http://repub.eur.nl/res/aut/56150/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/37670/ 2012-09-15T00:00:00Z BACKGROUND: Innate immunity plays a role in controlling adaptive immune responses. METHODS: We investigated the clinical relevance of single nucleotide polymorphisms in 22 genes encoding innate, secreted, and signaling pattern recognition receptors in a total of 520 donor-recipient pairs of postmortem, human leukocyte antigen-DR-compatible kidney transplantations. Associations with rejection incidence were tested in an a priori randomized training set and validation set. RESULTS: Polymorphisms in TLR-3 (rs3775296) in the recipients and in Ficolin-2 (rs7851696; Ala258Ser) and C1qR1 (rs7492) in the donors showed the strongest association with severe rejection. In multivariate analysis, presence of the Ficolin-2 Ala258Ser variant in the donor predicted lower incidence of severe rejection (odds ratio=0.3; 95% confidence interval, 0.1-0.9; P=0.024) and of graft loss (hazard ratio=0.5; 95% confidence interval, 0.2-1.0; P=0.046) independently of clinical risk factors. Ficolin-2 messenger RNA expression was detected in pretransplantation biopsies from 69 donor grafts. Serum and tissue Ficolin-2 levels were unaffected by genotype. Ficolin-2 protein, which bound to dying cells, was detected in donor kidneys in a passenger leukocyte-like pattern. Indeed, monocytes, monocyte-derived macrophages, and peripheral blood mononuclear cells expressed Ficolin-2. Donor grafts with the Ficolin-2 Ala258Ser variant contained significantly elevated expression of interleukin 6, having ascribed cytoprotective effects. It has been described that Ala258Ser leads to increased binding capacity of Ficolin-2 to N-acetylglucosamine. CONCLUSIONS: Presence of the Ficolin-2 Ala258Ser polymorphism in the donor independently predicts improved graft outcome. Based on mechanistic data, we propose that this functional polymorphism leads to more efficient handling of injured cells by phagocytozing cells, resulting in decreased intragraft exposure to danger signals and dampened alloimmune responses. Copyright http://repub.eur.nl/res/pub/35417/ 2007-05-14T00:00:00Z Dendritic cells (DCs) play critical roles in immune responses and can be distinguished in two major subsets, myeloid and plasmacytoid DCs. Although the presence of DC in all peripheral organs, including the kidney, has been well documented, no accurate estimates of DC subsets in human kidneys have been reported. This study shows a detailed analysis of DC subsets in cryosections of human renal tissue. The cortex of normal kidneys contains at least two different HLA-DR+myeloid DC subtypes characterized by BDCA-1+DC-SIGN+and BDCA-1+DC-SIGN-. The staining for DC-SIGN completely overlapped with CD68 in the renal interstitium. Unexpectedly, BDCA-2+DC-SIGN-plasmacytoid DCs are also abundantly present. Both subsets are located in the tubulo-interstitium often with a high frequency around, but rarely observed within glomeruli. Quantification of BDCA-1+, DC-SIGN+, and BDCA-2+cells in normal human renal tissue (pretransplant biopsy living donors; n=21) revealed that BDCA-1 is about four times as frequently present as BDCA-2. A preliminary cross-sectional analysis of DC in diseased kidneys, including rejection and immunoglobulin A nephropathy, revealed that the number of DC as well as their anatomical distribution might change under pathophysiological conditions. In conclusion, we show that human kidneys contain a dense network of myeloid and plasmacytoid DCs and provide the tools for phenotyping and enumeration of these cells to better understand interindividual differences in immune responses.