Клинико-лабораторные особенности пациентов с аутоиммунным лимфопролиферативным синдромом

Статья в Elpub

Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2017; 16: 27-34

Клинико-лабораторные особенности пациентов с аутоиммунным лимфопролиферативным синдромом

Швец О.А. , Дерипапа Е.В. , Захарова В.В. , Абрамов Д.С. , Деордиева Е.А. , Викторова Е.А. , Абрамова И.Н. , Родина Ю.А. , Шрагина О.А. , Байдильдина Д.Д. , Калинина И.И. , Петрова У.Н. , Райкина Е.В. , Коновалов Д.М. , Пшонкин А.В. , Масчан М.А. , Щербина А.Ю.

https://doi.org/10.24287/1726-1708-2017-16-4-27-34

Аннотация

Аутоиммунный лимфопролиферативный синдром (АЛПС) характеризуется нарушением лимфоцитарного гомеостаза вследствие дефекта Fas-опосредованного апоптоза с развитием лимфопролиферативного синдрома, аутоиммунных проявлений, повышением дубль-негативных /+-Т-клеток (ДНТ) и концентрации витамина B12 в сыворотке крови, гипергаммаглобулинемией. В данном исследовании обследованы 22 пациента с диагнозом "АЛПС", а также восемь бессимптомных родственников пациентов - носителей соответствующих мутаций. Тринадцать пациентов имели разнообразные мутации гена Fas; двое - одинаковую мутацию Casp10; у семи пациентов причинных мутаций не выявлено. Симптомы заболевания чаще включали сочетание гемопатии и лимфопролиферативного синдрома (n = 17); повышение биомаркеров: ДНТ (медиана - 8,9%) - у 19 пациентов, инициальное содержание B12 более 1500 нг/мл - у 13 пациентов, его концентрация коррелировала также со степенью тяжести заболевания, в большей степени - с лимфопролиферацией, что может быть использовано как критерий тяжести заболевания. В связи с гетерогенностью проявлений АЛПС при обследовании пациентов и их родственников, помимо стандартных критериев, важна молекулярно-генетическая диагностика.

Список литературы

1. Sneller M.C., Wang J., Dale J.K., Strober W., Middelton L.A., Choi Y., et al. Clinical, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood 1997; 89 (4): 1341-8.

2. Straus S.E., Sneller M., Lenardo M.J., Puck J.M., Strober W. An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med 1999; 130 (7): 591-601.

3. Bedere N., Su H.C., Lenardo M.J. Genetic disorder of programmed cell death in the immune system. Ann Rev Immunol 2006; 24: 321-52.

4. Worth A., Trasher A.J., Gaspar H.B. Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Br J Hematol 2006; 133: 124-40.

5. Holzelova E., Vonarbourg C., Stolzenberg M.C., Arkwright P.D., Selz F., Prieur A.M., et al. Autoimmune lymphoproliferative syndrome (ALPS) with somatic Fas mutations. N Engl J Med 2004; 351: 1409-18.

6. Dowdell K.C., Niemela J.E., Price S., Davis J., Hornung R.L., Oliveira J.B., et al. Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome. Blood 2010; 115 (25): 5164-9.

7. Magerus-Chatinet A., Neven B., Stolzenberg M.C., Daussy C., Arkwright P.D., Lanzarotti N., et al. Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defects accumulation. J Clin Invest 2011; 121: 106-12.

8. Agrebi N., Ben-Mustapha I., Matoussi N., Dhouib N., Ben-Ali M., Mekki N., et al. Rare splicing defects of FAS underly severe recessive autoimmune lymphoproliferative syndrome. Clin Immunol 2017; 183: 17-23.

9. Oliveira J.B., Bleesing J.J., Dianzani U., Fleisher T.A., Jaffe E.S., Lenardo M.J., 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.

10. Li P., Huang P., Yang Y., Hao M., Peng H., Li F. Updated Understanding of Autoimmune Lymphoproliferative Syndrome (ALPS). Clin Rev Allergy Immunol 2016; 50 (1): 55-63.

11. Canale V.C., Smith C.H. Chronic lymphadenopathy simulating malignant lymphoma. J Pediatr1967; 70: 891-9.

12. ESID Registry - Working Definitions for Clinical Diagnosis of PID. Available at: http://esid.org/WorkingParties/Registry/Diagnosiscriteria.

13. Швец О.А., Щербина А.Ю. Аутоиммун-ный лимфопролиферативный синдром. Вопросы гематологии/онкологии и иммунопатологии в педиатрии 2016; 15 (1): 34-40.

14. Fisher G.H., Rosenberg F.J., Straus S.E., et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995; 81 (6): 935-46.

15. Martin D.A., Zheng L., Siegel R.M., et al. Defective CD95/APO-1/Fas signaling complex formation in the human autoiimune lymphoproliferative syndrome, tipe Ia. Proc Natl Acad Sci USA 1999; 96 (8): 4552-7.

16. Price S., Shaw P.A., Seitz A., Joshi G., Davis J., Niemela J.E., et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood 2014; 123 (13): 1989-99.

17. Gualco G., van den Berg A., Koopmans S., Bacchi L.M., Carneiro S.S., Ruiz E.Jr., Vecchi A.P., Chan J.K. Autoimmune lymphoproliferative syndrome in a patient with a new minimal deletion in the death domen of the FAS gene. Hum Pathol 2008; 39 (1): 137-41.

