Asthma-Related Environmental Fungus, Alternaria, Activates Dendritic Cells and Produces Potent Th2 Adjuvant Activity

Abstract

Asthma is thought to result from dysregulated Th2-like airway inflammatory responses to the environment. Although the etiology of asthma is not fully understood in humans, clinical and epidemiological evidence suggest a potential link between exposure to environmental fungi, such as Alternaria, and development and/or exacerbation of asthma. The goal of this project was to investigate the mechanisms of airway Th2 responses by using Alternaria as a clinically relevant model for environmental exposure. Airway exposure of naive animals to an experimental Ag, OVA, or a common allergen, short ragweed pollen, induced no or minimal immune responses to these Ags. In contrast, mice developed strong Th2-like immune responses when they were exposed to these Ags in the presence of Alternaria extract. Extracts of other fungi, such as Aspergillus and Candida, showed similar Th2 adjuvant effects, albeit not as potently. Alternaria stimulated bone marrow-derived dendritic cells (DCs) to express MHC class II and costimulatory molecules, including OX40 ligand, in vitro. Importantly, Alternaria inhibited IL-12 production by activated DCs, and DCs exposed to Alternaria enhanced Th2 polarization of CD4+ T cells. Furthermore, adoptive airway transfer of DCs, which had been pulsed with OVA in the presence of Alternaria, showed that the recipient mice had enhanced IgE Ab production and Th2-like airway responses to OVA. Thus, the asthma-related environmental fungus Alternaria produces potent Th2-like adjuvant effects in the airways. Such immunogenic properties of certain environmental fungi may explain their strong relationships with human asthma and allergic diseases.

A triterpenoid methyl antcinate K isolated from Antrodia cinnamomea promotes dendritic cell activation and Th2 differentiation

“…5C). The 10 3 -fold difference between serum dilutions of anti-OVA IgG 1 versus IgG 2a has been reported by other groups [44,45]. However, the difference in absolute titers of anti-OVA IgG 1 versus IgG 2a appeared less dramatic, suggesting that antiIgG 1 and -IgG 2a Ab have different sensitivities.…”

Type 2 Innate Lymphoid Cells Drive CD4+ Th2 Cell Responses

“…For example, ILC2 are activated within a matter of hours following i.n. challenge of mice with the allergen Alternaria alternata (12), whereas T cell responses typically follow several days later (26). It is possible that early activation of ILC2 may contribute to the later development of a CD4 + Th2 response, whereas T cell production of IL-2 may reinforce this response in a feedback loop by further activating ILC2.…”

Necessary and Sufficient Role for T Helper Cells To Prevent Fungal Dissemination in Allergic Lung Disease

“…Fungal airway infections are also linked to a spectrum of T helper (Th) cell responses, including Th1, Th2, and Th17 cell activation (4,8,26,39,45). We previously demonstrated that the conidia of the ubiquitous fungus Aspergillus niger, given in relatively small amounts, trigger a highly polarized Th2-predominant allergic response in mice that provokes canonical features of asthma, including airway hyperreactivity, robust airway eosinophilia, and goblet cell metaplasia with mucus hypersecretion (45).…”