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Clinical Phenotypes and Immunological Characteristics of 18 Egyptian LRBA Deficiency Patients

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Abstract

LPS-responsive beige-like anchor (LRBA) deficiency is an autosomal recessive primary immunodeficiency disorder, OMIM (#614700). LRBA deficiency patients suffer from variable manifestations including recurrent infections, immune dysregulation, autoimmunity, cytopenias, and enteropathy. This study describes different clinical phenotypes and immunological characteristics of 18 LRBA deficiency patients diagnosed from Egypt. T and B lymphocyte subpopulations, LRBA, and cytotoxic T lymphocyte-associated protein 4 (CTLA4) expression were evaluated in resting and stimulated T cells using flow cytometry. Next-generation sequencing was used to identify mutations in the LRBA gene. LRBA deficiency patients had significantly lower B cells and increased percentage of memory T cells. CTLA4 levels were lower in LRBA-deficient T regulatory cells in comparison to healthy donors at resting conditions and significantly increased upon stimulation of T cells. We identified 11 novel mutations in LRBA gene ranging from large deletions to point mutations. Finally, we were able to differentiate LRBA-deficient patients from healthy control and common variable immunodeficiency patients using a simple flow cytometry test performed on whole blood and without need to prior stimulation. LRBA deficiency has heterogeneous phenotypes with poor phenotype-genotype correlation since the same mutation may manifest differently even within the same family. Low LRBA expression, low numbers of B cells, increased numbers of memory T cells, and defective CTLA4 expression (which increase to normal level upon T cell stimulation) are useful laboratory tests to establish the diagnosis of LRBA deficiency. Screening of the siblings of affected patients is very important as patients may be asymptomatic at the beginning of the disease course.

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Abbreviations

LRBA:

LPS-responsive beige-like anchor

PID:

Primary immunodeficiency

BEACH:

beige and Chediak-Higashi syndrome

CTLA4:

cytotoxic T lymphocyte-associated protein 4

ALPS:

Autoimmune lymphoproliferative syndrome

IBD:

inflammatory bowel disease

CVID:

Common variable immunodeficiency

ESID:

European society for immunodeficiency

IPEX:

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked

References

  1. Kiykim A, Ogulur I, Dursun E, Charbonnier LM, Nain E, Cekic S, et al. Abatacept as a long-term targeted therapy for LRBA deficiency. J Allergy Clin Immunol Pract. 2019;7(8):2790–800.

    Article  Google Scholar 

  2. Burnett DL, Parish IA, Masle-Farquhar E, Brink R, Goodnow CC. Murine LRBA deficiency causes CTLA-4 deficiency in Tregs without progression to immune dysregulation. Immunol Cell Biol. 2017;95(9):775–88.

    Article  CAS  Google Scholar 

  3. Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, et al. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436–40.

    Article  CAS  Google Scholar 

  4. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332(6029):600–3.

    Article  CAS  Google Scholar 

  5. Charbonnier L-M, Janssen E, Chou J, Ohsumi TK, Keles S, Hsu JT, et al. Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked–like disorder caused by loss-of-function mutations in LRBA. Journal of Allergy and Clinical Immunology. 2015;135(1):217–27. e9.

  6. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410–6.

    Article  CAS  Google Scholar 

  7. Alangari A, Alsultan A, Adly N, Massaad MJ, Kiani IS, Aljebreen A, et al. LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. Journal of Allergy and Clinical Immunology. 2012;130(2):481–8. e2.

  8. Bal SK, Haskologlu S, Serwas NK, Islamoglu C, Aytekin C, Kendirli T, et al. Multiple presentations of LRBA deficiency: a single-center experience. J Clin Immunol. 2017;37(8):790–800.

    Article  CAS  Google Scholar 

  9. Gámez-Díaz L, August D, Stepensky P, Revel-Vilk S, Seidel MG, Noriko M, et al. The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. J Allergy Clin Immunol. 2016;137(1):223–30.

    Article  CAS  Google Scholar 

  10. Azizi G, Abolhassani H, Habibi S, Rahamooz T, Mohammadi H, Jafarnezhad-Ansariha F, et al. Two faces of LRBA deficiency in siblings: hypogammaglobulinemia and normal immunoglobulin levels. J Investig Allergol Clin Immunol. 2018;28(1):48–50.

    Article  CAS  Google Scholar 

  11. Gámez-Díaz L, Sigmund EC, Reiser V, Vach W, Jung S, Grimbacher B. Rapid flow cytometry-based test for the diagnosis of lipopolysaccharide responsive beige-like anchor (LRBA) deficiency. Front Immunol. 2018;9.

