University of Groningen Identification of novel genes associated with renal tertiary lymphoid organ formation in aging

A hallmark of aging-related organ deterioration is a dysregulated immune response characterized by pathologic leukocyte infiltration of affected tissues. Mechanisms and genes involved are as yet unknown. To identify genes associated with agingrelated renal infiltration, we analyzed kidneys from aged mice ($20 strains) for infiltrating leukocytes followed by Haplotype Association Mapping (HAM) analysis. Immunohistochemistry revealed CD45 cell clusters (predominantly T and B cells) in perivascular areas coinciding with PNAd high endothelial venules and podoplanin lymph vessels indicative of tertiary lymphoid organs. Cumulative cluster size increased with age (analyzed at 6, 12 and 20 months). Based on the presence or absence of clusters in male and female mice at 20 months, HAM analysis revealed significant associations with loci on Chr1, Chr2, Chr8 and Chr14 in male mice, and with loci on Chr4, Chr7, Chr13 and Chr14 in female mice. Wisp2 (Chr2) showed the strongest association (P = 5.00610) in male mice; Ctnnbip1 (P = 6.42610) and Tnfrsf8 (P = 5.42610) (both on Chr4) showed the strongest association in female mice. Both Wisp2 and Ctnnbip1 are part of the Wnt-signaling pathway and the encoded proteins were expressed within the tertiary lymphoid organs. In conclusion, this study revealed differential lymphocytic infiltration and tertiary lymphoid organ formation in aged mouse kidneys across different inbred mouse strains. HAM analysis identified candidate genes involved in the Wnt-signaling pathway that may be causally linked to tertiary lymphoid organ formation. Citation: Huang Y, Caputo CR, Noordmans GA, Yazdani S, Monteiro LH, et al. (2014) Identification of Novel Genes Associated with Renal Tertiary Lymphoid Organ Formation in Aging Mice. PLoS ONE 9(3): e91850. doi:10.1371/journal.pone.0091850 Editor: David Long, UCL Institute of Child Health, United Kingdom Received June 25, 2013; Accepted February 17, 2014; Published March 17, 2014 Copyright: 2014 Huang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by the University of Groningen Graduate School of Medical Sciences (YH [Bernoulli Bursary], GAN and SY), GM076468 from the NIGMS (RK), AG038070 from NIA (RK), and the National Cancer Institute Cancer Core grant (CA034196) to The Jackson Laboratory. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: j.l.hillebrands@umcg.nl