| Background Systemic lupus erythematosus (SLE) is an autoimmune disease that characterized by B cell hyperactivity, abnormally activated T cells and defects in the clearance of apoptotic cells and immune complexes. A notable hallmark of the disease is that a diverse array of autoantibody production, complement activation and immune complex deposition, causing tissue and organ damage. The etiopathogenesis of SLE remains poorly understood. A complex interaction of genetic and environmental factors are thought to contribute to SLE immune disorder. For many years, investigations into its pathogenesis have focused on abnormalities in adaptive immunity. Recent studies suggest that abnormal stimulation of innate immune system may contribute importantly to the immunopathogenesis of SLE.The TLR family plays a critical role in the mammalian innate immune system, the first line of host defence against invading pathogens. Nucleic acids are rendered immunogenic through hypomethylation, oxidation, and high content CpG. Recognition of self nucleic acids by toll-like receptors (TLRs) on B cells and plasmacytoid dendritic cells (PDCs) is an important step in the pathogenesis of SLE. Each TLR recognize a specific set of these molecular patterns, including components of bacterial cell walls for TLR2 and 4 and nucleic acids such as dsRNA, ssRNA, and unmethylated CpG dinucleotide-containing DNA for TLR3, 7, and 9, respectively. However, They differ not only in their ability to recognize distinct ligands and their differences in subcellular localization but also in the signaling pathways that they activate. It has demonstrated that SLE patients had a significant higher expression of TLRs than controls. Moreover, several groups showed abnormal expression of TLRs, TLR related cytokines and chemokines in peripheral blood lymphocytes of SLE patient. Studies indicated that TLR activation leading to type I-IFNs contributed to the pathogenesis of SLE. Furthermore, overexpression of TLRs may result in aberrant activation of monocytes, T and B lymphocytes for the production of cytokines and chemokines, implicating that the abnormalities of TLR signaling pathway play a key role in the pathogenesis of SLE.At present, there is no cure for SLE while treatment is aimed at controlling symptoms; despite this, exploration into the disease mechanisms might lead to the development of improved therapeutic approaches. Information of the expression profiles of TLRs pathway may not only provide a new platform for evaluating TLR's role in the manifestation of antoimmune disease, but also facilitate the development of TLR targeting therapy in autoimmune disorders. Most studies were focused on the association of locus variants or a single gene with SLE susceptibility, whereas the systemic study on all functional genes related to one immune signaling pathway was very limited. Therefore, on the basis of SLE genetic resources, we used case-control design and a Quantitative RT-PCR Array(Human Toll-Like Receptor Signaling Pathway) to profile the expression of 84 genes related to TLR-mediated signal transduction and analyze the relationship of the gene expression levels and organ damage in SLE patients.Objective To identify the abnormally expressed genes of TLR signaling pathway by comparing the mRNA expression levels of peripheral leukocytes between SLE patients and controls. Despite this, the relationship of the gene expression levels and SLE organ damages were also analyzed. Methods SLE patients were recruited at the Department of Rheumatology of First Affiliated Hospital and, Auhui Provincial Hospital Anhui Medical University, while healthy volunteers were recruited as controls. Self-designed questionnaire according to the SLE disease activity index (SLEDAI) and the diagnostic and classification criteria were used to collect general epidemiological information, the data of clinical manifestations and clinical laboratory indexes. The total RNA was extracted from peripheral leukocytes of the collected blood samples and reversely transcribed in cDNA. Real-time quantitative PCR array was used to detect the mRNA expression level of TLR signaling pathway related genes between SLE patients and controls. Data were analyzed by Statistical Package for Social Sciences version 10.01 software (SPSS, Chicago, IL, USA). A p value less than 0.05 and a mean difference equal to or greater than 2-fold were considered statistically significant.Results(1) 25 new onset SLE patients and 15 normal controls were collected in the study. The 3 most common initial symptoms in SLE patients were arthritis (60.0%),disciod erythema (56.0%) and kidney damage (32.0%). Most patients had more than two symptoms.(2)In total, we identified 23 candidate genes that were differentially expressed between SLE patients and normal controls. Of the 23 genes, 17 genes (CCL2, CD14, CLEC4E, CXCL10, EIF2AK2, FOS, IL10, IL8, JUN, LY96, MAP2K3, NFKBIA, PELI1, REL, RIPK2, TBK1, TLR2, TLR4) were up-regulated and 6 genes (CASP8, FADD, HSPA1A, HSPD1, CD180, SIGIRR, TNFRSF1A) were down-regulated.(3) The expression of TLR5 has significantly decreased by 2.10 times in LN patients compared with SLE patients without .(4) 8(CASP8, CD86, HSPA1A, HSPD1, IL1B, TLR7, TLR8, TNFRSF1A) candidate genes were down-regulated in SLE patients with arthritis compared with SLE patients without arthritis.Conclusion In conclusion, our study showed the significant abnormal expression levels of multiple genes related to TLR signaling pathway in SLE patients. These genes include TLRs family members, adaptors and TLR interacting proteins, effectors, downstream pathways and target genes and so on. Result suggests that TLR signaling pathway may be an important immune regulatory pathway in the pathogenesis of SLE. Meanwhile as candidate susceptibility genes for SLE, the abnormally expressed genes might be involved in the pathogenesis of SLE and related to lupus nephritis and arthritis. Thus, an systemic and in-depth study of the role of TLR signaling pathway in SLE might help elucidating the pathogenesis of SLE and developing therapeutic targets. |
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