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SHR Neuro Cancer Cardio Lipid Metab Microb
Pfajfer, L; Mair, NK; Jiménez-Heredia, R; Genel, F; Gulez, N; Ardeniz, Ö; Hoeger, B; Bal, SK; Madritsch, C; Kalinichenko, A; Chandra, Ardy, R; Gerçeker, B; Rey-Barroso, J; Ijspeert, H; Tangye, SG; Simonitsch-Klupp, I; Huppa, JB; van, der, Burg, M; Dupré, L; Boztug, K.
Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity.
J Allergy Clin Immunol. 2018; 142(5): 1589-1604.e11.
Doi: 10.1016/j.jaci.2018.04.023
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- Co-authors Med Uni Graz
- Kalinichenko Artem
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Adaptive Immunity - administration & dosage
- Adult - administration & dosage
- B-Lymphocytes - immunology
- Child - administration & dosage
- Female - administration & dosage
- Humans - administration & dosage
- Immunological Synapses - administration & dosage
- Male - administration & dosage
- Microfilament Proteins - genetics, immunology
- Mutation - administration & dosage
- T-Lymphocytes - immunology
- Young Adult - administration & dosage