Systemic Lupus Erythematosus
Casitas B Lineage Lymphoma b Is a Key Regulator of Peripheral Tolerance in Systemic Lupus Erythematosus
Article first published online: 28 MAR 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 65, Issue 4, pages 1032–1042, April 2013
How to Cite
Gómez-Martín, D., Ibarra-Sánchez, M., Romo-Tena, J., Cruz-Ruíz, J., Esparza-López, J., Galindo-Campos, M., Díaz-Zamudio, M. and Alcocer-Varela, J. (2013), Casitas B Lineage Lymphoma b Is a Key Regulator of Peripheral Tolerance in Systemic Lupus Erythematosus. Arthritis & Rheumatism, 65: 1032–1042. doi: 10.1002/art.37833
- Issue published online: 28 MAR 2013
- Article first published online: 28 MAR 2013
- Accepted manuscript online: 21 DEC 2012 03:42PM EST
- Manuscript Accepted: 11 DEC 2012
- Manuscript Received: 25 JUN 2012
- Consejo Nacional de Ciencia y Tecnología (CONACYT). Grant Numbers: 37950, 84769
To analyze whether the expression and modulation of T cell receptor (TCR) signaling is dependent on Casitas B lineage lymphoma b (Cbl-b) in T cells from patients with systemic lupus erythematosus (SLE) upon stimulation with a tolerogenic substance.
Peripheral blood mononuclear cells were obtained from 20 patients with SLE (active disease or in remission) and 20 healthy controls. Levels of Cbl-b expression were measured using reverse transcription–polymerase chain reaction and Western blotting in peripheral CD4+ T cells from SLE patients and healthy controls upon anergy induction. Cell proliferation was measured using the carboxyfluorescein diacetate succinimidyl ester dilution method. Cytokine production was analyzed by luminometry, and surface expression of activation markers was assessed by flow cytometry. Transfection assays were performed to induce overexpression of Cbl-b, and phosphorylation of TCR-associated kinases was evaluated.
CD4+ T cells from SLE patients displayed resistance to anergy (as evidenced by increased cell proliferation, interleukin-2 production, and expression of activation and costimulatory markers), and this was associated with altered Cbl-b expression. Upon ionomycin treatment, primary T cells showed enhanced MAPK activity and decreased Akt phosphorylation, which was representative of the anergic state. In T cells from lupus patients, Cbl-b overexpression led to increased expression of phosphorylated MAPK, thus indicating the reversibility of anergy resistance.
These findings suggest that abnormal peripheral tolerance in SLE is caused by a deficiency in Cbl-b, and that this ubiquitin ligase plays a key role in regulating TCR signaling during the induction of peripheral tolerance.