2. Academic Validation
  3. Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity

Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity

  • J Allergy Clin Immunol. 2018 Nov;142(5):1589-1604.e11. doi: 10.1016/j.jaci.2018.04.023.
Laurène Pfajfer 1,  Nina K Mair 2,  Raúl Jiménez-Heredia 2,  Ferah Genel 3,  Nesrin Gulez 3,  Ömür Ardeniz 4,  Birgit Hoeger 2,  Sevgi Köstel Bal 5,  Christoph Madritsch 6,  Artem Kalinichenko 2,  Rico Chandra Ardy 2,  Bengü Gerçeker 7,  Javier Rey-Barroso 8,  Hanna Ijspeert 9,  Stuart G Tangye 10,  Ingrid Simonitsch-Klupp 11,  Johannes B Huppa 6,  Mirjam van der Burg 9,  Loïc Dupré 12,  Kaan Boztug 13
Affiliations

Affiliations

  • 1 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; INSERM, UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France; CNRS, UMR 5282, Toulouse, France.
  • 2 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 3 Department of Pediatrics, Dr Behcet Uz Children's Hospital, Izmir, Turkey.
  • 4 EÜTF Internal Medicine, Division of Allergy and Clinical Immunology, Bornova, Izmir, Turkey.
  • 5 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Pediatric Allergy and Immunology, Ankara University School of Medicine, Ankara, Turkey.
  • 6 Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Vienna, Austria.
  • 7 Division of Dermatology, EÜTF Internal Medicine, Bornova, Izmir, Turkey.
  • 8 INSERM, UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France; CNRS, UMR 5282, Toulouse, France.
  • 9 Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
  • 10 Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia.
  • 11 Department of Pathology, Medical University of Vienna, Vienna, Austria.
  • 12 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; INSERM, UMR1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France; CNRS, UMR 5282, Toulouse, France. Electronic address: [email protected].
  • 13 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria; St Anna Kinderspital and Children's Cancer Research Institute, Department of Pediatrics, Medical University of Vienna, Vienna, Austria. Electronic address: [email protected].
PMID: 29751004 DOI: 10.1016/j.jaci.2018.04.023
Abstract

Background: The actin-interacting protein WD repeat-containing protein 1 (WDR1) promotes cofilin-dependent actin filament turnover. Biallelic WDR1 mutations have been identified recently in an immunodeficiency/autoinflammatory syndrome with aberrant morphology and function of myeloid cells.

Objective: Given the pleiotropic expression of WDR1, here we investigated to what extent it might control the lymphoid arm of the immune system in human subjects.

Methods: Histologic and detailed immunologic analyses were performed to elucidate the role of WDR1 in the development and function of B and T lymphocytes.

Results: Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis. In addition to defective adhesion and motility of neutrophils and monocytes, WDR1 deficiency was associated with aberrant T-cell activation and B-cell development. T lymphocytes appeared to develop normally in the patients, except for the follicular helper T-cell subset. However, peripheral T cells from the patients accumulated atypical actin structures at the immunologic synapse and displayed reduced calcium flux and mildly impaired proliferation on T-cell receptor stimulation. WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells, reduced clonal diversity, abnormal B-cell spreading, and increased Apoptosis on B-cell receptor/Toll-like Receptor stimulation.

Conclusion: Our study identifies a novel role for WDR1 in adaptive immunity, highlighting WDR1 as a central regulator of actin turnover during formation of the B-cell and T-cell immunologic synapses.

Keywords

WD repeat–containing protein 1; actin cytoskeleton; immunodeficiency; immunologic synapse; lymphocytes.

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