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.
- 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].
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.