Role of polymorphonuclear neutrophil leukocytes and their integrin CD11a (LFA-1) in the pathogenesis of severe murine malaria.
Infection of CBA mice with Plasmodium berghei ANKA results in severe malaria, which is characterized by mortality 6 to 10 days after infection and is associated with alterations of the brain microcirculation. These alterations consist of (i) intravascular sequestration of monocytes, (ii) an increase in vascular permeability as documented by Evans blue diffusion, and (iii) microhemorrhages. This syndrome may be due to an increase of production of tumor necrosis factor alpha which upregulates the endothelial expression of ICAM-1 and thus leads to adhesion of CD11a/CD18 (LFA-1)-bearing cells. During severe malaria, we found an important sequestration of the CD11a-bearing polymorphonuclear neutrophil leukocytes (PMN) in the lung but not in the brain. Treatment with a monoclonal antibody (MAb) against PMN, which induces profound neutropenia, prevented mortality and Evans blue diffusion in the brain and the lung, while it unexpectedly increased the occurrence of microhemorrhages. The anti-PMN MAb abolished PMN sequestration in the lung and also partially decreased monocyte sequestration in the brain and the lung. Treatment with an anti-CD11a MAb also prevented mortality, Evans blue diffusion, and PMN and monocyte sequestration. This study shows that PMN contribute to the mortality and the microvascular lesions resulting from severe malaria. This may be due to their CD11a-dependent sequestration in the lung and also to their indirect influence on vascular permeability and the sequestration of monocytes.
Senaldi
G
G
Department of Pathology, University of Geneva, Switzerland.
Vesin
C
C
Chang
R
R
Grau
G E
GE
Piguet
P F
PF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001921:Brain / Q000473:pathology; D002199:Capillary Permeability; D005260:Female; D008168:Lung / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008288:Malaria / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D009504:Neutrophils / Q000502:physiology*; D010962:Plasmodium berghei; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016169:Lymphocyte Function-Associated Antigen-1; D012709:Serum Albumin