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Blood, 15 March 2007, Vol. 109, No. 6, pp. 2438-2445.
Prepublished online as a Blood First Edition Paper on November 28, 2006; DOI 10.1182/blood-2006-06-026997.
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Submitted June 5, 2006
Accepted October 30, 2006
Involvement of fractalkine pathway in the pathogenesis of childhood hemolytic uremic syndrome
Maria Victoria Ramos, Gabriela C Fernandez, Natasha Patey, Pablo Schierloh, Ramon Exeni, Irene Grimoldi, Graciela Vallejo, Christian Elias-Costa, Maria del Carmen Sasiain, Howard Trachtman, Christophe Combadiere, Francois Proulx, and Marina S Palermo*
Division of Immunology, Institute of Hematological Investigations, Academia Nacional de Medicina, Buenos Aries, Argentina
Department of Pediatrics, Division of Pediatric Pathology, Hopital Neker Enfants-Malades, Paris, France
Department of Nephrology, Hospital Municipal del Nino, Buenos Aries, Argentina
Department of Nephrology, Hospital de Ninos "Ricardo Gutierrez", Buenos Aries, Argentina
Department of Pediatrics, Division of Pediatric Nephrology, Schneider Children's Hospital, New York, United States
Inserm U543, Universite Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France
Department of Pediatrics, Division of Pediatric Intensive Ca, Ste-Justine Hospital, Montreal, Canada
* Corresponding author; email: mspalermo{at}hematologia.anm.edu.ar.
Thrombotic microangiopathy and acute renal failure are cardinal features of post-diarrheal hemolytic uremic syndrome (HUS). These conditions are related to endothelial and epithelial cells damage induced by Shiga toxin (Stx), through the interaction with its globotriaosyl ceramide receptor. However, inflammatory processes contribute to the pathogenesis of HUS by sensitizing cells to Stx. Fractalkine (FKN), a CX3C transmembrane chemokine expressed on epithelial and endothelial cells upon activation, is involved in the selective migration and adhesion of specific leukocytes subsets to tissues. Here, we demonstrated a selective depletion of circulating mononuclear leukocytes expressing the receptor for FKN (CX3CR1) in HUS patients. We found a unique phenotype in children with HUS, distinct from that seen in healthy, uremic or infected controls, in which monocytes lost CX3CR1, down-modulated CD62L and increased CD16. In addition, CD56dim natural killer (NK) subpopulation was decreased leading to an altered peripheral ratio of CD56dim:CD56bright from 10.0 to 4.5. Noteworthy, we found a negative correlation between the percentage of circulating CX3CR1+ leukocytes and the severity of renal failure. Finally, CX3CR1+ leukocytes were observed in renal biopsies from HUS patients. We suggest that the interaction of CX3CR1+ cells with FKN present on activated endothelial cells may contribute to renal injury in HUS.
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