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Defects in Notch1 upregulation upon activation of T Cells from patients with systemic lupus erythematosus are related to lupus disease activity

Lupus Research Unit, Chulalongkorn University, Bangkok, Thailand; Inter-Department of Medical Microbiology, GraduateSchool, Chulalongkorn University, Bangkok, Thailand

N Hirankarn

Lupus Research Unit, Chulalongkorn University, Bangkok, Thailand; Inter-Department of Medical Microbiology, GraduateSchool, Chulalongkorn University, Bangkok, Thailand; Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

Y Avihingsanon

Lupus Research Unit, Chulalongkorn University, Bangkok, Thailand; Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

T Palaga

Inter-Department of Medical Microbiology, GraduateSchool, Chulalongkorn University, Bangkok, Thailand; Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand, tanapat.p{at}chula.ac.th

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of autoantibodies and deposition of immune complexes in various organs. T cells play a central role in driving disease progression, and multiple defects in T cells from patients with SLE have been uncovered. Notch signalling is an evolutionarily well-conserved signalling cascade involved in the proliferation, differentiation and apoptosis of T lymphocytes during development and peripheral effector functions. In this study, we investigated the correlation between expression of Notch receptor and the severity of SLE disease. On the contrary to T lymphocytes from healthy controls (n = 11), Tlymphocytes from patients with active SLE (n = 12) failed to upregulate Notch1 upon in-vitro stimulation as quantified by quantitative real time RT-PCR (P  0.025). Among patients with inactive SLE (n = 10), those with late onset of flare exhibited significantly less Notch1 upregulation compared with SLE patients with remission. Expression of the Notch target genes, Hes1 and deltex, was also lower in patients with active SLE. The decrease in Notch1 mRNA expression was consistent with less Notch1 protein expression in patients with active SLE. The defects in Notch1 upregulation correlated with decreased proliferation, CD25 and Foxp3 expression upon stimulation in vitro. Taken together, the failure of T cells to upregulate Notch1 upon activation may be a key feature of active SLE and a potential therapeutic target.

Key Words: activation • disease activity • notch receptor • SLE • T cells

Lupus, Vol. 17, No. 7, 645-653 (2008)
DOI: 10.1177/0961203308089406


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