Progressive Depletion of B and T Lymphocytes in Patients with Ataxia Telangiectasia: Results of the Italian Primary Immunodeficiency Network.
Ataxia telangiectasia
B lymphocytes
T lymphocytes
genotype
lymphopenia
primary immunodeficiency
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
received:
27
09
2021
accepted:
20
02
2022
pubmed:
9
3
2022
medline:
9
6
2022
entrez:
8
3
2022
Statut:
ppublish
Résumé
Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated (ATM) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype-phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects.
Identifiants
pubmed: 35257272
doi: 10.1007/s10875-022-01234-4
pii: 10.1007/s10875-022-01234-4
pmc: PMC9166859
doi:
Substances chimiques
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
783-797Informations de copyright
© 2022. The Author(s).
Références
Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis. 2016;11(1):159. https://doi.org/10.1186/s13023-016-0543-7 .
doi: 10.1186/s13023-016-0543-7
pubmed: 27884168
pmcid: 5123280
Amirifar P, Ranjouri MR, Yazdani R, Abolhassani H, Aghamohammadi A. Ataxia-telangiectasia: a review of clinical features and molecular pathology. Pediatr Allergy Immunol. 2019;30(3):277–88. https://doi.org/10.1111/pai.13020 .
doi: 10.1111/pai.13020
pubmed: 30685876
Rotman G, Shiloh Y. ATM: from gene to function. Hum Mol Genet. 1998;7(10):1555–63. https://doi.org/10.1093/hmg/7.10.1555 .
doi: 10.1093/hmg/7.10.1555
pubmed: 9735376
Chessa L, Piane M, Magliozzi M, Torrente I, Savio C, Lulli P, et al. Founder effects for ATM gene mutations in Italian ataxia telangiectasia families. Ann Hum Genet. 2009;73(Pt 5):532–9. https://doi.org/10.1111/j.1469-1809.2009.00535.x .
doi: 10.1111/j.1469-1809.2009.00535.x
pubmed: 19691550
Driessen GJ, Ijspeert H, Weemaes CM, Haraldsson Á, Trip M, Warris A, et al. Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity. J Allergy Clin Immunol. 2013;131(5):1367-75.e9. https://doi.org/10.1016/j.jaci.2013.01.053 .
doi: 10.1016/j.jaci.2013.01.053
pubmed: 23566627
Guleria A, Chandna S. ATM kinase: Much more than a DNA damage responsive protein. DNA Repair (Amst). 2016;39:1–20. https://doi.org/10.1016/j.dnarep.2015.12.009 .
doi: 10.1016/j.dnarep.2015.12.009
Levy A, Lang AE. Ataxia-telangiectasia: a review of movement disorders, clinical features, and genotype correlations. Mov Disord. 2018;33(8):1238–47. https://doi.org/10.1002/mds.27319 .
doi: 10.1002/mds.27319
pubmed: 29436738
Reina-San-Martin B, Chen HT, Nussenzweig A, Nussenzweig MC. ATM is required for efficient recombination between immunoglobulin switch regions. J Exp Med. 2004;200(9):1103–10. https://doi.org/10.1084/jem.20041162 .
doi: 10.1084/jem.20041162
pubmed: 15520243
pmcid: 2211855
Chun HH, Gatti RA. Ataxia-telangiectasia, an evolving phenotype. DNA Repair (Amst). 2004;3(8–9):1187–96. https://doi.org/10.1016/j.dnarep.2004.04.010 .
doi: 10.1016/j.dnarep.2004.04.010
Jackson TJ, Chow G, Suri M, Byrd P, Taylor MR, Whitehouse WP. Longitudinal analysis of the neurological features of ataxia-telangiectasia. Dev Med Child Neurol. 2016;58(7):690–7. https://doi.org/10.1111/dmcn.13052 .
doi: 10.1111/dmcn.13052
pubmed: 26896183
Cirillo E, Del Giudice E, Micheli R, Cappellari AM, Soresina A, Dellepiane RM, et al. Minimum effective betamethasone dosage on the neurological phenotype in patients with ataxia-telangiectasia: a multicenter observer-blind study. Eur J Neurol. 2018;25(6):833–40. https://doi.org/10.1111/ene.13606 .
