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

• Published in: Clinical and experimental immunology Vol. 200; no. 1; pp. 73 - 86
• Main Authors: Bhatt, D., Stan, R. C., Pinhata, R., Machado, M., Maity, S., Cunningham‐Rundles, C., Vogel, C., Camargo, M. M.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.04.2020; John Wiley and Sons Inc
• Subjects: AMP; Apoptosis; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cells, Cultured; Chaperones; Common variable immunodeficiency; Common Variable Immunodeficiency - genetics; Common Variable Immunodeficiency - metabolism; Common Variable Immunodeficiency - pathology; Dimethyl sulfoxide; Dimethyl Sulfoxide - pharmacology; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - genetics; Gene Expression Profiling - methods; Gene Expression Regulation - drug effects; Gene Expression Regulation - immunology; Gene Regulatory Networks - drug effects; Gene Regulatory Networks - immunology; human B cells; Humans; Immunoglobulins; Immunoglobulins - genetics; Immunoglobulins - metabolism; Lymphocytes B; Original; Patients; Phenotypes; Phenylbutyrates - pharmacology; Phenylbutyric acid; Protein folding; regulatory circuits; Taurochenodeoxycholic Acid - pharmacology; Tauroursodeoxycholic acid; Thapsigargin; Thapsigargin - pharmacology; Transcription Factors - genetics; Transcription Factors - metabolism; Tunicamycin; Tunicamycin - pharmacology; unfolded protein response; Unfolded Protein Response - drug effects; Unfolded Protein Response - genetics; unfolded protein response; regulatory circuits; common variable immunodeficiency; human B cells; chaperones
• ISSN: 0009-9104; 1365-2249; 1365-2249
• DOI: 10.1111/cei.13410

Summary 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. We found an early and robust decrease of the Unfolded Protein Response (UPR) upon ER stress in Common Variable Immunodeficiency (CVID) patient cells compared to the healthy control consistent with the disease phenotype. Chemical chaperones (4‐phenylbutyrate, dimethyl sulfoxide, and tauroursodeoxycholic acid) had positive impact on expression of Ighm (IgM heavy chain) in the CVID patient cells in response to the stressors, suggesting that misfolded immunoglobulins were stabilized. Our findings suggest that a subgroup of hypogammaglobulinemia patients shows delayed transcriptional response to ER stress resulting in failure to homeostasis and subsequent immunoglobulin secretion – providing new insights into the molecular basis of the disease.