRef
67.
Scaffidi C, Kirchhoff S, Krammer PH, et al. Apoptosis signaling in lymphocytes. Curr Opin Immunol 1999; 11: 277–85PubMedCrossRef
68.
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: 3161–70PubMedCrossRef
69.
Avila N, Dwyer A, Dale J, et al. Autoimmune lymphoproliferative syndrome: a syndrome associated with inherited genetic defects that impair lymphocytic apoptosis: CT and US features. Radiology 1999; 212: 257–63PubMed
70.
Bleesing JJ, Brown MR, Dale JK, 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. Clin Immunol 2001; 100: 314–24PubMedCrossRef
Metadata
Title
Autoimmune Lymphoproliferative Syndrome
Etiology, Diagnosis, and Management
Author
Dr Jutte van der Werff ten Bosch
Publication date
01-03-2003
Publisher
Springer International Publishing
Published in
Pediatric Drugs / Issue 3/2003
Print ISSN: 1174-5878
Electronic ISSN: 1179-2019
DOI
https://doi.org/10.2165/00128072-200305030-00005

Other articles of this Issue 3/2003

Pediatric Drugs 3/2003 Go to the issue

Therapy In Practice

Antithrombotic Drug Treatment of Pediatric Patients with Ischemic Stroke

Review Article

Treatment of Apnea of Prematurity

Current Opinion

Congenital Hypothyroidism

Therapy In Practice

Strategies for Optimizing Immunosuppression in Adolescent Transplant Recipients

Therapy In Practice

Treatment of Infectious Diarrhea in Children