Revisiting double-negative T cells in autoimmune lymphoproliferative immunodeficiencies: a case series
Main Article Content
Keywords
ALPID, ALPS, flowcytometry, immune dysregulation, inborn error of immunity, primary immune -regulatory disorder
Abstract
Background: Elevated level of double-negative T (DNT) cells is a historical hallmark of autoimmune lymphoproliferative syndrome (ALPS) diagnosis. However, the peripheral blood level of DNT cells might also be compromised in autoimmune lymphoproliferative immunodeficiencies (ALPID) other than ALPS, inattention to which would increase the delay in diagnosis of the underlying genetic defect and hinder disease-specific treatment.
Materials and Methods: This cross-sectional study recruited patients suffering from ALPID (exclusion of ALPS) with established genetic diagnosis. Following thorough history taking, immunophenotyping for lymphocyte subsets was performed using flowcytometry.
Results: Fifteen non-ALPS ALPID patients (60% male and 40% female) at a median (interquartile range: IQR) age of 14.0 (7.6–21.8) years were enrolled. Parental consanguinity and family history of immunodeficiency were present in 8 (53.3%) patients. The median (IQR) age at first presentation, clinical and molecular diagnosis were 18 (4–36) months, 8.0 (4.0–17.0) years, and 9.5 (5.0–20.9) years, respectively. Molecular defects were observed in these genes: LRBA (3, 20%), CTLA-4 (2, 13.3%), BACH2 (2, 13.3%), AIRE (2, 13.3%), and FOXP3, IL2Rβ, DEF6, RASGRP1, PIK3CD, and PIK3R1 each in one patient (6.7%). The most common manifestations were infections (14, 93.3%), autoimmunity (12, 80%), and lymphoproliferation (10, 66.7%). The median (IQR) count of white blood cells (WBCs) and lymphocytes were 7160 (3690–12,600) and 3266 (2257–5370) cells/mm3, respectively. The median (IQR) absolute counts of CD3+ T lymphocytes and DNTs were 2085 (1487–4222) and 18 (11–36) cells/mm3, respectively. Low lymphocytes and low CD3+ T cells were observed in 3 (20%) patients compared to normal age ranges. Only one patient with FOXP3 mutation had DNT cells higher than the normal range for age.
Conclusions: Most non-ALPS ALPID patients manifested normal DNT cell count. For a small subgroup of patients with high DNT cells, defects in other IEI genes may explain the phenotype and should be included in the diagnostic genetic panel.
References
2. Consonni F, Gambineri E, Favre C. ALPS, FAS, and beyond: from inborn errors of immunity to acquired immunodeficiencies. Ann Hematol. 2022; 101(3):469–84. 10.1007/s00277-022-04761-7
3. Magerus A, Rensing-Ehl A, Rao VK, Teachey, DT, Rieux-Laucat F, Ehl S. Autoimmune lymphoproliferative immunodeficiencies (ALPIDs): A proposed approach to redefining ALPS and other lymphoproliferative immune disorders. J Allergy Clin Immunol. 2024; 153(1):67–76. 10.1016/j.jaci.2023.11.004
4. Bousfiha A, Moundir A, Tangye SG, Picard C, Jeddane L, Al-Herz W, et al. The 2022 update of IUIS phenotypical classification for human inborn errors of immunity. J Clin Immunol. 2022; 42(7):1508–20. 10.1007/s10875-022-01352-z
5. Cox F, Bigley V, Irvine A, Leahy R, Conlon N. PAMI syndrome: two cases of an autoinflammatory disease with an ALPS-like phenotype. J Clin Immunol. 2022; 42(5):955–8. 10.1007/s10875-022-01265-x
6. Eslamian G, Jamee M, Momen T, Rohani P, Ebrahimi S, Mesdaghi M, et al. Genomic testing identifies monogenic causes in patients with very early-onset inflammatory bowel disease: a multicenter survey in an Iranian cohort. Clin Exp Immunol. 2024; 217(1):1–11. 10.1093/cei/uxae037
7. Gangadharan H, Singh A., Singh K, Rahman K, Aggarwal A. A rare cause of double negative αβ T cell lymphocytosis. Indian J Hematol Blood Transfus. 2021; 37(3):511–3. 10.1007/s12288-020-01381-x
8. Hafezi N, Zaki-Dizaji M, Nirouei M, Asadi G, Sharifinejad N, Jamee M, et al. Clinical, immunological, and genetic features in 780 patients with autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like diseases: a systematic review. Pediatr Allergy Immunol. 2021; 32(7):1519–32. 10.1111/pai.13535
9. López-Nevado M, González-Granado LI, Ruiz-García R, Pleguezuelo D, Cabrera-Marante O, Salmón, N, et al. Primary immune regulatory disorders with an autoimmune lymphoproliferative syndrome-like phenotype: immunologic evaluation, early diagnosis and management. Front Immunol. 2021; 12:671755. 10.3389/fimmu.2021.671755
10. Ogishi M, Yang R, Aytekin C, Langlais D, Bourgey M, Khan T, et al. Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child. Nat Med. 2021; 27(9):1646–54. 10.1038/s41591-021-01388-5
11. Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, 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. 10.1182/blood-2010-04-280347
12. Abinun MA, Cohen SB, Buckland M, Bustamante J, Cant A, et al. ESID Diagnostic Criteria. 2019. https://esid.org/Working-Parties/Registry-Working-Party/Diagnosis-criteria.
