title: Interstitial inflammation in Alport syndrome.
abstract: The Alport syndrome is a hereditary glomerular disease linked to structural abnormalities of collagen IV. In a mouse model of Alport syndrome, the interstitial lymphocyte influx was important for disease progression. CXCR3 is a chemokine receptor involved in lymphocyte recruitment to the kidney. We hypothesized that CXCR3-positive T cells might be involved in human Alport syndrome. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded biopsies from 17 patients with Alport syndrome, 10 with immunoglobulin A (IgA) nephropathy, and 11 healthy donor kidneys. We investigated the expression of the alpha5 chain of collagen IV to confirm the morphologic diagnosis, the chemokine receptor CXCR3 and CD3-positive T cells. Alport syndrome biopsies demonstrated a complete loss of the alpha5 chain of collagen IV from the glomerular basement membrane and the morphologic features consistent with Alport syndrome on electron microscopy. A prominent number of CXCR3-positive cells were found in the tubulointerstitium. Most of the CXCR3-positive cells were CD3-positive T cells, demonstrated by double-labeling in selected biopsies. The number of CXCR3-positive cells in kidneys with Alport syndrome correlated with serum creatinine (P < .05) and with morphologic features of a progressive disease (eg, interstitial fibrosis, glomerulosclerosis, and tubular atrophy). The severity of interstitial CXCR3-positive cell influx was similar in Alport syndrome as compared to immunoglobulin A nephropathy. The noninflammatory glomerular lesion of Alport syndrome is associated with prominent interstitial accumulation of CD3- and CXCR3-positive lymphocytes. The degree of infiltration correlated with renal function. We speculate that targeting T lymphocytes, for example, by CXCR3 blocking agents, might be a novel approach to inhibit disease progression in patients with Alport syndrome.
authors.affiliation: Medizinische Poliklinik Campus Innenstadt, University of Munich, 80336 Munich, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Jedlicka
authors.forename: Afschin
authors.initials: A
authors.lastname: Soleiman
authors.forename: Dan
authors.initials: D
authors.lastname: Draganovici
authors.forename: Jana
authors.initials: J
authors.lastname: Mandelbaum
authors.forename: Urs
authors.initials: U
authors.lastname: Ziegler
authors.forename: Heinz
authors.initials: H
authors.lastname: Regele
authors.forename: Rudolf P
authors.initials: RP
authors.lastname: Wüthrich
authors.forename: Oliver
authors.initials: O
authors.lastname: Gross
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D009394:Nephritis, Hereditary / Q000276:immunology* / Q000473:pathology; D009395:Nephritis, Interstitial / Q000276:immunology* / Q000473:pathology; D054367:Receptors, CXCR3 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D017252:CD3 Complex; C515187:CXCR3 protein, human; D054367:Receptors, CXCR3