18. Bi L.L., Pan G., Atkinson T.P., Zheng L., Dale J.K., Makris C., et al. Dominant inhibition of Fas-ligand mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) Type Ib. BMC Med Genet 2007; 8: 41.

19. Wu J., Wilson J., He J., Xiang L., Schur P.H., Mountz J.D. Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J Clin Invest 1996; 98: 1107-13.

20. Bowen R.A., Dowdell K.C., Dale J.K., Drake S.K., Fleisher T.A., Hortin G.L., et al. Elevated vitamin B₁₂ levels in autoimmune lymphoproliferative syndrome attributable to elevated haptocorrin in lymphocytes. Clin Biochem 2012; 45 (6): 490-2.

21. Neven B., Bruneau J., Stolzenberg M.C., Meyts I., MagerusChatinet A., Moens L., et al. Defective antipolysaccharide response and splenic marginal zone disorganization in ALPS patients. Blood 2014; 124 (10): 1597-609.

22. Infante A.J., Britton H.A., DeNapoli T., Middelton L.A., Lenardo M.J., Jackson C.E., et al. The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis. J Pediatr 1998; 133 (5): 629-33.

23. Jackson C.E., Fischer R.E., Hsu A.P., Anderson S.M., Choi Y., Wang J., et al. Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. Am J Hum Genet 1999; 64 (4): 1002-14.

24. RieuxLaucat F. Inherited and acquired death receptor defects in human autoimmune lymphoproliferative syndrome. Curr Dir Autoimmun 2006; 9: 18-36.

25. RieuxLaucat F., Blachère S., Danielan S., De Villartay J.P., Oleastro M., Solary E., et al. Lymphoproliferative syndrome with autoimmunity: a possible genetic basis for dominant expression of the clinical manifestations. Blood 1999; 94 (8): 2575-82.

26. Neven B., Magerus-Chatinet A., Florkin B., Gobert D., Lambotte O., De Somer L., et al. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood 2011; 118: 4798-807.

27. Lambotte O., Neven B., Galicier L., Magerus-Chatinet A., Schleinitz N., Hermine O., et al. Diagnosis of autoimmune lymphoproliferative syndrome caused by FAS deficiency in adults. Haematologica 2013; 98 (3): 389-92.

Pediatric Hematology/Oncology and Immunopathology. 2017; 16: 27-34

Clinical and laboratory characteristics of a group of patients with autoimmune lymphoproliferative syndrome

Shvetz O. A., Deripapa E. V., Zakharova V. V., Abramov D. S., Deordieva E. A., Victorova E. A., Abramova I. N., Rodina Yu. A., Shragina O. A., Baildildina D. D., Kalinina I. I., Petrova Y. N., Raikina E. V., Konovalov D. M., Pshonkin A. V., Machan M. A., Shcherbina A. Yu.

https://doi.org/10.24287/1726-1708-2017-16-4-27-34

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by abnormal lymphocyte homeostasis due to the defect of Fas-mediated apoptosis. Symptoms include lymphoproliferation, autoimmune complications, increased double-negative α/β+-Т cells (DNT) and vitamin B12 concentration and hypergammaglobulinemia. The study group included 22 patients with ALPS, and eight symptoms-free relatives who carried respective mutations. Thirteen patients had various Fas gene mutations, two – the same mutation of Casp10, in seven patients genetic defect has not been found. Symptoms included combination of cytopenia and lymphoproliferation (n = 17), increased biomarkers: high DNT (Ме = 8,9%) were found in 19 patients, high B12 levels – in 13 patients. B12 level correlated with disease severity, predominantly with lymphoproliferation, which can be used as a marker of disease severity. Due to the heterogeneous nature of ALPS symptoms molecular genetic test play an important role in diagnostic testing of the patients and their relatives.

References

2. Straus S.E., Sneller M., Lenardo M.J., Puck J.M., Strober W. An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med 1999; 130 (7): 591-601.

3. Bedere N., Su H.C., Lenardo M.J. Genetic disorder of programmed cell death in the immune system. Ann Rev Immunol 2006; 24: 321-52.

4. Worth A., Trasher A.J., Gaspar H.B. Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Br J Hematol 2006; 133: 124-40.

10. Li P., Huang P., Yang Y., Hao M., Peng H., Li F. Updated Understanding of Autoimmune Lymphoproliferative Syndrome (ALPS). Clin Rev Allergy Immunol 2016; 50 (1): 55-63.

11. Canale V.C., Smith C.H. Chronic lymphadenopathy simulating malignant lymphoma. J Pediatr1967; 70: 891-9.

12. ESID Registry - Working Definitions for Clinical Diagnosis of PID. Available at: http://esid.org/WorkingParties/Registry/Diagnosiscriteria.

13. Shvets O.A., Shcherbina A.Yu. Autoimmun-nyi limfoproliferativnyi sindrom. Voprosy gematologii/onkologii i immunopatologii v pediatrii 2016; 15 (1): 34-40.

14. Fisher G.H., Rosenberg F.J., Straus S.E., et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995; 81 (6): 935-46.

19. Wu J., Wilson J., He J., Xiang L., Schur P.H., Mountz J.D. Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J Clin Invest 1996; 98: 1107-13.

24. RieuxLaucat F. Inherited and acquired death receptor defects in human autoimmune lymphoproliferative syndrome. Curr Dir Autoimmun 2006; 9: 18-36.