BackgroundChronic Chagas cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi. Even though the Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis, little is known about the factors controlling inflammatory cell migration to CCC myocardium.Methods and ResultsUsing confocal immunofluorescence and quantitative PCR, we studied cell surface staining and gene expression of the CXCR3, CCR4, CCR5, CCR7, CCR8 receptors and their chemokine ligands in myocardial samples from end-stage CCC patients. CCR5+, CXCR3+, CCR4+, CCL5+ and CXCL9+ mononuclear cells were observed in CCC myocardium. mRNA expression of the chemokines CCL5, CXCL9, CXCL10, CCL17, CCL19 and their receptors was upregulated in CCC myocardium. CXCL9 mRNA expression directly correlated with the intensity of myocarditis, as well as with mRNA expression of CXCR3, CCR4, CCR5, CCR7, CCR8 and their ligands. We also analyzed single-nucleotide polymorphisms for genes encoding the most highly expressed chemokines and receptors in a cohort of Chagas disease patients. CCC patients with ventricular dysfunction displayed reduced genotypic frequencies of CXCL9 rs10336 CC, CXCL10 rs3921 GG, and increased CCR5 rs1799988CC as compared to those without dysfunction. Significantly, myocardial samples from CCC patients carrying the CXCL9/CXCL10 genotypes associated to a lower risk displayed a 2–6 fold reduction in mRNA expression of CXCL9, CXCL10, and other chemokines and receptors, along with reduced intensity of myocarditis, as compared to those with other CXCL9/CXCL10 genotypes.Conclusions Results may indicate that genotypes associated to reduced risk in closely linked CXCL9 and CXCL10 genes may modulate local expression of the chemokines themselves, and simultaneously affect myocardial expression of other key chemokines as well as intensity of myocarditis. Taken together our results may suggest that CXCL9 and CXCL10 are master regulators of myocardial inflammatory cell migration, perhaps affecting clinical progression to the life-threatening form of CCC.

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BackgroundChagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage.MethodsOur genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects.ResultsThe CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%.ConclusionsOur data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.

GalectinKeywords: Galectin-3 r IL-10 r Leishmania major r T regulatory (Treg) cells r Notch signaling IntroductionGalectins are a family of glycan-binding proteins composed of 15 members that are conserved throughout animal evolution Correspondence: Prof. Gabriel A. Rabinovich e-mail: gabyrabi@gmail.com and share sequence similarities in their carbohydrate-recognition domain [1][2][3]. Galectin-3, a widely distributed member of the family, plays pleiotropic roles in innate and adaptive immunity by regulating cytokine production, phagocytosis, chemotaxis, * These authors contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1806-1817 Immunity to infection 1807 signaling, and survival [4][5][6][7]. Through these mechanisms, galectin-3 has been proposed to control host immunity against several infectious agents [1,[6][7][8]]. Yet, despite considerable evidence on the role of galectin-3 in the control of immune responses, its contribution to T regulatory (T REG ) cell function during microbial attack has not yet been explored. T REG cells, either inducible or naturally occurring, suppress effector T (T EFF )-cell responses through different mechanisms including cell-cell contact and secretion of immunosuppressive cytokines such as IL-10, . Interestingly, galectin-1 and -10 have been proposed to mediate the immunosuppressive activity of Foxp3 + T REG cells [10, 11] Results Leishmania major infected Lgals3−/− mice show increased frequency of CD4To investigate the role of galectin-3 within the T REG cell compartment, we first compared the outcome of L. major infection in Lgals3 −/− and WT mice on BALB/c background. Mice were inoculated with 1 × 10 7 metacyclic promastigotes into one hind footpad, and the development of the lesions was monitored weekly. Lgals3 −/− mice developed more pronounced footpad swelling starting from 35 days postinfection and exhibited an increased parasite burden (at day 35) compared with WT mice (Fig. 1A). To examine the possible mechanisms underlying the increased susceptibility to L. major infection, we examined the impact of galectin-3 deficiency in different immune cell types. We found no significant differences in the frequency of F4 Fig. 2A and B). In addition, real-time RT-PCR analysis showed increased Foxp3 mRNA expression in footpad tissue from Lgals3 −/− -infected animals as compared with their WT counterpart (Fig. 2C). Of note, galectin-3 protein was detected at high levels in footpad tissue from WT mice ( Fig. 2A; infection sites, but also limits the immunosuppressive function of these cells during the course of parasitic protozoa infection. mRNA was substantially upregulated after stimulation with anti-CD3 and anti-CD28 antibodies in both T EFF and T REG WT cells (Fig. 5C). Galectin-3 controls IL-10 production by T REG cells even in the absence of infectionTo further dissect the role of galectin-3 within the T REG -cell compartment during infection, we isolated T EFF and T REG cells from draining LNs...