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| Item Type: | Article |
|---|---|
| Title: | Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity |
| Creators Name: | Pfajfer, L., Mair, N.K, Jiménez-Heredia, R., Genel, F., Gulez, N., Ardeniz, Ö., Hoeger, B., Bal, S.K., Madritsch, C., Kalinichenko, A., Chandra Ardy, R., Gerçeker, B., Rey-Barroso, J., Ijspeert, H., Tangye, S.G., Simonitsch-Klupp, I., Huppa, J.B., van der Burg, M., Dupré, L. and Boztug, K. |
| 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, Lymphocytes, Immunologic Synapse |
| Source: | Journal of Allergy and Clinical Immunology |
| ISSN: | 0091-6749 |
| Publisher: | Elsevier |
| Volume: | 142 |
| Number: | 5 |
| Page Range: | 1589-1604.e11 |
| Date: | November 2018 |
| Official Publication: | https://doi.org/10.1016/j.jaci.2018.04.023 |
| PubMed: | View item in PubMed |
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