Functional study of the Unfolded Protein Response in human b lymphocytes: primary hypogammaglobulinemia as a model for dysfunctional UPR

• Grant number: 11/51778-6
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2012
• End date: November 30, 2015
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Maristela Martins de Camargo
• Grantee: Maristela Martins de Camargo
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

During terminal differentiation of B lymphocytes into plasma cells, large amounts of nascent immunoglobulins are translated and translocated into the Endoplasmic Reticulum (ER). Many immunoglobulins are not folded properly, and along with differentiation signals, activate an intracellular pathway named Unfolded Protein Response (UPR). The UPR aims at resolving the ER stress by promoting expression of chaperones, attenuation of translation, and degradation of misfolded/unfolded proteins in the ER. Among its three branches, the IRE-1α/XBP1 arm is the most conserved in evolution. XBP1 is the main transcription factor involved in expression of UPR target genes. Previously, our group identified one patient (patient P) with Common Variable immunodeficiency (CVID), characterized by hypogammaglobulinemia, that presents dysregulation of the IRE1/XBP1 arm. In the present proposal we aim at evaluating the other branches of the UPR in immortalized B cells from this patient, as well as expanding our analyses to immortalized B cells from other CVID patients. Furthermore, we aim to study the relationship between the UPR and the defective proliferation found in B cells from patient P and other CVID patients. Finally, we will evaluate the potential use of chemical chaperones as a therapeutic agent in hypogammaglobulinemias caused by defects in the UPR pathway. (AU)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

STAN, R. C.; BONIN, C. PINTO; PORTO, R.; SORIANO, F. G.; DE CAMARGO, M. M.. Increased grp78 transcription is correlated to reduced tlr4 transcription in patients surviving sepsis. CLINICAL AND EXPERIMENTAL IMMUNOLOGY, v. 198, n. 2, AUG 2019. (11/51778-6)

OLIVEIRA, CAMILA D.; LARSSON, CARLOS E.; DE CAMARGO, MARISTELA M.. Longitudinal assessment of T-lymphocyte subpopulations during generalized demodicosis in dogs and their relationship with remission. VETERINARY DERMATOLOGY, v. 26, n. 1, p. 18+, FEB 2015. (09/51326-8, 11/51778-6)

STAN, RAZVAN C.; DE CAMARGO, MARISTELA M.. Memory of Periodic Thermal Stimulation in an Immune Complex. CHEMISTRYSELECT, v. 4, n. 12, p. 3325-3328, MAR 29 2019. (11/51778-6)

STAN, RAZVAN C.; FRANCOSO, KATIA S.; ALVES, RUBENS P. S.; FERREIRA, LUIS CARLOS S.; SOARES, IRENE S.; DE CAMARGO, MARISTELA M.. Febrile temperatures increase in vitro antibody affinity for malarial and dengue antigens. PLoS Neglected Tropical Diseases, v. 13, n. 4, APR 2019. (11/51778-6, 12/13032-5, 14/17595-0, 16/20045-7)

BHATT, D.; STAN, R. C.; PINHATA, R.; MACHADO, M.; MAITY, S.; CUNNINGHAM-RUNDLES, C.; VOGEL, C.; DE CAMARGO, M. M.. Chemical chaperones reverse early suppression of regulatory circuits during unfolded protein response in B cells from common variable immunodeficiency patients. CLINICAL AND EXPERIMENTAL IMMUNOLOGY, v. 200, n. 1, JAN 2020. (17/06289-3, 12/04657-1, 11/51778-6)

STAN, RAZVAN C.; SILVA, RAISSA L.; DE CAMARGO, MARISTELA M.. Human GRP78 affinity towards its signaling partners Ire1 alpha and PERK is differently modulated by an unfolded protein client. Biochemical and Biophysical Research Communications, v. 487, n. 2, p. 375-380, MAY 27 2017. (11/51778-6)