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- Ahlgren, Kerstin, M., et al.
(författare)
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Type I Interferon signature in Nova Scotia duck tolling retriever dogs with steroid responsive meningitis-arteritis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objective: Dogs of the breed Nova Scotia duck tolling retriever (NSDTR) are prone to develop a disease complex in some aspects resembling human systemic lupus erythematosus (SLE). Peripheral blood mononuclear cells (PBMCs) from human SLE patients have an increased mRNA expression type I interferon (IFN) regulated genes. However, it is unknown whether diseased dogs also display the typical type I IFN signature. Methods: To test canine sera for their capacity to induce type I IFN response Mardin-Darby canine kidney (MDCK) cells were cultured with sera from healthy dogs (n=25), immune-mediated rheumatic disease (IMRD) dogs with anti-nuclear antibodies (ANA+) (n=30) or dogs with steroid responsive meningitis-arteritis (SRMA) (n=25). mRNA expression of the genes MX1, IFIT1 and CXCL10 was measured by quantitative Real Time PCR. Results: A highly significant (p=0.0009) increase in mRNA expression of the type I IFN responsive gene MX1 was detected in cells stimulated by sera from dogs with SRMA, but not from IMRD ANA+ dogs. Expression of IFIT1 was twice as high in cells stimulated by sera from dogs with SRMA compared to both healthy dogs and ANA+ dogs. The mean expression of CXCL10 was nearly ten times higher in cells stimulated by sera from SRMA dogs than by ANA+ dogs and four times higher compared to cells stimulated by control dogs. Conclusion: Presence of type I IFN in sera from diseased NSDTR dogs was found in this study. This implies that this canine model can be used for identification of pathways of importance for autoimmune disorders in humans and for testing of novel therapeutic approaches. Our results can also be a step on the way towards personalized drugs in these dogs.
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- Hagberg, Niklas, 1977-, et al.
(författare)
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Autoantibodies to the CD94/NKG2A and CD94/NKG2C receptors in patients with systemic lupus erythematosus
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: To investigate the occurrence and function of autoantibodies (autoabs) targeting the CD94/NKG2A, CD94/NKG2C or NKG2D receptors in patients with systemic lupus erythematosus (SLE).Method: Murine Ba/F3 cells transfected with CD94/NKG2A, CD94/NKG2C or NKG2D, and untransfected cells were incubated with sera from 203 patients with SLE and 90 healthy individuals. Binding of immunoglobulin (Ig) to the cells was determined by flow cytometry. Autoabs were characterized with regard to isotype, subclass, λ/κ exclusion and interference with HLA-E-binding. IgG were evaluated for effect on NK cell degranulation in response to HLA-E-transfected K562 target cells, as well as their capacity to induce antibody-dependent cellular cytotoxicity (ADCC). The frequency and phenotype of NK cells from these patients were determined by flow cytometry and the exons encoding NKG2A (KLRC1), NKG2C (KLRC2) and CD94 (KLRD1) were sequenced. The titers of anti-CD94/NKG2A and -CD94/NKG2C autoabs were determined in longitudinally sampled sera and correlated to disease activity (SLEDAI score) and severity (SLICC/ACR damage index).Results: Seven patients with autoabs targeting the CD94/NKG2A receptor were identified. Two of these patients’ autoabs also recognized the CD94/NKG2C receptor. IgG from six of the patients interfered with the binding of HLA-E to CD94/NKG2A, whereas IgG from one patient increased this binding. Of the two patients with anti-CD94/NKG2C autoabs, IgG from one patient blocked, and IgG from the other patient stabilized the binding of HLA-E to CD94/NKG2C. Anti-CD94/NKG2A autoabs abrogated the HLA-E-mediated inhibition of NK cell cytotoxicity by CD94/NKG2A+ NK cells, whereas anti-CD94/NKG2C autoabs interfered with the HLA-E-mediated increased cytotoxicity of CD94/NKG2C+ NK cells. Furthermore, these autoabs induced ADCC of CD94/NKG2A- and CD94/NKG2C-expressing target cells. No uncommon non-synonymous sequence variations were found in the genes encoding NKG2A, NKG2C or CD94. The titers of anti-CD94/NKG2A and -CD94/NKG2C autoabs were associated to the SLEDAI score.Conclusions: Autoabs targeting the CD94/NKG2A or the CD94/NKG2C receptor are found in a subset of patients with SLE. These autoabs affects the cytotoxicity of NK cells, mediate ADCC in vitro and their titers are associated to the disease activity and a more severe SLE phenotype. Consequently, anti-CD94/NKG2A and anti-CD94/NKG2C autoabs may contribute to the pathogenesis of SLE and our findings highlight the possible importance of NK cells in the SLE disease process.
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