The Immunogenetics Group conducts several ongoing research projects within the Laboratory of Respiratory Biology.
Bacterial product-mediated allergic sensitization through the airway
The bacterial products, lipopolysaccharide (LPS) and flagellin, are present in common house dust and potently promote T helper (Th)2 and Th17 responses to common indoor allergens. The different T cell responses lead to eosinophilic and neutrophilic inflammation, respectively. Proteases can also act as adjuvants to promote allergic responses, but do so through distinct molecular pathways. Bacterial product mediated allergic sensitization is dependent on the cytokine, TNF, which signals through the receptor TNFR1 to promote sensitization. By contrast, protease-mediated allergic sensitization does not require TNF, but is dependent on IL-33. Both Th2 and Th17 responses are required for the development of airway hyperresponsiveness (AHR), a salient feature of asthma. Current studies are aimed at further understanding the molecular mechanisms that underlie bacterial product- and protease-mediated allergic sensitization through the airway, with an aim towards developing novel therapies targeted to distinct forms of asthma.
The roles of pulmonary dendritic cell subsets in the maintenance of allergic airway disease
Dendritic cells (DCs) are highly efficient antigen-presenting cells that reside in many organs, including the epithelial lining of the lung. Conventional (c)DCs are Flt3 ligand-dependent antigen presenting cells critical for the initiation of allergic responses, as well as for their maintenance in the context of continued allergen challenge. By combining mouse models of asthma with precision cut lung slices, we are studying how DC movement within the lung maintains allergic airway inflammation and is dependent on the continued presence of both allergens and adjuvants. Additional studies are underway to study the role of interstitial macrophages (formerly termed monocyte-derived DCs) in the regulation of established allergic responses.
Epigenetic regulation of epithelial and dendritic cell function
Recent evidence suggests that epithelial cells can contribute to the induction of allergic responses, but the molecular mechanisms underlying this observation remain unclear. To study this, we have selectively deleted the adaptor molecule MYD88 is airway epithelial cells (AECs), or in Cd11c-expressing cells, which include dendritic cells and alveolar macrophages. Our findings suggest that the epigenetic landscape and transcriptional profiles of cDCs are dependent on MYD88 signaling in DCs themselves, but also in AECs. Furthermore, MYD88 signaling in these two cell types promotes distinct types of inflammatory cell recruitment. Studies are underway to determine how early life exposures to environmental sources of allergens and adjuvants affects long lasting chromatin accessibility in these two major cells types, thereby shaping responses to subsequent allergen exposure during adulthood.