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Journal of Clinical Immunology

, Volume 39, Issue 7, pp 726–738 | Cite as

A Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects

  • Deniz CagdasEmail author
  • Sevil Oskay Halaçlı
  • Çağman Tan
  • Bernice Lo
  • Pınar Gür Çetinkaya
  • Saliha Esenboğa
  • Betül Karaatmaca
  • Helen Matthews
  • Burcu Balcı-Hayta
  • Tuba Arıkoğlu
  • Fatih Ezgü
  • Elifcan Aladağ
  • İnci N. Saltık-Temizel
  • Hülya Demir
  • Barış Kuşkonmaz
  • Visal Okur
  • Fatma Gümrük
  • Hakan Göker
  • Duygu Çetinkaya
  • Kaan Boztuğ
  • Michael Lenardo
  • Özden Sanal
  • İlhan Tezcan
Original Article

Abstract

Introduction

Autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management.

Methods

Fifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES).

Results

The median age on admission and age of diagnosis were 7 years (0.3–16.5) and 11 years (5–44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαβ+CD4CD8) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2 years (1–3). In total, one patient died from sepsis during adulthood before HSCT.

Conclusion

Patients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell’s important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.

Keywords

LRBA deficiency LATAIE Hsct Malignancy 

Notes

Acknowledgments

We are thankful to our patients and families. We appreciate our laboratory staff Ozlem Karapınar, Mehtap Sonmez, Menekse Kocak and our nurses Meliha Erol and Feride Ozkan. This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank Merck and Co. for support.

Funding Information

This study includes the data of three studies (Project codes: 013 D08103 001-341, 11/19-23, and 16/9087) which are funded by Hacettepe University Coordination Unit for Scientific Research Projects. The study is additionally funded by TUBITAK.

Compliance with Ethical Standards

The studies were approved by the Institutional Review Board of Hacettepe University.

Conflict of Interest

The authors declare that they have no conflict of interest

Supplementary material

10875_2019_677_MOESM1_ESM.docx (27 kb)
ESM 1 (DOCX 26.8 KB)

