Relação entre obesidade, perfil fenotípico e funcional das células T CD4+ e gravidade da asma alérgica: estudo centrado no papel da leptina

Abstract

Allergic asthma is a chronic disease characterized by bronchial hyperreactivity to allergens, such as the glycoprotein Fel d1 found in cats. Obesity and hypovitaminosis D have been associated with the severity of AA.The aim of the study was to evaluate the impact of obesity and its relationship with the effects of leptin and vitamin D on the functional profile of CD4+ T cells and B cells in patients with AA. Therefore, under different stimulation conditions, cultures of total peripheral blood mononuclear cells, or purified CD4+ T cells, cytokine levels were measured via ELISA or Luminex, while immunophenotyping was evaluated by flow cytometry. Furthermore, serum levels of IgE, leptin and 25(OH)D3 were determined by ELISA and Feld1-specific IgE titers were measured by ImmunoCAP. In the study, high levels of IL-5, IL-6 and IL-17 and low concentration of IL-10 were quantified in CD4+ T cell cultures from patients with severe AA. The severity of AA, especially in the obese, was directly associated with the frequency of Th17 cells and hybrid Th2/Th17 cells. In contrast, the frequency of Tr-1/Treg and Br-1 lymphocytes was lower when compared to eutrophic ones. Hyperleptinemia was directly correlated with IL-5, IL-6 and IL-17 levels, and inversely associated with IL-10 measured in CD4+ T cell cultures. Furthermore, serum leptin levels correlated directly with the proportion of Th17 and Th2/Th17 hybrid cells, but were negatively correlated with the percentage of Tr-1/Treg and Br-1 lymphocytes. Additionally, high leptin levels were negatively associated with the ability of 1,25(OH)2D3 to inhibit, in vitro, cytokine production by effector CD4+ T cells from patients with AA. In those allergic to cats, Fel d1 induced the production of IgE and cytokines related to Th2, Th9 and Th17 cell phenotypes, as well as TFH IL21- lymphocytes capable of synthesizing IL-4, IL-5 and IL-13. The addition of leptin favored the expansion of the aforementioned phenotypes, with the exception of Th17 cells and, on the other hand, reduced the proportion of conventional regulatory CD4+ T cells (Tr-1/Treg) and follicular (TFR) cells. The ability of leptin to increase IgE production in vitro correlated directly with the percentage of TFH IL21+IL5+ and TFH IL21- cells (IL4+, IL5+ and IL13+), and inversely correlated with the frequency of Treg and TFR lymphocytes. Finally, many of the Fel d1-specific CD4+ T cell imbalances have been associated with elevated serum levels of leptin and Fel d1-specific IgE. These findings suggest that obesity, partly due to the condition associated with hyperleptinemia and hypovitaminosis D, must negatively impact the prognosis of AA by favoring the expansion of hybrid Th17 and Th2/Th17 cells and decreasing the proportion of Tr-1/Treg and Br-1 lymphocytes. Finally, high doses of leptin should exacerbate the hypersensitivity condition by reducing the frequency of Treg cells and inducing the expansion of TFH subtypes related to the production of high-affinity IgE involved in anaphylactic reactions.