The immune system and kidney disease: basic concepts and clinical implications.

1] Institutes of Molecular Medicine and Experimental Immunology (IMMEI), Rheinische Friedrich-Wilhelms-Universität, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. [2].
Nature Reviews Immunology 09/2013; DOI: 10.1038/nri3523
Source: PubMed

ABSTRACT The kidneys are frequently targeted by pathogenic immune responses against renal autoantigens or by local manifestations of systemic autoimmunity. Recent studies in rodent models and humans have uncovered several underlying mechanisms that can be used to explain the previously enigmatic immunopathology of many kidney diseases. These mechanisms include kidney-specific damage-associated molecular patterns that cause sterile inflammation, the crosstalk between renal dendritic cells and T cells, the development of kidney-targeting autoantibodies and molecular mimicry with microbial pathogens. Conversely, kidney failure affects general immunity, causing intestinal barrier dysfunction, systemic inflammation and immunodeficiency that contribute to the morbidity and mortality of patients with kidney disease. In this Review, we summarize the recent findings regarding the interactions between the kidneys and the immune system.

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    ABSTRACT: Objective The CD4+ T-cell immune response plays a pivotal role in the immunopathogenesis of human and experimental lupus nephritis, but the contribution of TH17/IL-17 immunity to renal tissue injury in systemic lupus erythematosus (SLE) remains to be elucidated. Here we characterize the function of the TH17/IL-17A immune response in two murine models of lupus nephritis (MRL/lpr and NZB/W F1 mice).Methods We generated MRL/lpr mice deficient in IL-17A and analyzed the clinical course of the nephritis with respect to albuminuria, renal tissue injury, and functional parameters. In addition, lupus-prone NZB/W F1 mice were treated with anti-IL-17A- and anti-IFNγ-antibodies.ResultsThe characterization of renal IL-17A- and IFNγ-producing T cells in MRL/lpr and NZB/W F1 mice revealed low numbers of infiltrating CD3+ IL-17A + cells. Renal IL-17A was mainly produced by CD4/CD8 double-negative CD3+ T cells and CD4+ TH17 cells. In contrast, renal CD3+ IFNγ+ cells continuously increased over time and largely consisted of typical CD4+ TH1 cells. IL-17A deficiency did not affect the morphological or functional parameters in MRL/lpr mice with lupus nephritis, nor did IL-17A neutralization affect the clinical course of the nephritis in NZB/W F1 mice, but anti-IFNγ treatment attenuated the severity of the disease.Conclusion The TH17/IL-17A immune response plays no major role in the immunopathogenesis of lupus nephritis in MRL/lpr and NZB/W F1 mice. Thus, our results do not support the hypothesis that IL-17A targeting may be an intriguing new therapeutic approach for all patients with lupus nephritis. © 2014 American College of Rheumatology.
    11/2014; DOI:10.1002/art.38955
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    ABSTRACT: Necrotic cell death in vivo induces a robust neutrophilic inflammatory response and the resulting inflammation can cause further tissue damage and disease. Dying cells induce this inflammation by releasing pro-inflammatory intracellular components, one of which is uric acid. Cells contain high levels of intracellular uric acid, which is produced when purines are oxidized by the enzyme xanthine oxidase. Here we test whether a non-nucleoside xanthine oxidase inhibitor, Febuxostat (FBX), can reduce intracellular uric acid levels and inhibit cell death-induced inflammation in two different murine tissue injury models; acid-induced acute lung injury and acetaminophen liver injury. Infiltration of inflammatory cells induced by acid injection into lungs or peritoneal administration of acetaminophen was evaluated by quantification with flow cytometry and tissue myeloperoxidase activity in the presence or absence of FBX treatment. Uric acid levels in serum and tissue were measured before giving the stimuli and during inflammation. The impact of FBX treatment on the peritoneal inflammation caused by the microbial stimulus, zymosan, was also analyzed to see whether FBX had a broad anti-inflammatory effect. We found that FBX reduced uric acid levels in acid-injured lung tissue and inhibited acute pulmonary inflammation triggered by lung injury. Similarly, FBX reduced uric acid levels in the liver and inhibited inflammation in response to acetaminophen-induced hepatic injury. In contrast, FBX did not reduce inflammation to zymosan, and therefore is not acting as a general anti-inflammatory agent. These results point to the potential of using agents like FBX to treat cell death-induced inflammation. Copyright © 2014. Published by Elsevier B.V.
    European Journal of Pharmacology 11/2014; DOI:10.1016/j.ejphar.2014.11.013 · 2.68 Impact Factor