Antigen Is Required for Maturation and Activation of Pathogenic Anti-DNA Antibodies and Systemic Inflammation
| Autor: | Christine M. Grimaldi, Prameladevi Chinnasamy, Jeganathan Venkatesh, Joel Cohen-Solal, Anfisa Stanevsky, Hajime Yoshifuji, Betty Diamond, Daisuke Kawabata |
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| Rok vydání: | 2011 |
| Předmět: |
Immunology
Enzyme-Linked Immunosorbent Assay Mice Transgenic Cell Separation Biology Systemic inflammation Autoantigens Article Immune tolerance Mice Immune system Antigen Immune Tolerance medicine Animals Lupus Erythematosus Systemic Immunology and Allergy B cell Inflammation Mice Inbred BALB C Systemic lupus erythematosus Reverse Transcriptase Polymerase Chain Reaction Dendritic cell Flow Cytometry medicine.disease Disease Models Animal medicine.anatomical_structure Antibodies Antinuclear biology.protein medicine.symptom Antibody |
| Zdroj: | The Journal of Immunology. 186:5304-5312 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1000224 |
| Popis: | Systemic lupus erythematosus is an autoimmune disease characterized by autoantibodies and systemic inflammation that results in part from dendritic cell activation by nucleic acid containing immune complexes. There are many mouse models of lupus, some spontaneous and some induced. We have been interested in an induced model in which estrogen is the trigger for development of a lupus-like serology. The R4A transgenic mouse expresses a transgene-encoded H chain of an anti-DNA Ab. This mouse maintains normal B cell tolerance with deletion of high-affinity DNA-reactive B cells and maturation to immunocompetence of B cells making nonglomerulotropic, low-affinity DNA-reactive Abs. When this mouse is given estradiol, normal tolerance mechanisms are altered; high-affinity DNA-reactive B cells mature to a marginal zone phenotype, and the mice are induced to make high titers of anti-DNA Abs. We now show that estradiol administration also leads to systemic inflammation with increased B cell-activating factor and IFN levels and induction of an IFN signature. DNA must be accessible to B cells for both the production of high-affinity anti-DNA Abs and the generation of the proinflammatory milieu. When DNase is delivered to the mice at the same time as estradiol, there is no evidence for an abrogation of tolerance, no increased B cell-activating factor and IFN, and no IFN signature. Thus, the presence of autoantigen is required for positive selection of autoreactive B cells and for the subsequent positive feedback loop that occurs secondary to dendritic cell activation by DNA-containing immune complexes. |
| Databáze: | OpenAIRE |
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