  12. Habibi S, Zaki-Dizaji M, Rafiemanesh H, Lo B, Jamee M, Gámez-Díaz L, et al. Clinical, immunologic, and molecular spectrum of patients with LPS-responsive beige-like anchor protein deficiency: a systematic review. J Allergy Clin Immunol Pract. 2019;7(7):2379–86.13.

    Article  Google Scholar 

  13. Liphaus BL, Caramalho I, Rangel-Santos A, Silva CA, Demengeot J, Carneiro-Sampaio MM. LRBA deficiency: a new genetic cause of monogenic lupus. Ann Rheum Dis. 2020;79(3):427–8.

    Article  Google Scholar 

  14. Taylan C, Wenzel A, Erger F, Göbel H, Weber LT, Beck BB. Case report: exome sequencing reveals LRBA deficiency in a patient with end-stage renal disease. Front Pediatr. 2020;8.

  15. Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, Plaeger S, Stiehm ER, et al. Lymphocyte subsets in healthy children from birth through 18 years of age: the pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol. 2003;112(5):973–80.

    Article  Google Scholar 

  16. Wallach JB. Interpretation of diagnostic tests: Lippincott Williams & Wilkins; 2007.

  17. De Bruyne M, Bogaert DJ, Venken K, Van den Bossche L, Bonroy C, Roels L, et al. A novel LPS-responsive beige-like anchor protein (LRBA) mutation presents with normal cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and overactive TH17 immunity. J Allergy Clin Immunol. 2018.

  18. Serwas NK, Kansu A, Santos-Valente E, Kuloğlu Z, Demir A, Yaman A, et al. Atypical manifestation of LRBA deficiency with predominant IBD-like phenotype. Inflamm Bowel Dis. 2014;21(1):40–7.

    Article  Google Scholar 

  19. Revel-Vilk S, Fischer U, Keller B, Nabhani S, Gámez-Díaz L, Rensing-Ehl A, et al. Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation. Clin Immunol. 2015;159(1):84–92.

    Article  CAS  Google Scholar 

  20. Azizi G, Abolhassani H, Mahdaviani SA, Chavoshzadeh Z, Eshghi P, Yazdani R, et al. Clinical, immunologic, molecular analyses and outcomes of Iranian patients with LRBA deficiency: a longitudinal study. Pediatr Allergy Immunol. 2017;28(5):478–84.

    Article  Google Scholar 

  21. Tesch VK, Abolhassani H, Shadur B, Zobel J, Mareika Y, Sharapova S, Karakoc-Aydiner E, Rivière JG, Garcia-Prat M, Moes N, Haerynck F. Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score. J Allergy Clin Immunol 2019 27.

  22. Alkhairy OK, Abolhassani H, Rezaei N, Fang M, Andersen KK, Chavoshzadeh Z, et al. Spectrum of phenotypes associated with mutations in LRBA. J Clin Immunol. 2016;36(1):33–45.

    Article  CAS  Google Scholar 

  23. Al Sukaiti N, AbdelRahman K, AlShekaili J, Al Oraimi S, Al Sinani A, Al Rahbi N, et al. Agammaglobulinaemia despite terminal B-cell differentiation in a patient with a novel LRBA mutation. Clinical & translational immunology. 2017;6(5):e144.

    Article  CAS  Google Scholar 

  24. Lopez-Herrera G, Tampella G, Pan-Hammarström Q, Herholz P, Trujillo-Vargas CM, Phadwal K, et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet. 2012;90(6):986–1001.

    Article  CAS  Google Scholar 

  25. Bhargava P, Calabresi P. Novel therapies for memory cells in autoimmune diseases. Clinical & Experimental Immunology. 2015;180(3):353–60.

    Article  CAS  Google Scholar 

  26. Elaziz DSA, Hafez MH, Galal NM, Meshaal SS, El Marsafy AM. CD4+ CD25+ cells in type 1 diabetic patients with other autoimmune manifestations. J Adv Res. 2014;5(6):647–55.

    Article  Google Scholar 

  27. Johnson MB, De Franco E, Allen HL, Al Senani A, Elbarbary N, Siklar Z, et al. Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes. Diabetes. 2017;66(8):2316–22.

    Article  CAS  Google Scholar 

  28. Azizi G, Abolhassani H, Kiaee F, Tavakolinia N, Rafiemanesh H, Yazdani R, et al. Autoimmunity and its association with regulatory T cells and B cell subsets in patients with common variable immunodeficiency. Allergol Immunopathol. 2018;46(2):127–35.

