An Immunohistochemical Study of Cytokine and Adhesion Molecule Expression In Human Brain in Fatal Cerebral Malaria.

Abstract

Introduction: Although the role of systemic proinflammatory cytokines, IL-ip and TNF-a, and their up-regulation of adhesion molecules, ICAM-1, VCAM-1 and E-Selectin, in the pathogenesis of cerebral malaria (CM) is well established, the role of local cytokine release remain unclear. Methods: Immunohistochemistry (IHC) was used to compare the expression of ICAM-1, VCAM-1, E-Selectin, IL-ip, TNF-a and TGF- P at light microscopic level in cerebral, cerebellar and brainstem postmortem cryostat sections from 10 CM, 5 severe malarial anaemia (SMA), 1 purulent bacterial meningitis (PBM), 2 non-central nervous system infections (NCNSI) and 3 non-infections (NI) deaths in Ghanaian children. Results: Fatal malaria and Salmonella sepsis showed significantly higher vascular expression of all 3 adhesion molecules, though their expression in the sepsis case was not as intense as that in the fatal malaria sections. There was highly significant co-localization of receptor expression with sequestration in the malaria cases, though there was negligible difference in their expression between the CM and SMA sections. TGF-P showed intravascular and perivascular distribution in all cases, but expression was most intense in the PBM case and CM group. TNF-a and IL-ip showed prominent brain parenchymal staining, in addition to intravascular and perivascular staining, in only the PBM case and CM group. The increased expression of the adhesion molecules was associated with increased local proinflammatory cytokine release in the CM sections, but not in the SMA group. The maximal expression of all 6 antigens studied was in the cerebellar sections of the malaria cases. Conclusions: Endothelial activation is a feature of fatal malaria and Salmonella sepsis, with adhesion molecule expression being highly co-localized with sequestration in fatal malaria. IL-ip and TNF-a are expressed in only cases with neurodegenerative lesions, whilst TGF-P is present in all cases. Both cytokines and adhesion molecules were maximally expressed in the cerebellar sections of the malaria cases.