doi: 10.1111/ene.13606
pubmed: 29489040
Prencipe R, Cirillo E, Giardino G, Gallo V, Menotta M, Magnani M, et al. In ataxia-telangiectasia, oral betamethasone administration ameliorates lymphocytes functionality through modulation of the IL-7/IL-7Rα axis paralleling the neurological behavior: a comparative report of two cases. Immunol Invest. 2021;50(2–3):295–303. https://doi.org/10.1080/08820139.2020.1761379 .
doi: 10.1080/08820139.2020.1761379
pubmed: 32397775
Notarangelo L, Casanova JL, Fischer A, Puck J, Rosen F, Seger R, et al. Primary immunodeficiency diseases: an update. J Allergy Clin Immunol. 2004;114(3):677–87. https://doi.org/10.1016/j.jaci.2004.06.044 .
doi: 10.1016/j.jaci.2004.06.044
pubmed: 15356576
Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. J Clin Immunol. 2018;38(1):96–128. https://doi.org/10.1007/s10875-017-0464-9 .
doi: 10.1007/s10875-017-0464-9
pubmed: 29226302
Abinun M, Albert M, Beaussant Cohen S, Buckland M, Bustamante J, Cant A, et al. ESID Registry — working definitions for clinical diagnosis of IEI. 2019:1–205.
Schatorjé EJ, Gemen EF, Driessen GJ, Leuvenink J, van Hout RW, de Vries E. Paediatric reference values for the peripheral T cell compartment. Scand J Immunol. 2012;75(4):436–44. https://doi.org/10.1111/j.1365-3083.2012.02671.x .
doi: 10.1111/j.1365-3083.2012.02671.x
pubmed: 22420532
Yel L. Selective IgA deficiency. J Clin Immunol. 2010;30(1):10–6. https://doi.org/10.1007/s10875-009-9357-x .
doi: 10.1007/s10875-009-9357-x
pubmed: 20101521
pmcid: 2821513
Schroeder SA, Zielen S. Infections of the respiratory system in patients with ataxia-telangiectasia. Pediatr Pulmonol. 2014;49(4):389–99. https://doi.org/10.1002/ppul.22817 .
doi: 10.1002/ppul.22817
pubmed: 23761391
van Os NJH, Haaxma CA, van der Flier M, Merkus P, van Deuren M, de Groot IJM, et al. Ataxia-telangiectasia: recommendations for multidisciplinary treatment. Dev Med Child Neurol. 2017;59(7):680–9. https://doi.org/10.1111/dmcn.13424 .
doi: 10.1111/dmcn.13424
pubmed: 28318010
Russo I, Cosentino C, Del Giudice E, Broccoletti T, Amorosi S, Cirillo E, et al. In ataxia-teleangiectasia betamethasone response is inversely correlated to cerebellar atrophy and directly to antioxidative capacity. Eur J Neurol. 2009;16(6):755–9. https://doi.org/10.1111/j.1468-1331.2009.02600.x .
doi: 10.1111/j.1468-1331.2009.02600.x
pubmed: 19475758
Zannolli R, Buoni S, Betti G, Salvucci S, Plebani A, Soresina A, et al. A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia. Mov Disord. 2012;27(10):1312–6. https://doi.org/10.1002/mds.25126 .
doi: 10.1002/mds.25126
pubmed: 22927201
Chessa L, Leuzzi V, Plebani A, Soresina A, Micheli R, D’Agnano D, et al. Intra-erythrocyte infusion of dexamethasone reduces neurological symptoms in ataxia teleangiectasia patients: results of a phase 2 trial. Orphanet J Rare Dis. 2014;9:5. https://doi.org/10.1186/1750-1172-9-5 .
doi: 10.1186/1750-1172-9-5
pubmed: 24405665
pmcid: 3904207
Leuzzi V, Micheli R, D’Agnano D, Molinaro A, Venturi T, Plebani A, et al. Positive effect of erythrocyte-delivered dexamethasone in ataxia-telangiectasia. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e98. https://doi.org/10.1212/nxi.0000000000000098 .
