Top Reads

Kidney disease represents a major medical and economic burden for which improved treatments are urgently needed. Emerging data have implicated Th17 cells and IL-17 signaling in the underlying pathogenesis of autoantibody-induced glomerulonephritis (AGN). However, the downstream transduction pathways mediated by IL-17 in autoimmunity are not well defined. In this article, we show that CCAAT/enhancer-binding protein (C/EBP) δ is elevated in kidney biopsies from multiple manifestations of human AGN. C/EBPδ is similarly upregulated in a mouse model of anti-glomerular basement membrane protein–mediated kidney disease, and Cebpd^−/− mice were fully refractory to disease. Although C/EBPδ is expressed in a variety of cell types, C/EBPδ was required only in the radioresistant compartment to drive GN pathology. C/EBPδ induced expression of several IL-17–induced kidney injury markers and cytokines implicated in disease, including Il6 and Lcn2. Because mouse AGN models do not progress to fibrosis, we employed a nephrotoxic injury model using aristolochic acid I to assess the contribution of the IL-17–C/EBPδ pathway to renal fibrotic events. Surprisingly, deficiency of either C/EBPδ or the IL-17 receptor caused kidney fibrosis to be enhanced. Thus, C/EBPδ and IL-17 play divergent and apparently stage-specific roles in the pathogenesis of kidney disease.

Candida spp. are the fourth leading cause of bloodstream infections in hospitalized patients and the most common cause of invasive fungal infection. No vaccine against Candida spp. or other fungal pathogens of humans is available. We recently discovered the Blastomyces Dectin-2 ligand endoglucanase 2 that harbors antigenic and adjuvant functions and can function as a protective vaccine against that fungus. We also reported that the adjuvant activity, which is mediated by O-mannans decorating the C terminus of Blastomyces Dectin-2 ligand endoglucanase 2, can augment peptide Ag-induced vaccine immunity against heterologous agents, including Cryptococcus, Candida, and influenza. In this article, we report that the O-linked mannans alone, in the absence of any antigenic peptide, can also protect against systemic candidiasis, reducing kidney fungal load and increasing survival in a Dectin-2–dependent manner. We found that this long-term glycan-induced protection is mediated by innate lymphocyte populations including TCR-γδ⁺ T cells, innate lymphoid cells, and NK cells that subsequently activate and release reactive oxygen species from neutrophils and monocytes. Our findings suggest that Blastomyces O-mannan displayed by Eng2 induces a form of protective trained immunity mediated by innate lymphocyte populations.