Interstitial inflammation in Alport syndrome.
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.
Jedlicka
Jan
J
Medizinische Poliklinik Campus Innenstadt, University of Munich, 80336 Munich, Germany.
Soleiman
Afschin
A
Draganovici
Dan
D
Mandelbaum
Jana
J
Ziegler
Urs
U
Regele
Heinz
H
Wüthrich
Rudolf P
RP
Gross
Oliver
O
Anders
Hans-Joachim
HJ
Segerer
Stephan
S
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
D017252:CD3 Complex; C515187:CXCR3 protein, human; D054367:Receptors, CXCR3