Figure 1.

Immunopathology of ECM. In response to Plasmodium blood-stage infection, pro-inflammatory cytokines such as IFN-γ and TNF are produced by various immune cells. (1) These cytokines promote the up-regulation of adhesion molecules on brain endothelial cells. iRBCs sequester in the cerebral microvasculature and bind to receptors on the endothelial cells such as ICAM-1. (2) IFN-γ induces the expression of CXCL10 by brain endothelial cells. IFN-γ-induced CXCL10 enhances the adhesion of T cells to cerebrovascular endothelium and prevents their detachment from the brain vasculature. (3) Parasite antigens can be transferred from the iRBC into the endothelial cell. This interaction leads to opening of the intercellular tight junctions. Brain endothelial cells can phagocytize parasite antigens and cross-present them to CD8⁺ T lymphocytes. (4) iRBC can also directly activate platelets and stimulate the release of CXCL4 early in the course of ECM. CXCL4 induces the production of TNF by T cells and macrophages, which then causes more platelets to adhere to the endothelium. Enhanced expression of CXCR3-binding chemokines such as CXCL9, CXCL10, and CXCL4 in the brains of PbA-infected mice induces T cell migration to the brain in the late stage of ECM. (5) Accumulation of iRBCs and immune cells in cerebral vessels leads to vascular obstruction, increased pressure within the brain blood vessels, and increased permeability of the BBB, facilitating edema, and brain swelling.