Abstract
Air pollution is known to exacerbate chronic inflammatory conditions of the lungs including pulmonary hypertension, cardiovascular diseases and autoimmune diseases. Directly pathogenic antibodies bind pro-inflammatory cell receptors and cause or exacerbate inflammation. In contrast, anti-inflammatory antibody isotypes (e.g. mouse immunoglobulin G1, IgG1) bind inhibitory cell receptors and can inhibit inflammation. Our previous studies showed that co-exposure to antigen and urban ambient particulate matter (PM2.5) induced severe pulmonary arterial thickening and increased right ventricular systolic pressures in mice via T-cell produced cytokines, Interleukin (IL)-13 and IL-17A. The aim of the current study was to understand how B cell and antibody responses integrate into this T cell cytokine network for the pulmonary hypertension phenotype. Special focus was on antigen-specific IgG1 that is the predominant antibody in the experimental response to antigen and urban ambient PM2.5. Wild type and B cell-deficient mice were primed with antigen and then challenged with antigen and urban particulate matter and injected with antibodies as appropriate. Our data surprisingly showed that B cells were necessary for the development of increased right ventricular pressures and molecular changes in the right heart in response to sensitization and intranasal challenge with antigen and PM2.5. Further, our studies showed that both, the increase in right ventricular systolic pressure and right ventricular molecular changes were restored by reconstituting the B cell KO mice with antigen specific IgG1. In addition, our studies identified a critical, non-redundant role of B cells for the IL-17A-directed inflammation in response to exposure with antigen and PM2.5, which was not corrected with antigen-specific IgG1. In contrast, IL-13-directed inflammatory markers, as well as severe pulmonary arterial remodeling induced by challenge with antigen and PM2.5 were similar in B cell-deficient and wild type mice. Our studies have identified B cells and antigen specific IgG1 as potential therapeutic targets for pulmonary hypertension associated with immune dysfunction and environmental exposures.
Highlights
Pulmonary hypertension significantly decreases quality of life and shortens life expectancy [1,2,3]
Serum antigen-specific IgG1 was highly significantly correlated with right ventricular systolic pressure (Fig 2A) and antigen-specific IgG1 titers were, as expected, significantly further increased in sensitized wild type mice upon challenge with OVA-PM2.5 (Fig 2B)
Co-neutralizing IL-13 and IL-17A resulted in a significant amelioration of the mean increase in antigen-specific IgG1 in sensitized mice exposed to the antigen and PM2.5 (18,170 ± 2,819 U in OVA-PM challenged control mice vs. 9,321 ± 2,146 U in OVA-PM challenged mice given neutralizing anti-IL-13 and anti-IL-17A antibodies, p = 0.013 Mann-Whitney U test)
Summary
Pulmonary hypertension significantly decreases quality of life and shortens life expectancy [1,2,3]. Pulmonary hypertension induced by exposure to silica is still a major problem in Asia and South America [9]. Environmental exposures to silica or organic chemicals can exacerbate autoimmune diseases, including systemic sclerosis [12], and environmental exposures can cause autoimmune alterations of the immune system [13]. Autoimmune disorders such as systemic sclerosis and systemic lupus erythematosus [14], in turn, are significant risk factors for the development of pulmonary hypertension
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