| Autor: |
Körholz, Julia, Gabrielyan, Anastasia, Sczakiel, Henrike Lisa, Schulze, Livia, Rejzek, Manuela, Laass, Martin W, Leuchten, Nicolai, Tiebel, Oliver, Aust, Diana, Conrad, Karsten, Röber, Nadja, Jacobsen, Eva-Maria, Ehmke, Nadja, Berner, Reinhard, Lucas, Nadja, Lee-Kirsch, Minae A, Wiedemuth, Ralf, Roesler, Joachim, Roers, Axel, Amendt, Timm |
| Předmět: |
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| Zdroj: |
Rheumatology; Apr2023, Vol. 62 Issue 4, p1699-1705, 7p |
| Abstrakt: |
Objectives Inborn errors of immunity manifest with susceptibility to infection but may also present with immune dysregulation only. According to the European Society for Immunodeficiencies Registry about 50% of inborn errors of immunity are classified as common variable immunodeficiencies (CVID). In only few CVID patients are monogenic causes identified. IFN regulatory factor-2 binding protein 2 (IRF2BP2) is one of 20 known genes associated with CVID phenotypes and has only been reported in two families so far. We report another IRF2BP2-deficient patient with a novel pathogenic variant and phenotype and characterize impaired B cell function and immune dysregulation. Methods We performed trio whole-exome sequencing, determined B cell subpopulations and intracellular calcium mobilization upon B cell receptor crosslinking in B cells. T cell subpopulations, T cell proliferation and a type I IFN signature were measured. Colonoscopy and gastroduodenoscopy including histopathology were performed. Results The 33-year-old male presented with recurrent respiratory infections since childhood, colitis and RA beginning at age 25 years. We identified a novel de novo nonsense IRF2BP2 variant c.1618C>T; p.(Q540*). IgG deficiency was detected as consequence of a severe B cell differentiation defect. This was confirmed by impaired plasmablast formation upon stimulation with CpG. No serum autoantibodies were detected. Intracellular cytokine production in CD4+ T cells and CTLA4 expression on FOXP3+ Tregs were impaired. Type I IFN signature was elevated. Conclusion The identified loss-of-function variant in IRF2BP2 severely impairs B cell development and T cell homeostasis, and may be associated with colitis and RA. Our results provide further evidence for association of IRF2BP2 with CVID and contribute to the understanding of the underlying pathomechanisms. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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