Early involvement of the cardiovascular and lymphatic systems results in perivascular cellular infiltration, haemorrhage and oedema

Fig. 14a.2 Life-cycle of T. brucei

(Pentreath, 1995). Widespread meningeal inflammation with injury to the choroid plexus soon follows, resulting in choroid plexus breakdown, allowing parasites to enter into the cerebrospinal fluid (CSF) and infiltrate periventricular areas and a relatively thin blood-brain barrier. Although parasite entry into the CSF is achieved at this early state, trypanosomes usually remain undetectable in the CSF until considerably later (weeks in the case of T. brucei var. rhodesiense

and months in T. brucei var. gambiense infection). This is probably because the CSF is a relatively hostile environment for trypanosomal survival. However, permeation into the CSF allows trypanosomes access to the perivascular extensions of the subarachnoid space, which penetrate deep into cerebral tissue. This generates an intense inflammatory reaction, resulting in generalised perivascular cuffing with T helper and B lymphocytes and morular cells (plasma cells producing IgM), particularly in the cerebellum and brainstem, and marks the transition from meningitis to encephalitis. There is also evidence of astrocyte and microglial hyperplasia and microglial activation (Chianella et al., 1999). The cellular infiltrates described suggest that the immune response against trypanosomal invasion of the central nervous system is primarily a T-dependent B cell response.

As disease progresses, vasogenic oedema is seen, with characteristic changes in brain tissue density and electrolyte levels. The blood-brain barrier is progressively more damaged. Trypanosomes infiltrate areas of cerebral parenchyma with relatively little blood-brain barrier (e.g. pineal gland, median eminence) and spinal sensory ganglia. Except in terminal disease, trypanosomal invasion of brain tissue is rare.

Expression of major histocompatibility complex (MHC) Class 1 molecules is upregulated in parasite-infiltrated parenchyma; this is accompanied by a cellular influx of CD8 + T lymphocytes and macrophages, and may be mediated largely by interferon-gamma (IFNy).

The biochemical disturbances produced by trypanosomal invasion of the CNS also extend to chemicals not directly related to the immune response. Several monoamine neurotransmitters have been shown to have increased turnover (Stibbs and Curtis, 1987), and there is substantial overproduction of lipid mediators, such as prostaglandins D2 and F2a, the release of which is the result of synergistic activity between endotoxin and various trypanosomal products (Pentreath et al., 1990). Endotoxaemia is a common occurrence in both the blood and CSF of patients with late-stage trypanosomiasis (Alafiatayo et al., 1983). The source of the endo-toxin is unclear, but non-specific endotoxin-like substances may be released by trypanosomes, and intestinal and hepatic damage could contribute by producing increased bacterial translocation and reduced clearance, respectively.

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