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Red Cell Biology & its Disorders
Factor H interferes with the adhesion
of sickle red cells to vascular endothelium: a novel disease-modulating molecule
Ferrata Storti Foundation
Haematologica 2019 Volume 104(5):919-928
Elisabetta Lombardi,1* Alessandro Matte,2* Antonio M. Risitano,3 Daniel Ricklin,4 John D. Lambris,5 Denise De Zanet,1,6 Sakari T. Jokiranta,7 Nicola Martinelli,2 Cinzia Scambi2, Gianluca Salvagno,8 Zeno Bisoffi,9,10 Chiara Colato,10 Angela Siciliano,2 Oscar Bortolami,11 Mario Mazzuccato,1 Francesco Zorzi,2 Luigi De Marco1,12# and Lucia De Franceschi2
1Department of Translational Research, National Cancer Center, Aviano, Italy; 2Department of Medicine, University of Verona-AOUI Verona; Italy; 3Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy; 4Molecular Pharmacy Group, Department of Pharmaceutical Sciences, University of Basel, Switzerland; 5Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; USA; 6Polytechnic Department of Engineering and Architecture, University of Udine, Italy; 7Research Programs Unit, Immunobiology, University of Helsinki and United Medix Laboratories, Helsinki, Finland; 8Laboratory of Clinical Biochemistry, Department of Life and Reproduction Sciences, University of Verona, Italy; 9Centre of Tropical Diseases, Sacro Cuore-Don Calabria Hospital Negrar, Verona, Italy; 10Department of Diagnostics and Public Health, University of Verona- AOUI Verona, Italy; 11Unit of Epidemiology and Medical Statistics, Department of Diagnostic & Public Health, University of Verona and 12Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
*EL and AM contributed equally to this work. #LDM are co-last author.
ABSTRACT
Sickle cell disease is an autosomal recessive genetic red cell disorder with a worldwide distribution. Growing evidence suggests a possible involvement of complement activation in the severity of clinical com- plications of sickle cell disease. In this study we found activation of the alternative complement pathway with microvascular deposition of C5b-9 on skin biopsies from patients with sickle cell disease. There was also dep- osition of C3b on sickle red cell membranes, which is promoted locally by the exposure of phosphatidylserine. In addition, we showed for the first time a peculiar “stop-and-go” motion of sickle cell red blood cells on tumor factor-a−activated vascular endothelial surfaces. Using the C3b/iC3b bind- ing plasma protein factor H as an inhibitor of C3b cell-cell interactions, we found that factor H and its domains 19-20 prevent the adhesion of sickle red cells to the endothelium, normalizing speed transition times of red cells. We documented that factor H acts by preventing the adhesion of sickle red cells to P-selectin and/or the Mac-1 receptor (CD11b/CD18), supporting the acti- vation of the alternative pathway of complement as an additional mecha- nism in the pathogenesis of acute sickle cell related vaso-occlusive crises. Our data provide a rationale for further investigation of the potential con- tribution of factor H and other modulators of the alternative complement pathway with potential implications for the treatment of sickle cell disease.
Introduction
Sickle cell disease (SCD; OMIM # 603903) is an autosomal recessive genetic red blood cell (RBC) disorder with a worldwide distribution. SCD results from a point mutation (βS, 6V) in codon 6 of the β-globin gene where the insertion of valine in place of glutamic acid leads to the production of a defective form of hemoglobin, termed hemoglobin S (HbS).1-3 Pathophysiological studies have shown that intravascular sickling in capillaries and small vessels leads to vaso-occlusion and
Correspondence:
LUCIA DE FRANCESCHI
lucia.defranceschi@univr.it
Received: May 27, 2018. Accepted: January 8, 2019. Pre-published: January 10, 2019.
doi:10.3324/haematol.2018.198622
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/5/919
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