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Immunopathological changes in human cerebral malaria
J Porta1, A Carota, G P Pizzolato
1Department of Pathology, CMU, University of Geneva, Switzerland.
Abstract:
Pathogenic mechanisms in human cerebral malaria remain unclear. We reevaluate the role of cell-mediated immune mechanisms in the pathogenesis of this disease based on autopsy findings in a 34-year-old Caucasian male. Histologic examination of brain tissue showed typical features of severe malaria infection (sequestration of Plasmodium falciparum-infected erythrocytes in vessels, cerebral oedema, petechial lesions and Dürck granulomas). In addition to these classical changes, we found that leukocytes that stained positively in immunohistochemistry for CD68 and tumor necrosis factor-alpha (TNF) coexisted with infected erythrocytes in capillaries, whereas in venules the monocyte population outnumbered the erythrocytes. Notable expression of ICAM-1 on endothelial cell surface was detected by immunohistochemistry in vessels with sequestered cells but not in unaffected vessels. These changes are identical to those of the murine model of the disease, in which cell-mediated immune mechanisms and TNF have been implicated. In vitro, ICAM-1 has been shown to be a potential ligand for P. falciparum-infected erythrocytes. In malaria patients, high serum TNF levels, which have been detected in close correlation with disease severity, may thus favor adhesion to endothelial cells of either red or white blood cells via enhanced ICAM-1 expression. The present observations are further evidence for a role of cell-mediated immunity in the pathogenesis of human cerebral malaria.
Insights
Cell-mediated immunity and tumor necrosis factor-alpha (TNF) play a role in severe malaria pathogenesis. Autopsy findings reveal leukocytes and TNF alongside infected cells, suggesting immune involvement in cerebral malaria.
Area of Science:
- Immunology
- Pathology
- Neuroscience
Background:
- Pathogenic mechanisms of human cerebral malaria are not fully understood.
- Severe malaria involves Plasmodium falciparum-infected erythrocytes sequestering in cerebral vessels.
- Cell-mediated immunity and TNF are implicated in murine malaria models.
Observation:
- Autopsy of a cerebral malaria patient revealed classic signs like erythrocyte sequestration, cerebral edema, and Dürck granulomas.
- Leukocytes expressing CD68 and TNF coexisted with infected erythrocytes in capillaries.
- Monocytes outnumbered erythrocytes in venules, and ICAM-1 was upregulated on endothelial cells with sequestered cells.
Findings:
- The observed changes mirror those in murine models, suggesting a similar pathogenic role for cell-mediated immunity and TNF.
- In vitro studies show ICAM-1 can bind to P. falciparum-infected erythrocytes.
- High serum TNF levels correlate with malaria severity and may enhance cell adhesion via ICAM-1.
Implications:
- These findings provide further evidence for the involvement of cell-mediated immunity in human cerebral malaria pathogenesis.
- Understanding these mechanisms could lead to targeted therapies for severe malaria.
- The study highlights the potential role of TNF and ICAM-1 in the adhesion of infected cells and leukocytes in cerebral malaria.