Investigating Genetic Polymorphism of Decoy Receptor 3 (DcR3) Gene in Rheumatoid Arthritis and Systemic Lupus Erythematosus
Abnormal immune responses permit sustained production of pathogenic subsets of
autoantibodies such as anti-DNA, and anti-RNP, anti-RBC, anti-platelet. T cell help is
critical to development of full-blown disease; CD4+, CD8+, CD4-, CD8- lymphocytes all help
autoantibody production in SLE. There are multiple abnormalities that permit hyper-activated
self-reactive B and T cells to dominate the immune repertoire. Defects in cell activation,
tolerance, apoptosis, idiotypic networks, immune complex clearance and generation of
regulatory cells are all accounted for. SLE may involve only one organ system at disease
onset or may be multi-systemic. Rheumatoid inflammation reflexes cause persistent
stimulation of T cells by synovial-derived antigens that cross-react with determinants
introduced during antecedent exposure to foreign antigens or infectious agents.
Decoy receptor 3 (DCR3/TR6) is a soluble, secreted factor that lacks a trans-membrane
domain. It belongs to the TNFR family and is capable of binding to TNF family members FasL,
LIGHT and TL1A. DcR3/TR6 mRNA is expressed at high levels in lymph nodes, the spleen and
activated T cells. DcR3/TR6 binds to FasL and inhibits the Fas-FasL interaction and
FasL-mediated apoptosis of lymphocytes and several tumor cell lines. LIGHT is highly
expressed on surface of activated T lymphocytes and macrophages, CD8+ tumor-infiltrating
lymphocyte, granulocytes and monocytes but not in the thymus and several human tumor cell
lines. LIGHT protein triggers apoptosis of several tumor cells expressing both lymphotoxin β
receptor (LTβR) and TR2. It was postulated that DcR3/TR6 modulated LIGHT-triggered
costimulation via TR2 in T cells. Human PBMCs secrete DcR3/TR6 after PHA or anti-CD3. The
leukocyte aggregation in mixed lymphocyte reaction was inhibited by adding soluble form
DcR3. On the other hand, it was shown that DcR3/TR6, TR2, LIGHT displayed complexity in
their interaction. The DcR3/TR6 expressed in solid phase actually transduced reverse,
costimulatory signals into the activated T cells. Soluble DcR3-Fc or solid-phase DcR3-Fc was
found to costimulate proliferation, lymphokine production and cytotoxicity of murine and
human T cells in the presence of suboptimal TCR ligation. Furthermore, cross linking Th1 and
Th2 cells with solid-phase DcR3-Fc along with suboptimal concentration of anti-CD3 enhanced
proliferation of both Th1 and Th2 cells, and augmented Th1 but not Th2 cytokine production.
These strongly suggest that DcR3/TR6 delivers costimulation through its ligand(s) on T
cells, at least part of the costimulation is transduced via LIGHT. Recently, we found that
soluble DcR3/TR6 level in circulating plasma in SLE patients was significantly higher than
that of non-autoimmune control subjects. Plate-bound form DcR3 enhanced proliferation of T
cells under suboptimal anti-CD3 stimulation in both normal and SLE patients. Addition of
soluble DcR3-Fc reduced activation-induced cell death in T cells subjected to anti-CD3
re-stimulation (unpublished data). Taken together, it raises the possibility that genetic
polymorphism in DcR3/TR6 locus might influence the expression level or function of DcR3,
which in turn is implicated in dysregulated lymphocyte activation and autoimmunity. With the
aim to establish the possible correlation between DcR3 genetic polymorphism, DcR3
expression, and autoimmune phenotypes, we give this proposal. We plan to investigate the
single nucleotide polymorphisms (SNPs) in DcR3 gene. The genetic polymorphisms on DcR3/TR6
gene and circulating DcR3 level will be compared between RA, SLE and non-autoimmune control
subjects.
The specific aims of this project are the following:
1. To study the allelic distribution of DcR3 genetic polymorphisms among the population in
Taiwan.
2. To investigate if there is any DcR3 allele correlate to serum level of DcR3.
3. To investigate if the genetic polymorphism on DcR3 gene be associated with autoimmune
diseases RA and SLE.
Observational
Observational Model: Case Control, Primary Purpose: Screening, Time Perspective: Cross-Sectional, Time Perspective: Retrospective
Chung-Yi Hu, PhD
Principal Investigator
Department of Clinical Laboratory Sciences and Medical Biotechnology
Taiwan: Department of Health
9361701218
NCT00172666
August 2005
July 2006
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