References

  1. 1.
    Alangari A, et al. LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. J Allergy Clin Immunol. 2012;130(2):481–488. e2.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lopez-Herrera G, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bogaert DJ, et al. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet. 2016;53(9):575–90.CrossRefPubMedGoogle Scholar
  4. 4.
    Revel-Vilk S, et al. Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation. Clin Immunol. 2015;159(1):84–92.CrossRefPubMedGoogle Scholar
  5. 5.
    Lo B, et al. CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency. Blood. 2016;128:1037–42.  https://doi.org/10.1182/blood-2016-04-712612.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Serwas NK, et al. Atypical manifestation of LRBA deficiency with predominant IBD-like phenotype. Inflamm Bowel Dis. 2014;21(1):40–7.CrossRefGoogle Scholar
  7. 7.
    Burns SO, et al. LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. J Allergy Clin Immunol. 2012;130(6):1428–32.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Alroqi FJ, et al. Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation. J Allergy Clin Immunol. 2018;141(3):1050–1059.e10.CrossRefPubMedGoogle Scholar
  9. 9.
    Gámez-Díaz L, et al. The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. J Allergy Clin Immunol. 2016;137(1):223–30.CrossRefPubMedGoogle Scholar
  10. 10.
    Oliveira JB, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome: report from the 2009 NIH International Workshop. Blood. 2010;116(14):e35–40.  https://doi.org/10.1182/blood-2010-04-280347.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Lo B, et al. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436–40.CrossRefPubMedGoogle Scholar
  12. 12.
    Ozen A, et al. CD55 deficiency, early-onset protein-losing enteropathy, and thrombosis. N Engl J Med. 2017;377(1):52–61.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Willmann, K.L., et al. Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Nat Commun. 2014;5:5360Google Scholar
  14. 14.
    Al-Mousa H, et al. High incidence of severe combined immunodeficiency disease in Saudi Arabia detected through combined TREC and next generation sequencing of newborn dried blood spots. Front Immunol. 2018;9:782.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kostel Bal S, et al. Multiple presentations of LRBA deficiency: a single-center experience. J Clin Immunol. 2017;37(8):790–800.CrossRefPubMedGoogle Scholar
  16. 16.
    Okur F, et al. Bone marrow transplantation with favorable outcome in three patients with LPS-responsive beige-like anchor (LRBA) deficiency. Clin Immunol (Orlando, Fla). 2019;203:162.CrossRefGoogle Scholar
  17. 17.
    Johnson MB, et al. Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes. Diabetes. 2017;66(8):2316–22.  https://doi.org/10.2337/db17-0040.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Cullinane AR, Schaffer AA, Huizing M. The BEACH is hot: a LYST of emerging roles for BEACH-domain containing proteins in human disease. Traffic. 2013;14(7):749–66.CrossRefPubMedGoogle Scholar
  19. 19.
    Tan Ç, et al. Polymorphisms in FAS and CASP8 genes may contribute to the development of ALPS phenotype: a study in 25 patients with probable ALPS. Turk J Pediatr. 2015;57(2):141.PubMedGoogle Scholar
  20. 20.
    Lee K-M, et al. Molecular basis of T cell inactivation by CTLA-4. Science. 1998;282(5397):2263–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Riaz IB, et al. A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity). Front Immunol. 2019;10:777.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Alkhairy OK, et al. Spectrum of phenotypes associated with mutations in LRBA. J Clin Immunol. 2016;36(1):33–45.CrossRefPubMedGoogle Scholar
  23. 23.
    Tarbox JA, et al. Elevated double negative T cells in pediatric autoimmunity. J Clin Immunol. 2014;34(5):594–9.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lévy E, et al. LRBA deficiency with autoimmunity and early onset chronic erosive polyarthritis. Clin Immunol. 2016;168:88–93.CrossRefPubMedGoogle Scholar
  25. 25.
    Azizi G, et al. New therapeutic approach by sirolimus for enteropathy treatment in patients with LRBA deficiency. Eur Ann Allergy Clin Immunol. 2017;49(5):235–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Jung SW, et al. BK virus-associated nephropathy with hydronephrosis in a patient with AIDS: a case report and literature review. Clin Nephrol. 2016;85(3):173–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Azizi G, et al. Polyautoimmunity in patients with LPS-responsive beige-like anchor (LRBA) deficiency. Immunol Investig. 2018;47(5):457–67.CrossRefGoogle Scholar
  28. 28.
    Jogl G, et al. Crystal structure of the BEACH domain reveals an unusual fold and extensive association with a novel PH domain. EMBO J. 2002;21(18):4785–95.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Schubert D, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Seidel MG, et al. Long-term remission after allogeneic hematopoietic stem cell transplantation in LPS-responsive beige-like anchor (LRBA) deficiency. J Allergy Clin Immunol. 2015;135(5):1384–1390. e8.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Seymour B, Miles J, Haeney M. Primary antibody deficiency and diagnostic delay. J Clin Pathol. 2005;58(5):546–7.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Deniz Cagdas
    • 1
    Email author
  • Sevil Oskay Halaçlı
    • 2
  • Çağman Tan
    • 2
  • Bernice Lo
    • 3
  • Pınar Gür Çetinkaya
    • 1
  • Saliha Esenboğa
    • 1
  • Betül Karaatmaca
    • 1
  • Helen Matthews
    • 4
  • Burcu Balcı-Hayta
    • 5
  • Tuba Arıkoğlu
    • 6
  • Fatih Ezgü
    • 7
  • Elifcan Aladağ
    • 8
  • İnci N. Saltık-Temizel
    • 9
  • Hülya Demir
    • 9
  • Barış Kuşkonmaz
    • 10
  • Visal Okur
    • 10
  • Fatma Gümrük
    • 10
  • Hakan Göker
    • 8
  • Duygu Çetinkaya
    • 10
  • Kaan Boztuğ
    • 11
  • Michael Lenardo
    • 4
  • Özden Sanal
    • 1
  • İlhan Tezcan
    • 1
  1. 1.Department of Pediatrics, Division of Pediatric ImmunologyHacettepe University Medical SchoolAnkaraTurkey
  2. 2.Institute of Child Health, ImmunologyHacettepe UniversityAnkaraTurkey
  3. 3.Sidra Medical and Research CenterAl RayyanQatar
  4. 4.National Institute of Allergy and Infectious DiseasesNational Institutes of HealthRockvilleUSA
  5. 5.Department of Medical BiologyHacettepe University Medical SchoolAnkaraTurkey
  6. 6.Department of Pediatrics, Division of Allergy and ImmunologyMersin University Medical SchoolMersinTurkey
  7. 7.Department of Pediatrics, Division of Pediatric Inborn Metabolic Disorders, Metabolism and GeneticsGazi University Medical SchoolAnkaraTurkey
  8. 8.Department of Internal Medicine, Division of HematologyHacettepe University Medical SchoolAnkaraTurkey
  9. 9.Department of Pediatrics, Division of Pediatric GastroenterologyHacettepe University Medical SchoolAnkaraTurkey
  10. 10.Department of Pediatrics, Division of Pediatric HematologyHacettepe University Medical SchoolAnkaraTurkey
  11. 11.CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria

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