Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Complement C3 deposition on nucleic acids is characteristic of immune complex initiated classical pathway overdrive in lupus erythematosus

ABSTRACT: Systemic lupus erythematosus is progressive, immune complex-mediated autoimmune disease targeting numerous organs. A central feature of the disease is the development of antibodies against nuclear components, including DNA. Antibodies against double-stranded DNA are so characteristic of this disease that their detection constitutes one of the criteria for diagnosis. We examined the formation of immune complexes on the surface of autoantigen microarrays incubated in the sera of 39 inactive and 22 active lupus patients and of 31 control subjects. Three different kinds of nucleic acids, dsDNA, ssDNA and RNA were used as antigens, along with chromatin (nucleosomal extract) and several other reference molecules. The composition with respect to IgG, IgM and complement components C3 and C4 was determined. We find that while IgM and C4 are physiological components of immune complexes formed from nucleic acids, both IgG and C3 are extremely characteristic of lupus patients. Complement C4 deposition changes were not consistent: these increased on ssDNA and RNA, decreased on chromatin and did not change significantly on dsDNA. The presence of IgG and C3 in the immune complexes formed from different nucleic acids was characteristic for both active and inactive lupus patients. Receiver-operating curve statistics indicate that C3 deposition measurements can improve the efficiency of identification of inactive lupus patients. These observations reveal the complexity of immune profile changes accompanying SLE. C3, IgM, C4 and IgG binding in 92 human serum samples were examined using custom-made protein arrays

ORGANISM(S): Homo sapiens

SUBMITTER: KrisztiÃ¡n Papp

PROVIDER: E-GEOD-26768 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are strongly associated in human genetic studies with an increased risk of developing the autoimmune disease systemic lupus erythematosus. However, the biological role of IRF5 in lupus pathogenesis, if any, is not known. In this study we show that IRF5 is absolutely required for disease development in the FcgRIIB-/-Yaa and FcgRIIB-/- lupus models. In contrast to IRF5-sufficient FcgRIIB-/-Yaa mice, IRF5-deficient FcgRIIB-/-Yaa mice do not develop lupus manifestations and have a phenotype comparable to wildtype mice. Strikingly, full expression of IRF5 is required for the development of autoimmunity, as IRF5-heterozygotes had dramatically reduced disease. One effect of IRF5 is to induce the production of the type I interferon IFN-gamma, a cytokine implicated in lupus pathogenesis. To address the mechanism by which IRF5 promotes disease, we evaluated FcgRIIB-/-Yaa mice lacking the type I interferon receptor IFNAR1. Unlike the IRF5-deficient and IRF5-heterozygous FcgRIIB-/-Yaa mice, IFNAR1-deficient FcgRIIB-/-Yaa mice maintained a substantial level of residual disease. Furthermore, in FcgRIIB-/- mice lacking Yaa, IRF5-deficiency also markedly reduced disease manifestations, indicating that the beneficial effects of IRF5 deficiency in FcgRIIB-/-Yaa mice are not due only to inhibition of the enhanced TLR7 signaling associated with the Yaa mutation. Overall, we demonstrate that IRF5 plays an essential role in lupus pathogenesis in murine models and that this is mediated through pathways beyond that of type I interferon production. The fact that even IRF5 heterozygous mice developed minimal disease makes IRF5 a particularly attractive therapeutic target. Serum samples from a total of 70 mice were run on the Utz Lab Whole Protein Autoantigen Array V1.0 (a single-color platform) in order to profile their autoantibodies against a library of autoimmune antigens. All samples were run once with no replicates. The samples consisted of the following groups: For data appearing in Figure 3D, illustrating that mice lacking IRF5 have their autoantibody levels significantly affected: R2Yaa IRF5+/+: 12 R2Yaa IRF5+/-: 11 R2Yaa IRF5-/-: 14 C57BL/6 ("WT" control): 13 Total mice (arrays) for this group: 50 For data appearing in Figure 6D, illustrating that mice lacking Ifnar1 do not have their autoantibody levels significantly affected: R2Yaa Ifnar+/+: 10 R2Yaa Ifnar-/-: 10 Total mice (arrays) for this group: 20

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Complement C3 deposition on nucleic acids is characteristic of immune complex initiated classical pathway overdrive in lupus erythematosus

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