    Article  CAS  Google Scholar 

  29. Hou TZ, Verma N, Wanders J, Kennedy A, Soskic B, Janman D, et al. Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations. Blood. 2017:blood-2016-10-745174.

  30. Gámez-Díaz L, Neumann J, Jäger F, Proietti M, Felber F, Soulas-Sprauel P, et al. Immunological phenotype of the murine Lrba knockout. Immunol Cell Biol. 2017;95(9):789–802.

    Article  CAS  Google Scholar 

  31. El Hawary R, Meshaal S, Deswarte C, Galal N, Abdelkawy M, Alkady R, et al. Role of flow cytometry in the diagnosis of chronic granulomatous disease: the Egyptian experience. J Clin Immunol. 2016;36(6):610–8.

    Article  CAS  Google Scholar 

  32. Jaramillo CM, Trujillo-Vargas CM. LRBA en el sistema de endomembranas. Colombia Medica. 2018;49(3):236–44.

    Article  Google Scholar 

  33. Meshaal SS, El Hawary RE, Eldash A, Grimbacher B, Camacho-Ordonez N, Elaziz DSA, et al. Diagnosis of DOCK8 deficiency using flow cytometry biomarkers: an Egyptian center experience. Clin Immunol. 2018;195:36–44.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors thank Drs Raif Geha and Janet Chua of the Immunology Division Children’s Hospital, Harvard Medical School, Boston, MA, USA, for sequencing eight of the patients reported in the study.

The authors thank the Jeffrey Modell Foundation for providing genetic sequencing services for patients 10 and 11 through their genetic sequencing pilot program.

For genetic diagnosis of patients 13 and 14: BG receives support through the Deutsche Forschungsgemeinschaft (DFG) under Germany’s Excellence Strategy (CIBSS – EXC-2189 – Project ID 390939984, and RESIST – EXC 2155 – Project ID 39087428); through the E-rare program of the EU, managed by the DFG, grant code GR1617/14-1/iPAD; and through the “Netzwerke Seltener Erkrankungen” of the German Ministry of Education and Research (BMBF), grant code: GAIN_ 01GM1910A.

Funding

Genetic sequencing for four patients was supported by the Jeffrey Modell Foundation through their genetic sequencing pilot program and through the Deutsche Forschungsgemeinschaft (DFG) under Germany’s Excellence Strategy (CIBSS – EXC-2189 – Project ID 390939984, and RESIST – EXC 2155 – Project ID 39087428); through the E-rare program of the EU, managed by the DFG, grant code GR1617/14-1/iPAD; and through the “Netzwerke Seltener Erkrankungen” of the German Ministry of Education and Research (BMBF), grant code: GAIN_ 01GM1910A received by BG.

Author information

Author notes

  1. Safa Meshaal and Rabab El Hawary contributed equally to this work.

Authors and Affiliations

  1. Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Giza, 11562, Egypt

    Safa Meshaal, Rabab El Hawary, Rana Adel, Aya Erfan & Nancy El-Guindy

  2. Pediatrics Department, Faculty of Medicine, Cairo University, Giza, Egypt

    Dalia Abd Elaziz, Sohilla Lotfy, Mona Hafez, Mona Hassan, Jeannette Boutros, Nermeen Galal & Aisha Elmarsafy

  3. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK

    Matthew Johnson

  4. Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CC), Medical Center, Faculty of Medicine, Albert-Ludwig-University of Freiburg, Freiburg, Germany

    Jessica Rojas-Restrepo, Laura Gamez-Diaz & Bodo Grimbacher

  5. DZIF – German Center for Infection Research, Satellite Center Freiburg, Germany, Freiburg, Germany

    Bodo Grimbacher

  6. CIBSS – Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany

    Bodo Grimbacher

  7. RESIST – Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany

    Bodo Grimbacher

  8. Pediatrics Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Walaa Shoman & Yasmine Abdelmeguid

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  1. Safa Meshaal
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  2. Rabab El Hawary
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Correspondence to Safa Meshaal.

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Nancy El-Guindy and Aisha Elmarsafy are equal senior co-authorship

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Meshaal, S., El Hawary, R., Adel, R. et al. Clinical Phenotypes and Immunological Characteristics of 18 Egyptian LRBA Deficiency Patients. J Clin Immunol 40, 820–832 (2020). https://doi.org/10.1007/s10875-020-00799-2

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