Abstract
Behcet’s disease (BD) is a chronic, systemic and recurrent inflammatory disease associated with hyperactive Th17 and Th1 immune responses. Recent studies have shown that B and T lymphocyte attenuator (BTLA) negatively regulates the immune response. In this study, we investigated whether BTLA activation could be exploited to inhibit the development of abnormal immune responses in BD patients. BTLA expression in PBMCs and CD4+ T cells was significantly decreased in active BD patients. Decreased BTLA level was associated with increased Th17 and Th1 responses. Activation of BTLA inhibited the abnormal Th17 and Th1 responses and IL-22 expression in both patients and controls. Addition of an agonistic anti-BTLA antibody remarkably inhibited DC-induced Th17 and Th1 cell responses, resulted in decreased production of the Th17 and Th1-related cytokines IL-1beta, IL-6, IL-23 and IL-12p70 and reduced CD40 expression in DCs. In conclusion, decreased BTLA expression in ocular BD may lead to inappropriate control of the Th17 and Th1 immune responses and DC functions. Therefore, BTLA may be involved in the development and recurrence of this disease. Agonistic agents of BTLA may represent a potential therapeutic approach for the treatment of BD and other inflammatory diseases mediated by abnormal Th17 and Th1 immune responses.
Highlights
The B and T lymphocyte attenuator (BTLA, known as CD272) belongs to the CD28 family and has been identified as a coinhibitory molecule expressed on T and B lymphocytes as well as other immune cells, including dendritic cells (DCs), monocytes, natural killer cells and natural killer T cells[17,18,19]
The Real-time quantitative polymerase chain reaction (RT-PCR) results showed that the BTLA mRNA expression was significantly decreased in Behcet’s disease (BD) patients with active ocular inflammation compared to the normal controls (p < 0.001); no differences were observed in the Peripheral blood mononuclear cells (PBMCs) from VKH patients and controls (Fig. 1A)
Because recent studies indicated that CD4+ T cells played a role in the inflammatory activity of BD8,11,24 and since a decreased expression of BTLA in CD4+ T cells was observed in ocular BD patients, we investigated the possible relationship between BTLA expression and the Th17 and Th1 cell responses in ocular BD patients and normal controls
Summary
The B and T lymphocyte attenuator (BTLA, known as CD272) belongs to the CD28 family and has been identified as a coinhibitory molecule expressed on T and B lymphocytes as well as other immune cells, including dendritic cells (DCs), monocytes, natural killer cells and natural killer T cells[17,18,19]. These studies indicate that BTLA may control excessive inflammatory responses. Whether BTLA expression is altered in clinical disease remains largely unknown and is the focus of the present study. Given the excessive Th17 and Th1 immune responses in BD and VKH patients, we investigated whether BTLA was involved in the development of abnormal T-lymphocyte responses in patients with these two diseases. The results indicate that decreased BTLA expression was associated with increased Th17 and Th1 immune responses in BD but not VKH patients
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