ROLE OF CD8+ KILLERS IN THE EXACERBATION OF CHRONIC IMMUNOPATHOLOGY
Andrade et al. (1997) have recently demonstrated that the canine model accurately reproduces the main features of the indeterminate form of human Chagas disease. They suggested that the heart lesions in the indeterminate stage of the disease are caused by self-limited cycles of focal inflammatory changes, probably determined by subtle shifts in the immunoregulatory activity of effector T lymphocytes. The canine model does not seem to support an obvious role for microvascular lesions in this stage of the disease. In contrast to the progressive nature of he chronic carditis observed in mice, the transition from indeterminate to chronic heart disease in dogs is not gradual. In humans, the distribution of cytokine-producing cells revealed that Th2 type cells are usually associated with higher deposition of parasite antigens (Higuchi et al. 1993, Reis et al. 1997).
Our model predicts a role for pathogenic clones in the exacerbation of chronic immunopathology. The pre-requisites for the onset of these pathological processes are: (i) infected cells in some tissues reservoirs sustain the growth of amastigote clones which can occasionally subvert the class I antigen presentation pathway (in other words, the amastigote-speciic killer T cells cannot effectively recognize and attack the infected target cells while the intracellular amastigotes multiply); (ii) these intracellular amastigotes transform into trypo-mastigotes; (iii) early after transformation, the trypomastigotes can successfully load class I MHC molecules with their T cell epitopes; (iv) the infected target cells are then killed by trypomastigote-specific CTL; (v) extracellular amastigotes (which are ultimately responsible for the exacerbation of immunopathology) are released in the interstitium; (vi) the extracellular amastigotes can invade and proliferate in suppressed macrophages; (vii) trypomastigote-specific killer cells from the Tc2 subset induce successive rounds of abortive infection in suppressed macrophages, causing the progressive deposition of amastigote antigens and pro-inflammatory factors inside macrophage apoptotic bodies (Morrot et al. 1997). Here the concept of a "pathogenic" clone is defined in the operational sense: it refers to an opportunistic population of intracellular amastigotes that somehow exploits antigen variation to subvert the class I presentation of target cells which express a given MHC-haplotype. In other words, a pathogenic clone isolated from one individual (outbred species) would not necessarily be more harmful to individuals that express a different MHC haplotype. As argued earlier in this article, subversion of class I pathway of antigen presentation in inbred mice may be a relatively easier process because these animals count with a limited number of alleles to compensate for the extreme antigen variability of the intracellular parasites. We may thus predict that, in immunocompetent chagasic patients (also in the canine model), the "pathogenic" parasite subpopulations were either eliminated due to the powerful selective pressure exerted by amastigote-specific killer T cells, or are present at very low levels somewhere in the body. The pathogenic clones should preferentially thrive in suppressed type of macrophages because these targets are sensitive to the modulatory influence of type-2 cytokines originating from polarized CD4 or CD8 effector T cells, which predominate in the indeterminate stage of the disease (Bahia-Oliveira et al. 1998).
Our model predicts that myocardial inflammation in genetically oubred individuals may be exacerbated when these tissues become colonized by pathogenic clones. From where would they come from? As already mentioned, extracellular amastigotes may infect tissue macrophages, using to this end the alternative pathway of invasion (Ley et al. 1988). Organs that usually maintain macrophages in a relatively supressed state (eg. adrenal glands, Teixeira et al. 1977) may allow for the outgrowth of these potentially pathogenic amastigote clones. In a period of a relatively profound immunosuppression, perhaps the threshold required for amastigote-epitope presentation by suppressed macrophages is no longer reached. This would allow for their escape from recognition by amastigote-specific killer T cells. Alternatively, the amastigotes would escape if the susceptible host exhibits a transient deficit of amastigote-specific killer T cells or, of trypomastigote-specific CD8+ function (Tc1). Once released into the bloodstream, the "pathogenic" clone may reach the heart tissues by traversing the blood capillaries which already express adhesion molecules (Zhang & Tarleton 1996). After lodging inside a cardiac fiber, or in a tissue macrophage, they again subvert the class I MHC presentation, avoiding recognition by amastigote-specific killer T cells. At this stage, the cardiac tissues may be already dominated by effector trypomastigote-specific Tc2 killer T cells and/or by effectors from the Th2 subset. Successive rounds of invasion and abortive infection of supressed macrophages would cause the progressive accumulation of amastigote-antigens and/or their pro-inflammatory products, such as GPI-mucins, inside dead macrophages (opoptotic bodies). In organs that are highly vascularized, such as the heart, cruzipain-isoforms secreted or leaked by T. cruzi amastigotes can process kininogen, thus releasing pro-inflammatory kinins. By acting on adjacent endothelial cells, these vasoactive peptides may induce plasma exudation, thereby expanding the inflammatory response, and contributing to interstitial fibrosis. The chemokines released by tissues exposed to tGPI-mucins and other pro-inflammatory mediators might also recruit autoreactive CD8+ or CD4+ lymphocytes (Cunha-Neto et al. 1996) into the myocardium, thus initiating the expanding wave of chronic immunopathology.
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