**2.2.5 The cytokines and chemokines**

Although proinflammatory cytokines seem to be necessary for controlling parasitemia during acute phase of the disease (Cunha-Neto E., et al., 2009), CCC patients display a rather proinflammatory cytokine while indeterminate patients display a down modulator one. CCC patients had higher levels of TNF- and CCL2 than indeterminate patients (Ferreira, et al., 2003, Talvani A., et al., 2004). Infiltrating macrophages from CCC patients expressed INF-, TNF- and IL-6 but showed low levels of IL-2, IL-4 and IL-10 (Abel, et al., 2001, Reis D. D., et al., 1993, Reis M. M., et al., 1997). Also CCR5, CXCR3 and CCR7 and their ligands were increased in hearts of CCC patients, as well as monocytes expressing CXCR3, CCR5, CXCL9 and CCL5 (Cunha-Neto E., et al., 2009). It has been shown that INF- and CCL2 induceed myocytes to secrete arial natriuretic factor and caused hypertrophy (Cunha-Neto E., et al., 2005), and IL-18 and CCR7 ligands, which are increased in CCC, caused cardiomyocyte hypertrophy and fibrosis (Reddy, et al., 2008, Riol-Blanco, et al., 2005, Sakai, et al., 2006).

#### **2.3 The third ingredient: fibrosis**

Fibrosis is one of the most striking characteristics of CCC. In our patients with CCC in endomyocardial biopsies, fibrosis had replaced between 8.2 and 49% of contractile myocardium, with only one patient having less than 10% (Milei, et al., 1992b). While in autopsies, fibrosis was more extensive reaching in the conduction system than in the contracting myocardium (51.5 ± 18% vs 43.4 ± 8%, p < 0.05) (Milei, et al., 1996a).

The deposition of laminin in extracellular and basement membranes has been implicated in the pathogenesis of inflammatory process, as laminin is able to bind proinflammatory citokines (Savino, et al., 2007). The inflammatory infiltrate in CCC was related to the production of citokines such as INF-, TNF-, IL-18, CCL2 and CCL21, that may have modulator actions on fibrotic process (Cunha-Neto E., et al., 2009).
