Thymic Atrophy during Infection as a Host Response to Avoid Tolerance to Persistent Pathogens.

The immune system consists in part of a functionally competent T-cell repertoire that is reactive to foreign antigens but tolerant to self-antigens. The repertoire of T cells is primarily formed in the thymus through positive and negative selection of developing thymocytes that are critical for establishing central tolerance. One of the features of the thymus is to sense stress hormones produced in pathophysiological conditions. Increased levels of these hormones are associated with infections and are able to induce thymic atrophy. We have shown that in acute Trypanosoma cruzi infections, the atrophic thymus is a consequence of increased thymocyte apoptosis and premature export of immature thymocytes to secondary lymph nodes. This atrophy does not necessarily result in dysfunction of the thymus since the organ micro architecture is preserved and maintains negative selection, thus avoiding the development of tolerance to the pathogen during the establishment of protective immunity. However, in chronic infections, the dissemination of invading pathogens able to target the thymus interferes with T cell differentiation, generating T cells that are tolerant to pathogen-specific antigens. In what follows we propose to describe what is known about thymic atrophy induced by infectious pathogens in the context of host-pathogen interactions.

A role for extracellular amastigotes in the immunopathology of Chagas disease

In spite of the growing knowledge obtained about immune control of Trypanosoma cruzi infection, the mechanisms responsible for the variable clinico-pathological expression of Chagas disease remain unknown. In a twist from previous concepts, recent studies indicated that tissue parasitism is a pre-requisite for the development of chronic myocarditis. This fundamental concept, together with the realization that T. cruzi organisms consist of genetically heterogeneous clones, offers a new framework for studies of molecular pathogenesis. In the present article, we will discuss in general terms the possible implications of genetic variability of T. cruzi antigens and proteases to immunopathology. Peptide epitopes from a highly polymorphic subfamily of trans-sialidase (TS) antigens were recently identified as targets of killer T cell (CTL) responses, both in mice and humans. While some class I MHC restricted CTL recognize epitopes derived from amastigote-specific TS-related antigens (TSRA), others are targeted to peptide epitopes originating from trypomastigote-specific TSRA. A mechanistic hypothesis is proposed to explain how the functional activity and specificity of class I MHC restricted killer T cells may control the extent to which tissue are exposed to prematurely released amastigotes. Chronic immunopathology may be exacerbated due the progressive accumulation of amastigote-derived antigens and pro-inflammatory molecules (eg. GPI-mucins and kinin-releasing proteases) in dead macrophage bodies.

The MHC-class II restricted immune response against parasitic proteinases: clearance-receptors as an alternative pathway for their endocytic uptake into antigen presenting cells

We have recently characterized the partial structure of a relatively dominant T cell epitope from the major T. cruzi cysteinyl proteinase (GP57/51 or cruzipain), and showed that it can trigger the secretion of gamma-interferon from CD4+ lymphocytes from chagasic patients. As generally observed for soluble antigens, T cell recognition of imunogenic peptides from cruzipain requires their prior uptake by antigen presenting cells (APC). Following endocytosis by the APC, cruzipain (a lysosomal proteinase by itself) has to unsergo intracellular degradation in acidic endosomes or lysosomes. The analysis of the fine specificity of cruzipain recognition by T lymphocytes (class II restricted responses) from chronic patients has implicated epitopes mapped to the catalytic domain of cruzipain rather than to its long COOH-terminal extension. Structural differences between these two domains may render them differentially susceptible to intracellular digestion in the APC. We now suggest that the functional inactivation of extracellular cruzipain by proteinase inhibitors available in tissue fluids may increase the efficieny of T cell responses. Recent data indicate that plasma inhibitor alpha2-macroglobulin M (alpha2M) can bind covalently to cruzipain, this being followed by APC uptake by means of the alpha2 macroglobulin receptor (alpha2MR) on monocytes. Similar clearance methanisms may allow highly efficient focusing, degradation and MHC-class II presentation of T cell stimulatory peptides from proteinases originating from allergens and other pathogenic parasites.