Role of cytokines and adhesion molecules in malaria immunopathology

Cerebral malaria (CM) is the most common cause of death in severe malaria; more than two million children die of CM annually. Although the mechanisms of this neurologic complication remain poorly understood, studies in an experimental model of CM suggest that a natural body protein seems to be a major cause of this deadliest complication of malaria, a finding that could point towards new methods of treatment. We have explored the pathogenesis of CM with particular attention to the possible relationship between susceptibility or resistance to CM and cytokine expression and secretion patterns. We found that CM is associated with an increased expression of tumor necrosis factor (TNF) and interferon (IFN)-gamma and a reduced expression of interleukin-4 (IL-4) and transforming growth factor (TGF)-beta. The data obtained are consistent with a predominantly Th1 response in mice developing the cerebral complications of malaria. The overexpression of TNF in brain was also correlated with the augmented expression of adhesion molecules involved in the sequestration of leukocytes in brain vessels, a distinctive feature of CM. These observations were seen in relation to the immune status of man, in which, akin to the mouse model, a predominant Th1 response and upregulation of adhesion molecules in brain endothelium appear to be associated with susceptibility to the neurological complications of CM.