Study On The Role Of JAK/STAT Signaling Pathway Related Genes In The Pathogenesis Of Systemic Lupus Erythematosus

Background Systemic lupus erythematosus(SLE) is prototype of autoimmune disease characterized by high level of autoantibody production and multiple organ systems involvement. The etiology and pathogenesis of SLE has not yet been completely clarified. It is thought that a complex interaction of genetic and environmental factors may contribute to immune disorder in the pathogenesis of SLE, resulting in a variety of immune abnormalities which along with a large number of autoantibodies and immune complex deposition to trigger corresponding pathological damages.The immune abnormalities in SLE was found to be closely correlated to cytokines and researches showed that the abnormalities of cytokines and its immune signaling pathway play a key role in the pathogenesis of SLE.Cytokines are small molecular proteins with broad biological activities. As cell signaling molecules, cytokines have an important effect on the regulation of the immune response, immune cell differentiation and development and inflammatory response. Studies have shown that abnormal expression of various cytokines was observed in SLE patients. Among these cytokines, the role of interferon (IFN), including type I interferon (IFN-α/β) and typeⅡinterferon (IFN-γ), in the pathogenesis of SLE have been confirmed.The biological effects of IFNs and other cytokines are mainly mediated through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway which is one major cytokine signal transduction pathway playing an important role in cytokine-mediated immune response and immune regulation.Studies have shown that abnormal gene expression of some JAK/STAT signaling pathway components such as JAK1, TYK2, STAT1and STAT3, was observed in SLE patients. The gene polymorphism of TYK2, IRF5 and STAT4 was also found to be associated with SLE genetic susceptibility. Recent studies have suggested that these gene variants linked to SLE might alter thresholds for immune response, resulting in the production of autoantibodies and immune abnormalities. These studies indicated that abnormal gene expression and gene polymorphism of JAK/STAT signaling pathway components might play an important role in the pathogenesis of SLE.However, little is known about the role of JAK/STAT signaling pathway in SLE at present. Most studies were focused on the association study of a single gene or locus variants with SLE susceptibility, whereas the systemic study on all functional genes related to one immune signaling pathway was very limited. Therefore, the study of the expression of the signaling pathway related genes in SLE would help to further reveal the pathogenesis of SLE and develop new potential diagnostic biomarkers and therapeutic targets.Thus, on the basis of SLE genetic resources, our study adopted case-control design and gene chip technology to screen the differentially expressed genes of JAK/STAT signaling pathway and analyze the relationship among the gene expression levels and SLE disease activity and organ damages.Objective To identify the differentially expressed genes of JAK/STAT signaling pathway by comparing the mRNA expression levels of peripheral leukocytes between SLE patients and normal controls. Combined with clinical data,the relationship among the gene expression levels and SLE disease activity and organ damages were further analyzed.Methods SLE patients were selected from two hospitals, and normal healthy volunteers were recruited as controls. General epidemiological information, the data of clinical manifestations and clinical laboratory indexes were collected by self-designed questionnaire according to the SLE disease activity index (SLEDAI) and the diagnostic and classification criteria. The total RNA was extracted from peripheral leukocytes of the collected blood samples and reversely transcribed in cDNA. Real-time quantitative PCR was used to detect the mRNA expression level of JAK/STAT signaling pathway related genes between SLE patients and normal controls. 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 patients with SLE and 15 normal controls were collected in the present study. The most common initial symptoms in SLE patients were arthritis (60.0%),disciod erythema (56.0%) , kidney damage (32.0%),etc. Most patients had two or more symptoms.(2) In total, we identified 16 candidate genes that were differentially expressed between SLE patients and normal controls. Of these 16 genes, 12 genes (SH2B2, CDKN1A, CRK, FAS, ISG15, IFNGR1,IRF9, JAK2, OAS1, OSM, SOCS3, SPI1)were up-regulated and 8 genes (FCER1A, PDGFRA, SIT1, RPL13A) were down-regulated in SLE patients.(2) The genes expression has no significant difference between lupus nephritis patients and SLE patients without lupus nephritis.(3) The expression of CDKN1A has significantly decreased by 2.53 times in active SLE patients compared with inactive SLE patients. (4) The expression of SRC has significantly decreased by 2.25 times in SLE patients with arthritis compared with SLE patients without arthritis.According to the biological function of these genes, the 16 genes contained JAK and STAT protein molecules (JAK2), negative regulators of the JAK/ STAT pathway (SOCS3), cytokines and receptors (IFNGR1), apoptosis-related genes (FAS), interferon-related gene (IRF9, ISG15 and OAS1), cell cycle and proliferation-related genes (CDNK1A, OSM and PDGFR), immune response genes (FCER1A) and adaptor protein molecules (SH2B2, CRK, SIT1 and SRC).Conclusion In summary, our study showed that the expression levels of multiple genes related to JAK/STAT signaling pathway were significantly altered in SLE patients. These genes are involved in various functions, including signal transduction, apoptosis, transcriptional regulation, immune responses and so on, suggesting that JAK / STAT signaling pathway may be an important immune regulatory pathway in the pathogenesis of SLE and the abnormally expressed genes, as candidate susceptibility genes for SLE, might be involved in the pathogenesis of SLE and related to disease activity and lupus arthritis. Therefore, an in-depth, systemic study of the role of JAK/STAT signaling pathway in SLE might provide clues for elucidating the pathogenesis of SLE and developing potential diagnostic biomarkers and therapeutic targets.