title: Identification of novel genes associated with renal tertiary lymphoid organ formation in aging mice.
abstract: 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 aging-related 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 = 5.00×10(-137)) in male mice; Ctnnbip1 (P = 6.42×10(-267)) and Tnfrsf8 (P = 5.42×10(-245)) (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.
authors.affiliation: Department of Pathology & Medical Biology - Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Caputo
authors.affiliation: Department of Pathology & Medical Biology - Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Gerda A
authors.initials: GA
authors.lastname: Noordmans
authors.affiliation: Department of Internal Medicine - Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Saleh
authors.initials: S
authors.lastname: Yazdani
authors.affiliation: Department of Pathology & Medical Biology - Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Luiz Henrique
authors.initials: LH
authors.lastname: Monteiro
authors.affiliation: Department of Internal Medicine - Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: van den Born
authors.affiliation: Department of Pathology & Medical Biology - Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.affiliation: Department of Pathology & Medical Biology - Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Heeringa
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Ron
authors.initials: R
authors.lastname: Korstanje
authors.affiliation: Department of Pathology & Medical Biology - Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jan-Luuk
authors.initials: JL
authors.lastname: Hillebrands
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000375:Aging / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000818:Animals; D005260:Female; D056726:Genetic Association Studies; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D017730:Ki-1 Antigen / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D042601:Lymphatic Vessels / Q000473:pathology; D008221:Lymphoid Tissue / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C411982:CTNNBIP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D017730:Ki-1 Antigen; C539089:WISP-2 protein, mouse