Chronic fatigue syndrome--a neuroimmunological model.

The aetiological and pathophysiological basis of chronic fatigue syndrome (CFS) remains a controversial field of inquiry in the research community. While CFS and similar disease conditions such as fibromyalgia (FM) and post-infectious encephalopathy have been the focus of intense scrutiny for the past 20 years, results of research were often contradictory and a cohesive pathological model has remained elusive. However, recent developments in understanding the unique immunophysiology of the brain may provide important clues for the development of a truly comprehensive explanation of the pathology of CFS. We argue that CFS pathogenesis lies in the influence of peripheral inflammatory events on the brain and the unique immunophysiology of the central nervous system. There is also evidence that CFS patients have a relative immunodeficiency that predisposes to poor early control of infection that leads to chronic inflammatory responses to infectious insults. The neurological and endocrine changes have been described in CFS patients support the view that CFS has an inflammatory pathogenesis when considered as a whole. An inflammatory model of disease also provides an explanation for the marked female sex bias associated with CFS. This review therefore posits the hypothesis that CFS as a disease of long-term inflammatory processes of the brain. We will also provide an investigative framework that could be used to justify the use of anti-TNF biological agents as a reliable and effective treatment approach to CFS, a syndrome that to date remains frustratingly difficult for both patients and health care professionals to manage.

High mobility group box 1 (HMGB1) protein: possible amplification signal in the pathogenesis of falciparum malaria.

High mobility group box 1 (HMGB1) protein, a DNA-binding protein that can also act as a pro-inflammatory cytokine if released from cells, is an important amplification signal in various forms of inflammation. The concentration of HMGB1 in serum taken at admission was increased in falciparum malaria in sixteen African children, more so in fatal cases than in those who subsequently recovered (P<0.001). Serum from both non-fatal (P=0.0048) and fatal (P<0.001) cases contained significantly more circulating HMGB1 than did serum from healthy Caucasian adults. These data provide an additional argument that malaria is fundamentally a systemic inflammatory state. In keeping with its developing role in sepsis, HMGB1 may enhance and prolong the inflammatory processes, and thus illness, in malaria.

Calcium regulation in the intraerythrocytic malaria parasite Plasmodium falciparum.

The regulation of intracellular Ca(2+) in the intraerythrocytic form of the human malaria parasite, Plasmodium falciparum, was investigated using parasites 'isolated' from their host cells by saponin-permeabilisation of the erythrocyte membrane. The isolated parasites maintained tight control over their resting cytosolic Ca(2+) concentration which ranged from approximately 100 nM in the absence of extracellular Ca(2+) to approximately 700 nM in the presence of 1 mM extracellular Ca(2+). The parasite has two functionally discrete intracellular Ca(2+) stores. One is an 'endoplasmic reticulum (ER)-like' store, the other an 'acidic store'. The ER-like store was discharged by cyclopiazonic acid (CPA), an inhibitor of sarco/endoplasmic reticulum Ca(2+)-ATPases (SERCAs) of animal and plant cells, but not by thapsigargin (TG), a more specific inhibitor of SERCAs of animal cells. The acidic store was discharged by nigericin and by NH(4)(+). The amount of Ca(2+) in the ER-like store increased with increasing extracellular Ca(2+) concentration, whereas the amount of Ca(2+) in the acidic store did not. Ca(2+) released from the ER-like store by CPA was cleared from the parasite cytosol by uptake into the acidic store (over a range of extracellular Ca(2+) concentrations), consistent with the acidic store serving as a Ca(2+) reservoir within the intracellular parasite.

Cytokines and immunological control of Eimeria spp.

Protozoan parasites belonging to the genus Eimeria cause considerable losses in livestock production in which stocking densities are high or environments restricted. The ability of hosts to mount immunological responses which limit parasite reproduction vary according to the particular species of Eimeria. Typically though, immune responses restrict parasite reproduction during primary infection and limit, if not prevent, subsequent infections. Although mechanisms of immunity are unknown, host immune responses have been exploited in the development of a method to control coccidiosis-immunisation with attenuated strains of Eimeria. Limitations of this control method, predominantly the cost of producing the attenuated parasites, necessitates identification of protective immune responses to facilitate selection of antigens for use in non-living vaccines. As in immune responses to many other parasitic infections of the gastrointestinal tract, the role of antibodies is at best minor, whereas T-cells are crucial. Numerous studies have shown that the intestinal mucosal T-cell population is dynamic; the number and phenotype of T-cells changes in response to Eimeria-infection. Specific changes in the intestinal T-cell population have not, however, been correlated with limitation of parasite reproduction. Experiments involving adoptive transfer of T-cell sub-populations and in vivo depletion of specific T-cells have shown that CD4+ T-cells and to a lesser extent CD8+ T-cells are important in immune responses which limit primary infection. In contrast, CD8+ T-cells are more important in subsequent infections with CD4+ T-cells having a lesser role. The effects of T-cells on Eimeria are partially mediated by the cytokines they release. Most attention has concentrated on interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) because these cytokines have been shown to limit other protozoan infections. IFN-gamma is produced in Eimeria-infected hosts but evidence that it is present at the site of infection is limited. Intestinal levels of IFN-gamma increase earlier in response to primary Eimeria-infection in mice which are relatively resistant, than in mice which are relatively susceptible. Neutralisation of endogenously produced IFN-gamma has shown that this cytokine limits oocyst production in either primary or secondary infections depending on the species of Eimeria. Production of TNF-alpha is also increased in infected hosts. In comparison with relatively susceptible mice, TNF-alpha is produced earlier and to a greater extent in the intestines of relatively resistant mice. Unexpectedly, injections of TNF-alpha into infected mice increased oocyst production. It remains to be determined whether the effects of endogenous TNF-alpha are the same as those of exogenous TNF-alpha. Mechanisms by which IFN-gamma and TNF-alpha modulate parasite reproduction have not been identified. A number of lines of experimentation have suggested that it is unlikely that IFN-gamma limits parasite reproduction through induction of the synthesis of reactive oxygen or reactive nitrogen intermediates, since both of these reactive intermediates have the capacity to exacerbate Eimeria-infection.