In SituExpression of Regulatory Cytokines by Heart Inflammatory Cells in Chagas' Disease Patients with Heart Failure

Abstract

<jats:p>Chagas' disease is caused by the protozoan parasite<jats:italic>Trypanosoma cruzi</jats:italic>. The immune system plays an important role in the reduction of parasite load, but may also contribute to the development of lesions observed during the chronic phase of the disease. We analyzed cytokines produced by inflammatory heart cells in 21 autopsy samples obtained from patients with Chagas' disease divided according to the presence or absence of heart failure (HF). Left ventricular sections were analyzed by immunohistochemistry using antibodies against human IL-4, IFN-<jats:italic>γ</jats:italic>, TGF-<jats:italic>β</jats:italic>, TNF-<jats:italic>α</jats:italic>, and NOS2.<jats:italic>In situ</jats:italic>mRNA expression was quantified by a Low Density Array. The number of IFN-<jats:italic>γ</jats:italic>-positive cells was significantly higher than IL-4 positive cells. TNF-<jats:italic>α</jats:italic>, TGF-<jats:italic>β</jats:italic>and NOS2 were detected in 65%, 62% and 94% of samples respectively. There was an association between TNF-<jats:italic>α</jats:italic>-producing cells and the presence of HF. Subjects with HF presented higher levels of STAT4 mRNA, whereas FoxP3 and STAT6 levels were similar in the two groups. A Th1 cytokine pattern predominated in the cardiac inflammatory cell infiltrate of Chagas’ disease patients associated with HF. High degree of fibrosis was associated with low NOS2 expression. These results support the idea that Th1 immune responses are involved in heart lesions of Chagas' disease patients.</jats:p>

Presence of Antigen-Experienced T Cells with Low Grade of Differentiation and Proliferative Potential in Chronic Chagas Disease Myocarditis

“…TNF-α has been pointed out as a key molecule in the generation of ectopic TLO which might facilitate the perpetuation of inflammation in the heart. Cells expressing TNF-α and IFN-γ have been identified in heart tissues from patients with chronic chagasic cardiomyopathy [9], [50]. Our findings showing T-bet expression in areas of high inflammation and proliferation further confirmed a type 1 T cell response in patients with severe heart disease.…”

“…Lymphocytes in these lesions express lymphocyte function antigen-a (LFA-1), CD44, very late antigen-4 (VLA-4) [7] and cytotoxic lymphocyte antigen 4 (CTLA-4) [8]. A Th1 cytokine pattern predominated in the cardiac inflammatory cell infiltrate of Chagas disease patients with heart failure [9].Whereas some authors have shown increased peripheral levels of IFN-γ in patients with severe heart disease [10]–[12], other studies have demonstrated an inverse association between disease severity and IFN-γ production [8], [13], [14].We have previously shown that most IFN-γ-secreting T cells in response to T. cruzi display a low grade of differentiation but high expression of the inhibitory receptor CTLA-4 in the circulation of subjects with chronic T. cruzi infection [8], [15], [16]. Conversely, the total T cell compartment in Chagas disease patients is enriched in highly differentiated T cells compared to uninfected controls [15]–[17].…”

Depletion of regulatory T cells decreases cardiac parasitosis and inflammation in experimental Chagas disease

“…The etiology of Chagas disease is multifaceted, and may involve an autoimmune component in addition to protracted damage to myocytes and cardiac neuronal and vascular networks caused by parasites persisting in host tissues (Bonney et al 2011; Cummings and Tarleton 2003; Davila et al 1989; Girones et al 2007; Leon et al 2004; Ribeiro dos Santos et al 1992; Rossi 1990; Teixeira et al 2011; Zhang and Tarleton 1999). Both cytotoxic CD8+ effector T lymphocytes and IFN-γ-producing CD4+ T cells (Th1 cells), are important for controlling T. cruzi parasitosis (Hoft et al 2000; Hunter et al 1997; Kumar and Tarleton 2001; Rodrigues et al 2000; Tzelepis et al 2007), yet these T cells may also contribute to the development of pathogenic inflammation during T. cruzi infection (Bonney et al 2011; Gomes et al 2003; Laucella et al 2004; Minoprio 2001; Ribeiro dos Santos et al 1992; Rizzo et al 1989; Rocha Rodrigues et al 2012; Soares et al 2001; Tarleton et al 1996; Tarleton et al 1994). IL-17, which is produced by Th17 cells and other cell types, has been associated with both pro- and anti-inflammatory functions in other disease models, and may play an anti-inflammatory role during T. cruzi infection by indirectly down-regulating the functions of pro-inflammatory Th1 cells, without interfering with parasite clearance (Guedes et al 2012; Soares et al 2012; Tosello Boari et al 2012).…”

A prolinemia como um fator de severidade na infecção causada pelo <i>Trypanosoma cruzi</i>.

“…Durante a fase crônica da infecção, o miocárdio de pacientes com CCC apresenta um infiltrado inflamatório com predominância de células correspondentes a uma resposta do tipo Th1, sendo composto principalmente por células T CD8 + , CD4 + e macrófagos (Abel et al, 2001;Higuchi et al, 1993;Milei et al, 1992;Morato et al, 1998;Reis et al, 1993;Rocha Rodrigues et al, 2012). Além disso, ocorre a produção de grandes quantidades de IFN-e TNF , por outro lado IL-4, IL-6, IL-7, e IL-15 são encontradas em pequenas quantidades no miocárdio (Abel et al, 2001;Cunha-Neto et al, 2005;Fonseca et al, 2007;Higuchi et al, 1993;Reis et al, 1993Reis et al, ,1997Rocha Rodrigues et al, 2012 (Kierszenbaum, 1980;Krettli, Brener, 1976).…”

“…Além disso, ocorre a produção de grandes quantidades de IFN-e TNF , por outro lado IL-4, IL-6, IL-7, e IL-15 são encontradas em pequenas quantidades no miocárdio (Abel et al, 2001;Cunha-Neto et al, 2005;Fonseca et al, 2007;Higuchi et al, 1993;Reis et al, 1993Reis et al, ,1997Rocha Rodrigues et al, 2012 (Kierszenbaum, 1980;Krettli, Brener, 1976). A resposta celular é importante para o controle inicial da infecção, no entanto, uma resposta efetiva mediada por anticorpos é crítica para o aumento da sobrevivência.…”