AUTHOR=Gomes Juliana de A. S. , de Araújo Fernanda F. , Vitelli-Avelar Daniele M. , Sathler-Avelar Renato , Lage Paula S. , Wendling Ana P. B. , do Vale Isabela N. P. C. , Dias João C. P. , Elói-Santos Silvana M. , Teixeira-Carvalho Andréa , Martins-Filho Olindo A. 

TITLE=Systems Biology Reveals Relevant Gaps in Fc-γR Expression, Impaired Regulatory Cytokine Microenvironment Interfaced With Anti-Trypanosoma cruzi IgG Reactivity in Cardiac Chagas Disease Patients

JOURNAL=Frontiers in Microbiology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2018.01608

DOI=10.3389/fmicb.2018.01608

ISSN=1664-302X

ABSTRACT=<p>The systems biology approach has become an innovative tool when it comes to shedding light on the complex immune response underlying the development/maintenance of distinct clinical forms of Chagas disease. The goal of this study was to describe an integrative overview of Fc-γR expression, cytokine microenvironment and anti-<italic>Trypanosoma cruzi</italic> IgG interface in indeterminate-(IND) and cardiac-(CARD) patients. Data demonstrated that IND displayed an overall higher Fcγ-R expression (CD16; CD32; CD64) on neutrophils-(NEU), along with (CD16; CD64) on monocytes-(MON) as compared to CARD. Additionally, CARD presented an increased expression of CD32 in B-cells. While preserved frequency of IL-10-producing cells was observed in IND, decreased levels of IL-10<sup>+</sup> phagocytes and enhanced TNF<sup>+</sup> MON and NK-cells were observed in CARD. <italic>T. cruzi</italic>-antigen recall <italic>in vitro</italic> induces a general decrease of Fc-γR expression in Chagas disease patients, especially in CARD. Moreover, <italic>T. cruzi</italic>-antigen stimuli triggered a concomitant increase of IFN-γ<sup>+</sup>NEU/TNF<sup>+</sup>NK-cells and IL-10<sup>+</sup>MON/IL-10<sup>+</sup>B-cells in IND. Biomarker signatures further emphasized the contrasting Fc-γR expression and cytokine microenvironment observed in Chagas disease patients with distinct clinical forms. Up-regulation of Fc-γR expression (CD16 on NEU;MON;NK) was observed in IND, whereas a general decrease was reported for CARD. Moreover, while a mixed cytokine microenvironment (TNF; IL-10) was observed in IND, CARD presented a contrasting profile with up-regulation of TNF<sup>+</sup>NEU and IL-12<sup>+</sup>NEU. Integrative network analysis revealed a distinct assemblage of biomarkers, with CARD presenting a large number of negative internode connectivity in comparison with IND. The relevant gaps in Fc-γR expression and impaired regulatory cytokine microenvironment interfaced with the anti-<italic>T. cruzi</italic> IgG reactivity throughout an exacerbated negative connectivity may account for the development/maintenance of the clinical status of cardiac Chagas disease.</p>