IKZF1 and UBR4 gene variants drive autoimmunity and Th2 polarization in IgG4-related disease
Qingxiang Liu, … , Cornelia M. Weyand, Jörg J. Goronzy
Qingxiang Liu, … , Cornelia M. Weyand, Jörg J. Goronzy
Published June 17, 2024
Citation Information: J Clin Invest. 2024;134(16):e178692. https://doi.org/10.1172/JCI178692.
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IKZF1 and UBR4 gene variants drive autoimmunity and Th2 polarization in IgG4-related disease

Abstract

IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease whose pathomechanisms remain poorly understood. Here, we identified gene variants in familial IgG4-RD and determined their functional consequences. All 3 affected members of the family shared variants of the transcription factor IKAROS, encoded by IKZF1, and the E3 ubiquitin ligase UBR4. The IKAROS variant increased binding to the FYN promoter, resulting in higher transcription of FYN in T cells. The UBR4 variant prevented the lysosomal degradation of the phosphatase CD45. In the presence of elevated FYN, CD45 functioned as a positive regulatory loop, lowering the threshold for T cell activation. Consequently, T cells from the affected family members were hyperresponsive to stimulation. When transduced with a low-avidity, autoreactive T cell receptor, their T cells responded to the autoantigenic peptide. In parallel, high expression of FYN in T cells biased their differentiation toward Th2 polarization by stabilizing the transcription factor JunB. This bias was consistent with the frequent atopic manifestations in patients with IgG4-RD, including the affected family members in the present study. Building on the functional consequences of these 2 variants, we propose a disease model that is not only instructive for IgG4-RD but also for atopic diseases and autoimmune diseases associated with an IKZF1 risk haplotype.

Authors

Qingxiang Liu, Yanyan Zheng, Ines Sturmlechner, Abhinav Jain, Maryam Own, Qiankun Yang, Huimin Zhang, Filippo Pinto e Vairo, Karen Cerosaletti, Jane H. Buckner, Kenneth J. Warrington, Matthew J. Koster, Cornelia M. Weyand, Jörg J. Goronzy

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Figure 4

FYN abundance and activity are upregulated in the patients.

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FYN abundance and activity are upregulated in the patients. (A) Immunobl...
(A) Immunoblot analysis of T cell blasts treated with or without PP2 (1 μM) left unstimulated or followed by anti-CD3/anti-CD28 stimulation for 15 minutes. Representative blot is from 1 healthy control and 1 patient and summary intensities are from 3 experiments. (B) Immunoblot analysis of FYN in T cell blasts derived from healthy controls (n = 3) and the patients (n = 3) after anti-CD3/anti-CD28 stimulation for 24 hours. (C) Immunoprecipitation of FYN from T cell blasts derived from 1 healthy control and 1 patient after 15 minutes of anti-CD3/anti-CD28 stimulation and immunoblot (IB) analysis of FYN phosphorylation at activating and inhibitory sites, normalized to FYN. (D) Kinase activity of FYN in T cell blasts derived from healthy controls (n = 3) and patients (n = 3) after anti-CD3/anti-CD28 stimulation for 15 minutes. Negative (Neg.) and positive (Pos.) indicate results from system controls. (E) Immunoblot analysis of EBV-transformed B cell lines from healthy controls (n = 3) and the patients (n = 3). (F) SYK phosphorylation measured by flow cytometry in EBV transformed B cell lines from healthy controls (n = 3) and patients (n = 3) after anti-IgM cross-linking for 5 minutes. (G) Immunoblot analysis of naive CD4+ T cells from healthy individuals; cells were lentivirally transduced with empty vector (EV) or a vector encoding FYN. Cells were left unstimulated or stimulated with anti-CD3/anti-CD28 for 15 minutes. Representative blots and intensity results from 3 independent experiments are shown. (H) T cell blasts derived from healthy controls (n = 3) and patients (n = 3) were transfected with control siRNA or FYN siRNA. FYN mRNA levels were determined by qPCR. CD69 and CD25 levels were determined by flow cytometry. Rel., relative. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA (A), 2-tailed, unpaired Student’s t test (B, D, E, and F), or 2-tailed, paired Student’s t test (G and H).