International Immunology, Vol 9, 825-834, Copyright © 1997 by Oxford University Press
A Morrot, DK Strickland, L Higuchi M de, M Reis, R Pedrosa and J Scharfstein
Chagas' disease patients (CDP) develop both humoral and cellular immune
responses against the major cysteine proteinase (cruzipain) from
Trypanosoma cruzi. Here we demonstrate that complexes formed by cruzipain
and alpha 2-macroglobulin (alpha 2M) are efficiently internalized by human
monocytes, and that this process results in enhanced presentation of
cruzipain peptides to CD4+ T cells from CDP. Purified or serum alpha 2M
binds to polymorphic cruzipains, but only a fraction of the proteinases
become covalently linked. Once bound to alpha 2M, fluorescein-labeled
cruzipain (FITC-cruzipain) or [125I]cruzipain were more efficiently
internalized by normal peripheral blood mononuclear cells (PBMC) or
monocytes; this effect was abolished by (I) pre-treating the cells with
receptor-associated protein (rRAP), a known antagonist the of alpha 2M
receptor (alpha 2MR/LRP), and (II) inactivating [125I]cruzipain's active
site prior to the reaction with alpha 2M, indicating that the exposure of
receptor binding sites on alpha 2M complexes required bait region cleavage.
We then sought to determine if the alpha 2MR/LRP-dependent uptake of alpha
2M:cruzipain by monocytes resulted in increased CD4+ T cell responses of
PBMC-CDP (n = 13). These effects were only revealed after depletion of
CD19+ B lymphocytes from PBMC-CDP; the threshold of T cell stimulation was
far lower in cultures stimulated with alpha 2M:cruzipain, as compared to
antigen alone. Myocardial specimens from CDP with chronic myocardiopathy
(three necropsies) were analyzed by immunohistochemistry with mAb
anti-cruzipain or anti-alpha 2MR/LRP (CD81+). Extracellular depots of
cruzipain were localized amidst inflammatory mononuclear infiltrates, part
of which contained CD91+ macrophage-like cells. Ongoing studies should
clarify if T. cruzi cysteinyl proteinases play a role in the pathogenesis
of Chagas' heart disease.
ARTICLES
Human T cell responses against the major cysteine proteinase (cruzipain) of Trypanosoma cruzi: role of the multifunctional alpha 2- macroglobulin receptor in antigen presentation by monocytes
Instituto de Biofisica Carlos Chagas Filho-UFRJ, Laboratorio de Imunologia Molecular, Rio de Janeiro, Brazil.
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