A Functional Polymorphism in B and T Lymphocyte Attenuator Is Associated with Susceptibility to Rheumatoid Arthritis

Mie Oki,Hiroshi Nakajima,Takayoshi Owada,Ryutaro Matsumura,Itsuo Iwamoto,Yoshihiro Oya,Yasushi Saito,Yohei Seto,Kei Ikeda,Norihiko Watanabe

doi:10.1155/2011/305656

Abstract

Inhibitory coreceptors are thought to play important roles in maintaining immunological homeostasis, and a defect in the negative signals from inhibitory coreceptors may lead to the development of autoimmune diseases. We have recently identified B and T lymphocyte attenuator (BTLA), a new inhibitory coreceptor expressed on immune cells, and we suggest that BTLA may be involved in the development of autoimmune diseases using BTLA-deficient mice. However, the role of BTLA in the pathogenesis of autoimmune diseases in humans remains unknown. We, therefore, examined the possible association between BTLA and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome (SS) by conducting a case-control genetic association study. We found that 590C single-nucleotide polymorphism (SNP) of BTLA gene was significantly associated with susceptibility to RA, but not to SLE or SS. Furthermore, RA patients bearing this 590C SNP developed the disease significantly earlier than the patients without this allele. We also found that BTLA with 590C allele lacked the inhibitory activity on concanavalin A- and anti-CD3 Ab-induced IL-2 production in Jurkat T cells. These results suggest that BTLA is an RA-susceptibility gene and is involved in the protection from autoimmunity in humans.

Highlights

The immune system has developed multiple mechanisms to prevent deleterious activation of T cells
Ligation of B and T lymphocyte attenuator (BTLA) induces its tyrosine phosphorylation and SHP-1/SHP-2 association and attenuates IL-2 production and proliferation of T cells [16, 21]. These findings suggest that BTLA functions as an inhibitory coreceptor through the interaction with herpesvirus entry mediator (HVEM) and that HVEM-BTLA interaction may play a role in the prevention of autoimmune diseases
We focused on #590 and #800 single-nucleotide polymorphism (SNP) of BTLA gene to determine whether these SNPs are associated with susceptibility to autoimmune diseases

Summary

Introduction

The immune system has developed multiple mechanisms to prevent deleterious activation of T cells. A defect in the negative signals from inhibitory coreceptors may reduce the threshold of autoreactive lymphocyte activation and, may lead to the development of autoimmune diseases. This notion has been evidenced by the autoimmune phenotype or lymphocyte hyperreactivity in genetically manipulated mice that lack CTLA-4 and PD-1 [8,9,10]. Ligation of BTLA induces its tyrosine phosphorylation and SHP-1/SHP-2 association and attenuates IL-2 production and proliferation of T cells [16, 21] These findings suggest that BTLA functions as an inhibitory coreceptor through the interaction with HVEM and that HVEM-BTLA interaction may play a role in the prevention of autoimmune diseases. Our results suggest that dysfunction of BTLA is involved in the pathogenesis of RA

Materials and Methods

Results

C Allele 41 52 24 28

Discussion