Cerebral Endothelial Activation and Signal Transduction Mechanisms during Inflammation and Infectious Disease

Abstract

Induction of cell surface molecules on cerebral endothelial cells, microglia, oligodendrocytes, choroidal epithelial cells, and (to a lesser degree) astrocytes has been reported in a few chronic inflammatory conditions and infectious diseases of the central nervous system (CNS). The elucidation of autoimmune mechanisms in multiple sclerosis and its experimental model, experimental allergic encephalomyelitis (EAE), has provided knowledge of the pleiotropic actions of cytokines and specific cellular interactions between the circulation-derived immune cells and brain elements. Although stereotypical immune interactions are mimicked in the CNS, they do not appear to measure up to what is encountered within systemic organs. This is due not only to the specialized cellular consistency of the CNS but also to its isolation behind the blood-brain barrier. It may not, therefore, be surprising that the targets, namely endothelial cells or macrophages (microglia) of the brain, do not fully respond to injury or infection in the same manner as or with the expected resilience of those in the periphery. However, inflammatory responses resulting from infections or injury of the CNS activate the brain endothelium and other nonneural cells of the brain to various degrees depending on the type, titer, or strength and duration of exposure to the agent or insult. The activation of these cells may be modulated by the action of one or more cytokines and relies on expression of respective cell surface receptors, though cytokines are known to work via receptor-independent systems. In an effort to understand the immunopathogenesis and find rational treatments several rodent and nonhuman primate models of infectious disease of the CNS have been devised. Such efforts have further been rewarded by the use of several mouse knockout strains or models deficient in molecules of interest. Infections of the CNS by viruses, bacteria, and protozoa reveal the presence of inflammatory nodules and perivascular cuffing around blood vessels by inflammatory cells including infiltrated lymphocytes, monocytes, and microglia. Astrocytes and oligodendrocytes also invariably become hypertrophic and exhibit hyperplasia. However, the consequences of these agents on neurones remain largely unknown. Protozoal infections of the CNS such as cerebral malaria (Plasmodium falciparum), toxoplasmosis (Toxoplasma gondii), and trypanosomiasis (Trypanosoma brucei and Chagas’ disease) lead to unique immunopathological features, although they also have features in common with those apparent in chronic inflammatory conditions such as multiple sclerosis. The molecular mechanisms involved in these conditions and how these might impinge on understanding brain inflammatory mechanisms are largely unexplored topics. Toxoplasmosis, an obligate intracellular protozoan, has recently attracted considerable attention because it is the most common CNS infection producing a mass lesion in acquired immune deficiency syndrome (AIDS). Ten to 25 percent of AIDS patients have toxoplasmosis of the CNS and Toxoplasma abscesses are a late complication of HIV infection associated with a low CD4+ cell count. It is well known that during chronic infection in AIDS and mouse models of toxoplasmosis, parasite-specific T lymphocytes release high levels of the cytokine interferon-γ (IFN-γ), which is required to prevent cyst reactivation and likely initiates several cascades of inflammatory and immune responses.