doi: 10.1212/nxi.0000000000000098
pubmed: 25884015
pmcid: 4396528
Schon K, van Os NJH, Oscroft N, Baxendale H, Scoffings D, Ray J, et al. Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia. Ann Neurol. 2019;85(2):170–80. https://doi.org/10.1002/ana.25394 .
doi: 10.1002/ana.25394
pubmed: 30549301
pmcid: 6590299
van Os NJH, Chessa L, Weemaes CMR, van Deuren M, Fiévet A, van Gaalen J, et al. Genotype-phenotype correlations in ataxia telangiectasia patients with ATM c.3576G>A and c.8147T>C mutations. J Med Genet. 2019;56(5):308–16. https://doi.org/10.1136/jmedgenet-2018-105635 .
doi: 10.1136/jmedgenet-2018-105635
pubmed: 30819809
Mandola AB, Reid B, Sirror R, Brager R, Dent P, Chakroborty P, et al. Ataxia telangiectasia diagnosed on newborn screening-case cohort of 5 years’ experience. Front Immunol. 2019;10:2940. https://doi.org/10.3389/fimmu.2019.02940 .
doi: 10.3389/fimmu.2019.02940
pubmed: 31921190
pmcid: 6932992
Dasouki M, Jabr A, AlDakheel G, Elbadaoui F, Alazami AM, Al-Saud B, et al. TREC and KREC profiling as a representative of thymus and bone marrow output in patients with various inborn errors of immunity. Clin Exp Immunol. 2020;202(1):60–71. https://doi.org/10.1111/cei.13484 .
doi: 10.1111/cei.13484
pubmed: 32691468
pmcid: 7488118
Speckmann C, Doerken S, Aiuti A, Albert MH, Al-Herz W, Allende LM, et al. A prospective study on the natural history of patients with profound combined immunodeficiency: an interim analysis. J Allergy Clin Immunol. 2017;139(4):1302-10.e4. https://doi.org/10.1016/j.jaci.2016.07.040 .
doi: 10.1016/j.jaci.2016.07.040
pubmed: 27658761
Abolhassani H, Chou J, Bainter W, Platt CD, Tavassoli M, Momen T, et al. Clinical, immunologic, and genetic spectrum of 696 patients with combined immunodeficiency. J Allergy Clin Immunol. 2018;141(4):1450–8. https://doi.org/10.1016/j.jaci.2017.06.049 .
doi: 10.1016/j.jaci.2017.06.049
pubmed: 28916186
Krauthammer A, Lahad A, Goldberg L, Sarouk I, Weiss B, Somech R, et al. Elevated IgM levels as a marker for a unique phenotype in patients with ataxia telangiectasia. BMC Pediatr. 2018;18(1):185. https://doi.org/10.1186/s12887-018-1156-1 .
doi: 10.1186/s12887-018-1156-1
pubmed: 29866155
pmcid: 5987459
Moeini Shad T, Yousefi B, Amirifar P, Delavari S, Rae W, Kokhaei P, et al. Variable abnormalities in T and B cell subsets in ataxia telangiectasia. J Clin Immunol. 2021;41(1):76–88. https://doi.org/10.1007/s10875-020-00881-9 .
doi: 10.1007/s10875-020-00881-9
pubmed: 33052516
D’Assante R, Fusco A, Palamaro L, Polishchuk E, Polishchuk R, Bianchino G, et al. Abnormal cell-clearance and accumulation of autophagic vesicles in lymphocytes from patients affected with ataxia-teleangiectasia. Clin Immunol. 2017;175:16–25. https://doi.org/10.1016/j.clim.2016.11.015 .
doi: 10.1016/j.clim.2016.11.015
pubmed: 27915003
Shiloh Y, Lederman HM. Ataxia-telangiectasia (A-T): an emerging dimension of premature ageing. Ageing Res Rev. 2017;33:76–88. https://doi.org/10.1016/j.arr.2016.05.002 .
doi: 10.1016/j.arr.2016.05.002
pubmed: 27181190
McGrath-Morrow SA, Ndeh R, Helmin KA, Khuder B, Rothblum-Oviatt C, Collaco JM, et al. DNA methylation and gene expression signatures are associated with ataxia-telangiectasia phenotype. Sci Rep. 2020;10(1):7479. https://doi.org/10.1038/s41598-020-64514-2 .
