Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex
Wayne Bainter, Craig D. Platt, Seung-Yeol Park, Kelsey Stafstrom, Jacqueline G. Wallace, Zachary T. Peters, Michel J. Massaad, Michel Becuwe, Sandra Andrea Salinas, Jennifer Jones, Sarah Beaussant-Cohen, Faris Jaber, Jia-Shu Yang, Tobias C. Walther, Jordan S. Orange, Chitong Rao, Seth Rakoff-Nahoum, Maria Tsokos, Shafiq Ur Rehman Naseem, Salem Al-Tamemi, Janet Chou, Victor W. Hsu, Raif S. Geha
Wayne Bainter, Craig D. Platt, Seung-Yeol Park, Kelsey Stafstrom, Jacqueline G. Wallace, Zachary T. Peters, Michel J. Massaad, Michel Becuwe, Sandra Andrea Salinas, Jennifer Jones, Sarah Beaussant-Cohen, Faris Jaber, Jia-Shu Yang, Tobias C. Walther, Jordan S. Orange, Chitong Rao, Seth Rakoff-Nahoum, Maria Tsokos, Shafiq Ur Rehman Naseem, Salem Al-Tamemi, Janet Chou, Victor W. Hsu, Raif S. Geha
View: Text | PDF
Research Article Immunology

Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex

Abstract

The coat protein I (COPI) complex mediates retrograde trafficking from the Golgi to the endoplasmic reticulum (ER). Five siblings with persistent bacterial and viral infections and defective humoral and cellular immunity had a homozygous p.K652E mutation in the γ1 subunit of COPI (γ1-COP). The mutation disrupts COPI binding to the KDEL receptor and impairs the retrieval of KDEL-bearing chaperones from the Golgi to the ER. Homozygous Copg1K652E mice had increased ER stress in activated T and B cells, poor antibody responses, and normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation. Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients. The ER stress-relieving agent tauroursodeoxycholic acid corrected the immune defects of the mutants and reversed the phenotype they acquired following exposure to pet store mice. This study establishes the role of γ1-COP in the ER retrieval of KDEL-bearing chaperones and thereby the importance of ER homeostasis in adaptive immunity.

Authors

Wayne Bainter, Craig D. Platt, Seung-Yeol Park, Kelsey Stafstrom, Jacqueline G. Wallace, Zachary T. Peters, Michel J. Massaad, Michel Becuwe, Sandra Andrea Salinas, Jennifer Jones, Sarah Beaussant-Cohen, Faris Jaber, Jia-Shu Yang, Tobias C. Walther, Jordan S. Orange, Chitong Rao, Seth Rakoff-Nahoum, Maria Tsokos, Shafiq Ur Rehman Naseem, Salem Al-Tamemi, Janet Chou, Victor W. Hsu, Raif S. Geha

×

Figure 7

Treatment of Copg1K652E mutant mice with TUDCA partially reverses the phenotype induced by microbial exposure.

Options: View larger image (or click on image) Download as PowerPoint
Treatment of Copg1K652E mutant mice with TUDCA partially reverses the ph...
Mutant mice received TUDCA or vehicle daily for 21 days starting on day 0 of cohousing. In the same experiment, a group of WT mice were cohoused with pet store mice as control. (A) Weight expressed as percentage of body weight at day 0 of cohousing. (B) Serum TNF-α, IL-6, and IFN-γ levels on day 21. (C) Splenocyte expression of sXbp1 on day 21. Values are relative to gene expression of cohoused WT mice. (D) Numbers of viable CD3+, CD4+, and CD8+ T cells in the spleens on day 21. (E) Proliferation of purified splenic T cells in response to αCD3+αCD28 stimulation on day 21. (F and G) Serum IgG levels (F) and numbers of B220loCD138+ plasmablasts in the spleens (G) on day 21. Results for A and G were pooled from 2 independent experiments each with 4 mice/group. Columns and bars represent mean and SEM. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001, 2-way ANOVA (A); Holm-Šídák test to control for multiple comparisons (B and G).