Obesidade e asma: alterações da resposta imune em órgãos linfóides periféricos e efeito do tratamento com azitromicina

Abstract

Both asthma and obesity present rising prevalence. Their concomitance is a reason for concern, as obese individuals present higher exacerbation rates, are refractory to conventional treatments and display a distinct phenotype of the disease. The occurrence of neutrophilia, over the establishment of the eosinophilia; associated with low IgE titers is one of the marks of obese-asthmatics. However, the influence of obesity on the immune response on the peripheral lymphoid organs, during allergic asthma development is still unknown, mainly when it comes to B cells and follicular helper T cells (TFH), the main components of the germinal centers. In addition, recent effort has been done towards the development of more efficient treatments for these patients. Among those alternatives, the use of macrolides, as azithromycin, can be highlighted as good approach for resistant-asthma, associated with neutrophilia. Therefore, the present study aimed to evaluate the obesity effects over the immunopathological mechanisms involved OVA/HDM-induced pulmonary allergy and the effect of azithromycin over these models. Histological analysis, cytokines quantification and lung function evaluation were performed on top of immunophenotyping of the cells from the peripheral lymphoid organs, during the allergic response. The immune response was dampened from the epithelium, as shown by the diminished IL-25 and TSLP production, associated with the diminished activation and migration of dendritic cells to the lymph nodes. The immune response observed in the peripheral lymphoid organs was affected, with B cell and TFH regulation, associated with increased follicular regulatory T cells (TFR) differentiation. Those organs displayed distinct allergic features, with greater obesity influence over the spleen, promoting the TH17 polarization; and TH2 exacerbation on the lymph nodes. Those changes were associated with low IgE titers and increased IgG2a levels. Meanwhile, the lungs exhibited an increased neutrophilia, over the eosinophilia, associated with the diminished CCL11 expression. The azithromycin treatment reduced several parameters related to asthma, as the neutrophilia, the TH17 response, the expression of neutrophil chemoattractants, (KC and MIP2), on top of the reduction of the bronchial hyperresponsiviness on obese allergic animals. In addition, the treatment also reduced the B cells and TFH frequency on their lymph nodes, followed by diminished frequencies of IL-4, IL-17A e IFN producing TH cells. Additionally, obese-allergic treated animals overexpressed mir155 in their lungs. However the treatment did not affect the TH2/eosinophilic response, and it even had worsen the neutrophilic response on lean allergic mice. Altogether, these results demonstrate obesity affects asthma development on the peripheral lymphoid organs, and also, azithromycin was efficient on the treatment of the neutrophilic profile of the obesity aggravated allergy.