Analysis of the bystander adrenoceptor reactivity of anti-Trypanosoma cruzi antibodies leads to the characterization of a novel clinical symptom of Chagas disease.

LABOVSKY V; SMULSKI C; GRIPPO V; LEVY G; GOMEZ KA; MATSUMOTO S; GUIDA MC; PAVETO C; LEVIN MJ

Tallinn

Encuentro; HHMI Meeting of International Research Scholars; 2004

Howard Hughes Medical Institute

Adrenergic and muscarinic cholinergic receptors function in the regulation of the cardiovascular system.They are bystander targets of anti-Trypanosoma cruzi antibodies in Chagas disease. In this regard, the best-studied of these antibodies are those reacting with the parasites ribosomal P proteins. To date, bystander reactions have been characterized only at the pharmacological level. CHO and COS 7 cells stably transfected with human beta1- and beta2-adrenergic receptors provide a most valuable tool with which to demonstrate this immunological reaction. Moreover, crystallographic studies of complexes formed by parasite P antigens with the Fab of an anti-P Mab, and mutagenesis of Mab-derived and human recombinant anti-P antibodies, accompanied by the determination of their affinities for different targets, allowed us to model their binding to the beta1-adrenoceptor. Additional evidence of the binding of these antibodies to G protein coupled receptors comes from studies of their binding to rhodopsin. The IgG fraction of patients with Chagas disease as well as poly- and monospecific antibodies against the P proteins of the parasite react with rhodopsin in Western blots of bovine rod outer segment (bROS) membranes.  Furthermore, incubation of preparations of bROS membranes with the above-mentioned antibodies inhibited the light-induced conformational change of rhodopsin, causing a marked decrease in the membranes cGMP-phosphodiesterase activity. Interestingly, complete electro-retinographic (ERG) and retinal fluorescein angiography studies in patients with Chagas disease showed a dissociated cone-rod ERG response, with reduction of the ERG b-wave amplitude or delayed latency under dark adaptation, and mild to moderate defects in retinal epithelium pigmentation, conditions compatible with a selective rod dysfunction in these individuals. This is the first observation of clinical retinal involvement in Chagas disease.