Összefoglaló. Az autoimmun lymphoproliferativ szindróma egy ritka, immundeficientiával járó genetikai betegség. Hátterében az extrinszik apoptotikus útvonal génjeinek örökletes vagy szerzett mutációi és a következményesen kialakuló, aktivált lymphocyták negatív szelekciójának a defektusa áll. Az autoimmun lymphoproliferativ szindróma klinikai megjelenésére jellemző a jóindulatú lymphocytaburjánzás következtében kialakuló lymphadenopathia és lépmegnagyobbodás. Gyakran társul olyan autoimmun kórképekkel, mint az autoimmun haemolyticus anaemia vagy az autoimmun thrombocytopenia. A betegségben jellemző laboratóriumi eltérések a következők: az αβ+ CD4–/CD8– kettős negatív T-sejtek szaporulata, a szolúbilis Fas-ligand, az interleukin-10 és interleukin-18, valamint a B12-vitamin szérumszintjének emelkedése. A kórkép diagnózisához hozzátartozik az in vitro Fas-mediált apoptózis funkciójának vizsgálata, valamint a genetikai vizsgálat. Differenciáldiagnosztikai szempontból fontos elkülöníteni a lymphomáktól, valamint az autoimmun lymphoproliferativ szindrómaszerű betegségektől. A kezelés alapja a társuló autoimmun kórképek tüneteinek csökkentése immunszuppresszív terápiával. Orv Hetil. 2022; 163(4): 123–131.
Summary. The autoimmune lymphoproliferative syndrome is a rare genetic disorder causing immunodeficiency. In the background of the disease, germline or somatic mutations of genes participating in the extrinsic apoptotic pathway and the consequential defect in the negative selection of activated lymphocytes were discovered. The clinical appearance of autoimmune lymphoproliferative syndrome consists of non-malignant lymphoproliferation, lymphadenopathy and splenomegaly, it is frequently accompanied by autoimmune disorders such as autoimmune haemolytic anaemia or autoimmune thrombocytopenia. The main diagnostic laboratory findings of this disease are the following: an elevation in αβ+, CD4–/CD8– double-negative T cell count, elevated serum levels of soluble Fas-ligand, interleukin-10, interleukin-18 and vitamin B12. Other useful laboratory tests are the in vitro Fas-mediated apoptotic functional assay and the genetic screening for gene mutations. Differential diagnosis should exclude malignant lymphoproliferation in lymphomas and non-malignant autoimmune lymphoprolipherative syndrome-like diseases. The main aim of the treatment is the amelioration of the accompanying autoimmune disease with immunosuppressive therapy. Orv Hetil. 2022; 163(4): 123–131.
Bleesing JJ. Autoimmune lymphoproliferative syndrome: a genetic disorder of abnormal lymphocyte apoptosis. Immunol Allergy Clin. 2002; 22: 339–355.
Jackson CE, Puck JM. Autoimmune lymphoproliferative syndrome, a disorder of apoptosis. Curr Opin Pediatr. 1999; 11: 521–527.
European Society for Immunodeficiencies. Working party. Registry working party. Diagnosis criteria. Geneva, 2020. Available from: https://esid.org/Working-Parties/Registry-Working-Party/Diagnosis-criteria [accessed: Jun 17, 2021].
Bleesing JJ, Janik JE, Fleisher TA. Common expression of an unusual CD45 isoform on T cells from patients with large granular lymphocyte leukaemia and autoimmune lymphoproliferative syndrome. Br J Haematol. 2003; 120: 93–96.
Straus SE, Sneller M, Lenardo MJ, et al. An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med. 1999; 130: 591–601.
Sneller MC, Wang J, Dale JK, et al. Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood 1997; 89: 1341–1348.
Teachey DT, Seif AE, Grupp SA. Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). Br J Haematol. 2010; 148: 205–216.
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: 194–200.
Capsoni F, Sarzi-Puttini P, Zanella A. Primary and secondary autoimmune neutropenia. Arthritis Res Ther. 2005; 7: 208–214.
Volpe E, Sambucci M, Battistini L, et al. Fas-fas ligand: checkpoint of T cell functions in multiple sclerosis. Front Immunol. 2016; 7: 382.
Tanaka M, Suda T, Takahashi T, et al. Expression of the functional soluble form of human Fas ligand in activated lymphocytes. EMBO J. 1995; 14: 1129–1135.
Kayagaki N, Kawasaki A, Ebata T, et al. Metalloproteinase-mediated release of human Fas ligand. J Exp Med. 1995; 182: 1777–1783.
Wachmann K, Pop C, van Raam BJ, et al. Activation and specificity of human caspase-10. Biochemistry 2010; 49: 8307–8315.
