B lymphocytes regulate airway granulocytic inflammation and cytokine production in a murine model of fungal allergic asthma

Abstract

Sensitization to fungi often leads to a severe form of asthma that is particularly difficult to manage clinically, resulting in increased morbidity and hospitalizations in these patients. Although B lymphocytes might exacerbate asthma symptoms through the production of IgE, these cells might also be important in the protective response against inhaled fungi. Through cytokine release and T-cell interactions, these lymphocytes might also influence the development and maintenance of airway wall fibrosis. J H 2/2 mice lack the JH gene for the heavy chain component of antibodies, which is critical for B-cell function and survival. These animals have facilitated the elucidation of the role of B lymphocytes in a number of immune responses; however, J H 2/2 mice have not been used to study fungal allergy. In this study, we examined the role of B lymphocytes using an Aspergillus fumigatus murine fungal aeroallergen model that mimics human airway disease that is triggered by environmental fungal exposure. We compared disease progression in sensitized wild-type BALB/c and J H 2/2 mice that were exposed to repeated fungal exposure and found no differences in airway hyperresponsiveness, overall pulmonary inflammation or collagen deposition around the large airways. However, the levels of the Th2-type cytokines IL-4 and IL-13 were significantly attenuated in the airways of J H 2/2 mice relative to the BALB/c controls. By contrast, levels of the inflammatory cytokines IL-17A and IL-6 were significantly elevated in the J H 2/2 animals, and there was significantly more robust airway eosinophilia and neutrophilia than in control animals. Taken together, these findings demonstrate that B lymphocytes help to regulate granulocytic responses to fungal exposure in the pulmonary compartment.

Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness

“…Rodent models of AHR, including those that are sensitive to ovalbumin, house dust mite, and A. fumigatus challenge, have a significant inflammatory component (8,9). We examined the lungs of Foxp1/4 DKO mutants for expression of the eosinophilic inflammatory marker IL-13 and neutrophilic inflammatory markers IL-17, IL-6, and keratinocyte-derived chemokine (KC) to assess whether loss of Foxp1 and Foxp4 evoked an inflamma- increased levels of Npy observed in the Foxp1/4 DKO mutant airway epithelium generated a paracrine signal to promote airway smooth muscle contraction rather than increased mass.…”

Humoral immune responses during asthma and influenza co-morbidity in mice

“…Characteristics of asthma are reduced in B cell deficient mice (47–49), underscoring their role as regulators of allergic inflammation. Herein, we determined trends in B kinetics during the course of influenza in hosts with underlying allergic asthma.…”

Hyaluronan stimulates ex vivo B lymphocyte chemotaxis and cytokine production in a murine model of fungal allergic asthma

“…Many of the acute and chronic features of clinical fungal asthma are recapitulated in the experimental model that we have developed in our laboratory in which sensitization with fungal extracts is followed by allergy challenge via inhaled Aspergillus (Hoselton et al, 2010; Schuh and Hoselton, 2013; Samarasinghe et al, 2011). We observe IgE production, eosinophilia, leukocyte recruitment, and pronounced peribronchial ECM changes that are exaggerated upon subsequent exposure to inhaled conidia (Ghosh et al, 2012a, 2013, 2014a; Chaudhary and Marr, 2011; Hoselton et al, 2010; Pandey et al, 2013). …”