Chemical chaperones reverse early suppression of regulatory circuits during unfolded protein response in B cells from common variable immunodeficiency patients

Author(s)

Bhatt, D. ^[1] ; Stan, R. C. ^{[1, 2]} ; Pinhata, R. ^[1] ; Machado, M. ^[1] ; Maity, S. ^[3] ; Cunningham-Rundles, C. ^[4] ; Vogel, C. ^[3] ; de Camargo, M. M. ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Immunol, Sao Paulo - Brazil

^[2] Cantacuzino Mil Med Res Dev Natl Inst, Dept Prote & Struct Biol, Bucharest - Romania

^[3] NYU, Ctr Genom & Syst Biol, New York, NY - USA

^[4] Mt Sinai Sch Med, Dept Med Allergy & Immunol, New York, NY - USA

• Document type: Journal article
• Source: CLINICAL AND EXPERIMENTAL IMMUNOLOGY; v. 200, n. 1 JAN 2020.
• Web of Science Citations: 1

Abstract

B cells orchestrate pro-survival and pro-apoptotic inputs during unfolded protein response (UPR) to translate, fold, sort, secrete and recycle immunoglobulins. In common variable immunodeficiency (CVID) patients, activated B cells are predisposed to an overload of abnormally processed, misfolded immunoglobulins. Using highly accurate transcript measurements, we show that expression of UPR genes and immunoglobulin chains differs qualitatively and quantitatively during the first 4 h of chemically induced UPR in B cells from CVID patients and a healthy subject. We tested thapsigargin or tunicamycin as stressors and 4-phenylbutyrate, dimethyl sulfoxide and tauroursodeoxycholic acid as chemical chaperones. We found an early and robust decrease of the UPR upon endoplasmic reticulum (ER) stress in CVID patient cells compared to the healthy control consistent with the disease phenotype. The chemical chaperones increased the UPR in the CVID patient cells in response to the stressors, suggesting that misfolded immunoglobulins were stabilized. We suggest that the AMP-dependent transcription factor alpha branch of the UPR is disturbed in CVID patients, underlying the observed expression behavior. (AU)

• FAPESP's process: 17/06289-3 - Gordon Research Conference - Stress Proteins in Growth, Development & Disease
• Grantee: Maristela Martins de Camargo
• Support Opportunities: Research Grants - Meeting - Abroad
• FAPESP's process: 12/04657-1 - 2012 Annual Meeting: Primary Immune Deficiency Disease North American Conference
• Grantee: Maristela Martins de Camargo
• Support Opportunities: Research Grants - Meeting - Abroad
• FAPESP's process: 11/51778-6 - Functional study of the Unfolded Protein Response in human b lymphocytes: primary hypogammaglobulinemia as a model for dysfunctional UPR
• Grantee: Maristela Martins de Camargo
• Support Opportunities: Regular Research Grants