Amber Luong, MD, PhD runs a basic science laboratory that is a member of the Center for Immunology and Autoimmune Diseases within the Institute of Molecular Medicine of the McGovern Medical School.
Over 40 million Americans suffer from chronic rhinosinusitis (CRS) which causes facial pain and pressure, nasal congestion and obstruction. These symptoms ultimately drive conservatively 18-22 million physician visits yearly with an annual direct healthcare treatment cost of over 3 billion dollars. In addition, patients suffering from CRS often are diagnosed with asthma. Together, CRS and asthma as chronic respiratory diseases represent some of the most prevalent chronic illnesses in the United States. Despite this healthcare burden, much remains unknown about its pathophysiology, and current treatment options, which typically involve recurrent surgeries and anti-inflammatory agents, are not curative. CRS represents an ideal human research model for studies in chronic inflammatory respiratory diseases. CRS patients often undergo surgery providing an opportunity to harvest critical diseased tissue and are seen regularly in clinic which allows periodic evaluation of the patient and diseased mucosa.
CRS is clinically classified into 2 groups defined by the absence or presence of nasal polyps. This clinical classification has been supported generally by immunologic profiles of the inflamed sinus tissue. CRS without nasal polyps is characterized by predominance of neutrophils and elevated T helper cell type 1 (Th1) cytokines, while CRS with nasal polyps (CRSwNP) has high presence of eosinophils, mast cells, and basophils and expression of type 2 cytokines such as IL-4, IL-5, and IL-13. However, recent study by our labs using cluster analysis of genetic information has identified endotypes within these clinical phenotypes, allowing for possible personalized treatment.
Allergic fungal rhinosinusitis (AFRS) is a clinical subtype of CRSwNP that is associated with an accumulation of thick entrapped mucus laden with fungal hyphae and eosinophils between the nasal polyps and within sinus cavities. This trapped mucus can cause expansion of sinus cavities and ultimately erosion of bone separating the sinuses from the intracranial and orbital cavities which can result in intracranial complications and blindness, respectively.
Respiratory epithelial cells represent the first line of defense against the environment for sinonasal mucosal. Recent studies have shown that epithelial cells serve an active role through regulation of cytokines and release of anti-microbials. Three identified epithelial cell derived cytokines, thymic stromal lymphopoietin, interleukin (IL)-25 and IL-33, have been linked to the type 2 immune response.
Our lab has focused on the role of IL-33 in orchestrating the type 2 immune response characteristic of CRS with nasal polyps. We confirmed that the receptor of IL-33 is upregulated in the diseased sinonasal mucosa of CRSwNP. We demonstrated an increased presence of innate lymphoid type 2 cells (ILC2) preferentially in CRSwNP patients relative to health controls. These ILC2 express ST2, the receptor for IL-33, and represent the major cell type producing IL-13 in response to IL-33. Interestingly, we found that fungal antigens, specifically Aspergillus, can stimulate respiratory epithelial cells to release IL-33.
Given the appreciation of the innate immunity and known data of the role of the adaptive immune response in CRS, we are currently interested in the distribution and ultimately in the function of innate lymphoid cells and T helper cells in various CRS subtypes.
In addition, our lab is interested in the molecular characterization of fungi-mediated signaling pathway(s) and the fungal component responsible for signaling in the inflammatory response in some CRS subtypes. This has led us to our recent interest in unraveling how fungal protease stimulate IL-33 expression and release from respiratory epithelial cells utilizing both mouse models and in vitro studies with primary human sinonasal cells.
- Characterization of immunologic and molecular defects contributing to pathophysiology of allergic fungal rhinosinusitis
- Molecular signaling through respiratory epithelial cells of fungi alone and with other environmental triggers responsible for initiating and/or maintaining the characteristic Th2 immune response
- Clinical characterization and identification of biomarkers for CRS subtypes
- Millien VO, Lu W, Shaw J, Yuan X, Mak G, Roberts L, Song LZ, Knight JM, Creighton CJ, Luong A, Kheradmand F, Corry DB. Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4. Science. 2013 Aug 16;341(6147):792-6.
- Shaw JL, Fakhri S, Citardi MJ, Porter PC, Corry DB, Kheradmand F, Liu YJ, Luong A. IL-33-responsive innate lymphoid cells are an important source of IL-13 in chronic rhinosinusitis with nasal polyps. Am J Respir Crit Care Med. 2013 Aug 15;188(4):432-9.
- Porter P, Lim DJ, Maskatia ZK, Mak G, Tsai CL, Citardi MJ, Fakhri S, Shaw JL, Fothergil A, Kheradmand F, Corry DB, and Luong A. Airway Surface Mycosis in Chronic Th2-Associated 1 Airway Disease. J Allergy Clin Immunol. 2014 Aug 134(2):325-331.
- Tyler MA, Russell CB, Smith DE, Rottman JB, Dietz CJ, Hu X, Citardi MJ, Fakhri S, Assassi S, and Luong A. Large scale gene expression profiling reveals distinct type 2 inflammatory patterns in chronic rhinosinusitis subtypes. J Allergy Clin Immunol, 2017 Mar;139(3):1061-1064.
- Tyler MA, Padro Dietz CJ, Russell CB, Citardi MJ, Assassi S, Ying J, and Luong AU. Distinguishing Molecular Features of Allergic Fungal Rhinosinusitis. Otolaryngol Head Neck Surg. 2018 Jul;159(1):185-193.