Abstract Introduction Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by various clinical manifestations. Several cytokines interact and play pathological roles in SLE, although the etiopathology is still obscure. In the present study we investigated the network of immune response-related molecules expressed in the peripheral blood of SLE patients, and the effects of cytokine interactions on the regulation of these molecules. Methods Gene expression profiles of peripheral blood from SLE patients and from healthy women were analyzed using DNA microarray analysis. Differentially expressed genes classified into the immune response category were selected and analyzed using bioinformatics tools. Since interactions among TNF, IFNγ, β-estradiol (E2), and IFNα may regulate the expression of interferon-inducible (IFI) genes, stimulating and co-stimulating experiments were carried out on peripheral blood mononuclear cells followed by analysis using quantitative RT-PCR. Results Thirty-eight downregulated genes and 68 upregulated genes were identified in the functional category of immune response. Overexpressed IFI genes were confirmed in SLE patient peripheral bloods. Using network-based analysis on these genes, several networks including cytokines – such as TNF and IFNγ – and E2 were constructed. TNF-regulated genes were dominant in these networks, but in vitro TNF stimulation on peripheral blood mononuclear cells showed no differences in the above gene expressions between SLE and healthy individuals. Co-stimulating with IFNα and one of TNF, IFNγ, or E2 revealed that TNF has repressive effects while IFNγ essentially has synergistic effects on IFI gene expressions in vitro . E2 showed variable effects on IFI gene expressions among three individuals. Conclusions TNF may repress the abnormal regulation by IFNα in SLE while IFNγ may have a synergistic effect. Interactions between IFNα and one of TNF, IFNγ, or E2 appear to be involved in the pathogenesis of SLE.
Rheumatology has pioneered in the study of autoantibodies by showing that they are not only involved in pathogenesis but are also highly useful as diagnostic biomarkers.The diagnostic biomarker aspect of autoimmunity has gained increasing importance in cancer and many of the insights gained in Rheumatology have contributed to understanding the significance of autoantibodies in cancer.Features of autoantibodies in rheumatic disorders: In rheumatic diseases no individual autoantibody-antigen system has sufficient combination of sensitivity and specificity to serve as a useful diagnostic biomarker.Instead, several antigen-antibody systems constructed as profiles of biomarkers are highly effective in distinguishing one disorder from another.In lupus, anti-double strand DNA and anti-Sm distinguishes it from scleroderma, where the profile is anti-DNA topoisomerase 1 and anti-centromere proteins.The autoantigensare cell components involved in universal and basic gene expression pathways, such as Sm in precursor mRNA splicing and DNA topoisomerase 1 in DNA replication and transcription [1].Features of autoantibodies in cancer: Autoantibodies in cancer target intracellular molecules referred to as TAAs (tumor-associated antigens).As in rheumatic disorders, no individual autoantibody-antigen system has sensitivity and specificity to serve as a stand-alone diagnostic marker [2].Most tumors show multiple antibody specificities and with panels of TAAanti-TAAs (analogous toprofiles) the cumulative sensitivity and specificity reaches diagnostic significance.Different tumorigenesis pathways are
Systemic lupus erythematosus (SLE) is an autoimmune disease more prominent in women and characterized by multiple organ damage. Imbalance in cytokine production and cytokine levels correlates with SLE progression, making the understanding of SLE cytokine networks very important for SLE treatment strategy and drug development. In this article, we review cytokine networks that may be involved in the pathogenesis of SLE by briefly describing abnormal cytokine production and serum cytokine levels in SLE patients. We also focus on the pathological roles of cytokines and their interactions in immunoregulatory networks and suggest how their disturbances may implicate in pathological conditions in SLE. Finally, we further discuss the influence of estrogen on these cytokine networks.
Abstract Introduction Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by various systemic symptoms and multiple organ damage. We clarify biological and functional abnormalities in SLE by comparing the gene expression profiles of SLE patients with those of healthy individuals. Methods Gene expression profiles from the peripheral blood of 21 SLE patients and 45 healthy individuals were obtained using a DNA microarray. Gene ontology analysis and network pathway analysis were performed on the genes differentially expressed between SLE and healthy individuals. Results A total of 2,329 upregulated genes and 1,884 downregulated genes were differentially expressed. Gene ontology analysis revealed that the upregulated genes were classified as response to biotic stimulus genes, which mainly includes genes related to immune response. Abnormalities in other categories such as cell motility and regulation of apoptosis were also revealed. Downregulated genes were mainly sorted into two gene categories, sensory perception and response to radiation/light. The sensory perception genes included ATPase/ATPase domain-containing genes, myosin-related genes, and two excision repair cross-complementing genes, which are involved in DNA repair. Other genes in this group - including three crystallin genes, genes encoding the receptor protein for melanocyte-stimulating hormone, and six mitochondrial-DNA encoded genes, which are involved in ATP synthesis - were also categorized as response to radiation genes. Using network pathway analysis, IL-6, transforming growth factor beta 1, TNF, and hepatocyte nuclear factor 4α were found to play central roles in the networks of sensory perception-related molecules. Conclusions Functional abnormalities in ATP synthesis and DNA repair are implicated in peripheral blood cells from SLE patients.
normalized using the global ratio median. Only gene expression data that were collected from at least 80% of samples from each group were selected for further analysis. Th e unpaired Mann–Whitney test was used to determine statistically signifi cant diff erences in the mRNA expression levels between the RA and healthy groups. Statistical signifi cance was set at P <0.05. Th e results of our DNA microarray analysis showed that the expressions of four out of the six RA susceptibility genes were signifi cantly higher in RA patients than in healthy individuals (1.0 x 10 –16 to 2.32 x 10 –5 )