Matson DR, Yang DT. Autoimmune lymphoproliferative syndrome: an overview. Arch Pathol Lab Med. 2020; 144: 245–251.
Castro JE, Listman JA, Jacobson BA, et al. Fas modulation of apoptosis during negative selection of thymocytes. Immunity 1996; 5: 617–627.
Kohn LA, Long JD, Trope EC, et al. Novel compound heterozygote variations in FADD identified to cause FAS-associated protein with death domain deficiency. J Clin Immunol. 2020; 40: 658–661.
Salmena L, Hakem R. Caspase-8 deficiency in T cells leads to a lethal lymphoinfiltrative immune disorder. J Exp Med. 2005; 202: 727–732.
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: e35–e40.
Rieux-Laucat F, Le Deist F, Fischer A. Autoimmune lymphoproliferative syndromes: genetic defects of apoptosis pathways. Cell Death Differ. 2003; 10: 124–133.
Molnár E, Radwan N, Kovács G, et al. Key diagnostic markers for autoimmune lymphoproliferative syndrome with molecular genetic diagnosis. Blood 2020; 136: 1933–1945.
Rieux-Laucat F, Le Deist F, Hivroz C, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 1995; 268: 1347–1349.
Jackson CE, Fischer RE, Hsu AP, et al. Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. Am J Hum Genet. 1999; 64: 1002–1014.
Holzelova E, Vonarbourg C, Stolzenberg MC, et al. Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med. 2004; 351: 1409–1418.
Dowdell KC, Niemela JE, Price S, et al. Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome. Blood 2010; 115: 5164–5169.
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: 336–343.
Takagi M, Hoshino A, Yoshida K, et al. Genetic heterogeneity of uncharacterized childhood autoimmune diseases with lymphoproliferation. Pediatr Blood Cancer 2018; 65: e26831.
Le Deist F, Emile JF, Rieux-Laucat F, et al. Clinical, immunological, and pathological consequences of Fas-deficient conditions. Lancet 1996; 348: 719–723.
Bettinardi A, Brugnoni D, Quiròs-Roldan E, et al. Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. Blood 1997; 89: 902–909.
Kasahara Y, Wada T, Niida Y, et al. Novel Fas (CD95/APO-1) mutations in infants with a lymphoproliferative disorder. Int Immunol. 1998; 10: 195–202.
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: 486–490.
Sneller MC, Straus SE, Jaffe ES, et al. A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Investig. 1992; 90: 334–341.
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: 851–860.
Swerdlow SH, Campo E, Harris NL, et al. (eds.) WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th edition. International Agency for Research on Cancer (IARC), Lyon, 2017.
Bowen RA, Dowdell KC, Dale JK, et al. Elevated vitamin B12 levels in autoimmune lymphoproliferative syndrome attributable to elevated haptocorrin in lymphocytes. Clin Biochem. 2012; 45: 490–492.
Seif A, Manno C, Grupp S, et al. Testing patients with Evans syndrome for the autoimmune lymphoproliferative syndrome (ALPS): results of a large multi-institutional clinical trial (ASPHO supplement). Pediatr Blood Cancer 2008; 50: S22–S23.
Charbonnier LM, Janssen E, Chou J, et al. Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J Allergy Clin Immunol. 2015; 135: 217–227.
Bousfiha A, Jeddane L, Picard C, et al. The 2017 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol. 2018; 38: 129–143.
Schubert D, Bode C, Kenefeck R, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014; 20: 1410–1416.
Kuehn HS, Ouyang W, Lo B, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 2014; 345: 1623–1627.
Milner JD, Vogel TP, Forbes L, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood 2015; 125: 591–599.
Snow AL, Xiao W, Stinson JR, et al. Congenital B cell lymphocytosis explained by novel germline CARD11 mutations. J Exp Med. 2012; 209: 2247–2261.
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: 2753–2758.
Niemela JE, Lu L, Fleisher TA, et al. Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis. Blood 2011; 117: 2883–2886.
Takagi M, Shinoda K, Piao J, et al. Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation. Blood 2011; 117: 2887–2890.
Lanzarotti N, Bruneau J, Trinquand A, et al. RAS-associated lymphoproliferative disease evolves into severe juvenile myelo-monocytic leukemia. Blood 2014; 123: 1960–1963.
Rieux-Laucat F. What’s up in the ALPS. Curr Opin Immunol. 2017; 49: 79–86.
Kossiva L, Theodoridou M, Mostrou G, et al. Mycophenolate mofetil as an alternate immunosuppressor for autoimmune lymphoproliferative syndrome. J Pediatr Hematol Oncol. 2006; 28: 824–826.
Price S, Shaw PA, Seitz A, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood 2014; 123: 1989–1999.