doi: 10.1038/s41598-020-64514-2
pubmed: 32366930
pmcid: 7198504
Stagni V, Ferri A, Cirotti C, Barilà D. ATM kinase-dependent regulation of autophagy: a key player in senescence? Front Cell Dev Biol. 2020;8:599048. https://doi.org/10.3389/fcell.2020.599048 .
doi: 10.3389/fcell.2020.599048
pubmed: 33490066
van Os NJH, Jansen AFM, van Deuren M, Haraldsson A, van Driel NTM, Etzioni A, et al. Ataxia-telangiectasia: immunodeficiency and survival. Clin Immunol. 2017;178:45–55. https://doi.org/10.1016/j.clim.2017.01.009 .
doi: 10.1016/j.clim.2017.01.009
pubmed: 28126470
Chiappini E, Santamaria F, Marseglia GL, Marchisio P, Galli L, Cutrera R, et al. Prevention of recurrent respiratory infections: inter-society consensus. Ital J Pediatr. 2021;47(1):211. https://doi.org/10.1186/s13052-021-01150-0 .
doi: 10.1186/s13052-021-01150-0
pubmed: 34696778
pmcid: 8543868
de Benedictis FM, Bush A. Recurrent lower respiratory tract infections in children. BMJ. 2018;362:k2698. https://doi.org/10.1136/bmj.k2698 .
doi: 10.1136/bmj.k2698
pubmed: 30002015
Garcia B, Flume PA. Pulmonary complications of cystic fibrosis. Semin Respir Crit Care Med. 2019;40(6):804–9. https://doi.org/10.1055/s-0039-1697639 .
doi: 10.1055/s-0039-1697639
pubmed: 31659729
Boone PM, Scott RM, Marciniak SJ, Henske EP, Raby BA. The genetics of pneumothorax. Am J Respir Crit Care Med. 2019;199(11):1344–57. https://doi.org/10.1164/rccm.201807-1212CI .
doi: 10.1164/rccm.201807-1212CI
pubmed: 30681372
pmcid: 6543724
Patrawala M, Cui Y, Peng L, Fuleihan RL, Garabedian EK, Patel K, et al. Pulmonary disease burden in primary immune deficiency disorders: data from USIDNET registry. J Clin Immunol. 2020;40(2):340–9. https://doi.org/10.1007/s10875-019-00738-w .
doi: 10.1007/s10875-019-00738-w
pubmed: 31919711
Jiang YN, Ni XY, Yan HQ, Shi L, Lu NN, Wang YN, et al. Interleukin 6-triggered ataxia-telangiectasia mutated kinase activation facilitates epithelial-to-mesenchymal transition in lung cancer by upregulating vimentin expression. Exp Cell Res. 2019;381(2):165–71. https://doi.org/10.1016/j.yexcr.2019.05.011 .
doi: 10.1016/j.yexcr.2019.05.011
pubmed: 31100307
Duecker R, Baer P, Eickmeier O, Strecker M, Kurz J, Schaible A, et al. Oxidative stress-driven pulmonary inflammation and fibrosis in a mouse model of human ataxia-telangiectasia. Redox Biol. 2018;14:645–55. https://doi.org/10.1016/j.redox.2017.11.006 .
doi: 10.1016/j.redox.2017.11.006
pubmed: 29172151
Schroeder SA, Swift M, Sandoval C, Langston C. Interstitial lung disease in patients with ataxia-telangiectasia. Pediatr Pulmonol. 2005;39(6):537–43. https://doi.org/10.1002/ppul.20209 .
doi: 10.1002/ppul.20209
pubmed: 15789441
Bhatt JM, Bush A, van Gerven M, Nissenkorn A, Renke M, Yarlett L, et al. ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia. Eur Respir Rev. 2015;24(138):565–81. https://doi.org/10.1183/16000617.0066-2015 .
doi: 10.1183/16000617.0066-2015
pubmed: 26621971
Duvvuri B, Duvvuri VR, Grigull J, Martin A, Pan-Hammarström Q, Wu GE, et al. Altered spectrum of somatic hypermutation in common variable immunodeficiency disease characteristic of defective repair of mutations. Immunogenetics. 2011;63(1):1–11. https://doi.org/10.1007/s00251-010-0483-7 .