13. Failing C, Blase JR., Walkovich K. Understanding the spectrum of immune dysregulation manifestations in autoimmune lymphoproliferative syndrome and autoimmune lymphoproliferative syndrome-like disorders. Rheum Dis Clin North Am. 2023; 49(4), 841–60. 10.1016/j.rdc.2023.07.001
14. Liapis K, Tsagarakis NJ, Panitsas F, Taparkou A, Liapis I, Roubakis C, et al. Causes of double-negative T-cell lymphocytosis in children and adults. J Clin Pathol. 2020; 73(7):431–8. 10.1136/jclinpath-2019-206255
15. Molnár E, Radwan N, Kovács G, Andrikovics H, Henriquez F, Zarafov A, et al. Key diagnostic markers for autoimmune lymphoproliferative syndrome with molecular genetic diagnosis. Blood. 2020; 136(17):1933–45. 10.1182/blood.2020005486
16. Ghaini M, Arzanian MT, Shamsian BS, Sadr S, Rohani P, Keramatipour M, et al. Identifying Novel Mutations in Iranian patients with LPS-responsive beige-like anchor protein (LRBA) deficiency. Immunol Invest. 2021; 50(4):399–405. 10.1080/08820139.2020.1770784
17. Fekrvand S, Delavari S, Chavoshzadeh Z, Sherkat R, Mahdaviani SA, Sadeghi Shabestari M, et al. The first iranian cohort of pediatric patients with activated phosphoinositide 3-kinase-δ (PI3Kδ) syndrome (APDS). Immunol Invest. 2022; 51(3):644–59. 10.1080/08820139.2020.1863982
18. Sharafian S, Tavakol M, Gharagozlou M, Parvaneh N. Delay in diagnosis of two siblings with severe ocular problems and autoimmune polyglandular syndrome. Iran J Allergy Asthma Immunol. 2020; 19(3):313–7. 10.18502/ijaai.v19i3.3460
19. Chan AY, Torgerson TR. Primary immune regulatory disorders: a growing universe of immune dysregulation. Curr Opin Allergy Clin Immunol. 2020; 20(6):582–90. 10.1097/aci.0000000000000689
20. Jamee M, Azizi G, Baris S, Karakoc-Aydiner E, Ozen A, Kiliç S, et al. Clinical, immunological, molecular and therapeutic findings in monogenic immune dysregulation diseases: Middle East and North Africa registry. Clin Immunol. 2022; 244:109131. 10.1016/j.clim.2022.109131
21. Cabral-Marques O, Schimke LF, de Oliveira EB Jr, El Khawanky N, Ramos RN, Al-Ramadi BK, et al. Flow Cytometry contributions for the diagnosis and immunopathological characterization of primary immunodeficiency diseases with immune dysregulation. Front Immunol. 2019; 10:2742. 10.3389/fimmu.2019.02742
22. Mazerolles F, Stolzenberg MC, Pelle O, Picard C, Neven B, Fischer A, et al. Autoimmune lymphoproliferative syndrome-FAS patients have an abnormal regulatory T cell (Treg) phenotype but display normal natural Treg-suppressive function on T cell proliferation. Front Immunol. 2018; 9:718. 10.3389/fimmu.2018.00718
23. Oliveira Mendonça L, Matucci-Cerinic C, Terranova P, Casabona F, Bovis F, Caorsi R, et al. The challenge of early diagnosis of autoimmune lymphoproliferative syndrome in children with suspected autoinflammatory/autoimmune disorders. Rheumatology. 2022; 61(2):696–704. 10.1093/rheumatology/keab361
24. Tahiat A, Belbouab R, Yagoubi A, Hakem S, Fernini F, Keddari M, et al. Flow cytometry-based diagnostic approach for inborn errors of immunity: experience from Algeria. Front Immunol. 2024; 15:1402038. 10.3389/fimmu.2024.1402038
25. Hägele P, Staus P, Scheible R, Uhlmann A, Heeg M, Klemann C, et al. Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study. Lancet Haematol. 2024; 11(2):e114–26. 10.1016/s2352-3026(23)00362-9
26. Li H, Tsokos GC. Double-negative T cells in autoimmune diseases. Curr Opin Rheumatol. 2021; 33(2):163–72. 10.1097/bor.0000000000000778
27. Jamee M, Zaki-Dizaji M, Lo B, Abolhassani H, Aghamahdi F, Mosavian M, et al. Clinical, immunological, and genetic features in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-like syndrome. J Allergy Clin Immunol Pract. 2020; 8(8), 2747–60.e2747. 10.1016/j.jaip.2020.04.070
28. Narula M, Lakshmanan U, Borna S, Schulze JJ, Holmes TH, Harre N, et al. Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation. J Allergy Clin Immunol. 2023; 151(1):233–46.e210. 10.1016/j.jaci.2022.09.013
29. Wyatt RC, Olek S, De Franco E, Samans B, Patel K, Houghton J, et al. FOXP3 TSDR measurement could assist variant classification and diagnosis of IPEX syndrome. J Clin Immunol. 2023; 43(3):662–9. 10.1007/s10875-022-01428-w
30. Tamiji M, Taheri SM, Motahari SA. “Stratification of Admixture Population: A Bayesian Approach,” 2019 7th Iranian Joint Congress on Fuzzy and Intelligent Systems (CFIS), Bojnord, Iran, 2019, pp. 1-4, 10.1109/CFIS.2019.8692151