doi: 10.1007/s00251-010-0483-7
pubmed: 20938659
Cinetto F, Scarpa R, Pulvirenti F, Quinti I, Agostini C, Milito C. Appropriate lung management in patients with primary antibody deficiencies. Expert Rev Respir Med. 2019;13(9):823–38. https://doi.org/10.1080/17476348.2019.1641085 .
doi: 10.1080/17476348.2019.1641085
pubmed: 31361157
Dhalla F, Lochlainn DJM, Chapel H, Patel SY. Histology of interstitial lung disease in common variable immune deficiency. Front Immunol. 2020;11:605187. https://doi.org/10.3389/fimmu.2020.605187 .
doi: 10.3389/fimmu.2020.605187
pubmed: 33329602
pmcid: 7718002
van de Ven A, Alfaro TM, Robinson A, Baumann U, Bergeron A, Burns SO, et al. Managing granulomatous-lymphocytic interstitial lung disease in common variable immunodeficiency disorders: e-GLILDnet international clinicians survey. Front Immunol. 2020;11:606333. https://doi.org/10.3389/fimmu.2020.606333 .
doi: 10.3389/fimmu.2020.606333
pubmed: 33324422
pmcid: 7726128
McGrath-Morrow SA, Collaco JM, Detrick B, Lederman HM. Serum interleukin-6 levels and pulmonary function in ataxia-telangiectasia. J Pediatr. 2016;171:256-61.e1. https://doi.org/10.1016/j.jpeds.2016.01.002 .
doi: 10.1016/j.jpeds.2016.01.002
pubmed: 26851119
pmcid: 5562399
McGrath-Morrow SA, Ndeh R, Collaco JM, Rothblum-Oviatt C, Wright J, O’Reilly MA, et al. Inflammation and transcriptional responses of peripheral blood mononuclear cells in classic ataxia telangiectasia. PLoS ONE. 2018;13(12):e0209496. https://doi.org/10.1371/journal.pone.0209496 .
doi: 10.1371/journal.pone.0209496
pubmed: 30586396
pmcid: 6306200
Jesus AA, Duarte AJ, Oliveira JB. Autoimmunity in hyper-IgM syndrome. J Clin Immunol. 2008;28(Suppl 1):S62–6. https://doi.org/10.1007/s10875-008-9171-x .
doi: 10.1007/s10875-008-9171-x
pubmed: 18246414
Zaki-Dizaji M, Akrami SM, Azizi G, Abolhassani H, Aghamohammadi A. Inflammation, a significant player of ataxia-telangiectasia pathogenesis? Inflamm Res. 2018;67(7):559–70. https://doi.org/10.1007/s00011-018-1142-y .
doi: 10.1007/s00011-018-1142-y
pubmed: 29582093
Soresina A, Meini A, Lougaris V, Cattaneo G, Pellegrino S, Piane M, et al. Different clinical and immunological presentation of ataxia-telangiectasia within the same family. Neuropediatrics. 2008;39(1):43–5. https://doi.org/10.1055/s-2008-1076736 .
doi: 10.1055/s-2008-1076736
pubmed: 18504682
Bender CF, Sikes ML, Sullivan R, Huye LE, Le Beau MM, Roth DB, et al. Cancer predisposition and hematopoietic failure in Rad50(S/S) mice. Genes Dev. 2002;16(17):2237–51. https://doi.org/10.1101/gad.1007902 .
doi: 10.1101/gad.1007902
pubmed: 12208847
pmcid: 186667
Alterman N, Fattal-Valevski A, Moyal L, Crawford TO, Lederman HM, Ziv Y, et al. Ataxia-telangiectasia: mild neurological presentation despite null ATM mutation and severe cellular phenotype. Am J Med Genet A. 2007;143a(16):1827–34. https://doi.org/10.1002/ajmg.a.31853 .
doi: 10.1002/ajmg.a.31853
pubmed: 17632790
d’Adda di Fagagna F. Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008;8(7):512–22. https://doi.org/10.1038/nrc2440 .
doi: 10.1038/nrc2440
pubmed: 18574463