The Role of Transforming Growth Factor Beta (TGFbeta) in Promoting Allergic Inflammation

National Institute Of Allergy And Infectious Diseases

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Abstract

Although allergic diseases are one of the most pervasive medical conditions to affect humans in the world, surprisingly little is known regarding the basic pathophysiologic mechanisms involved. While we have a good understanding of the major cell types that participate in T helper 2 (Th2) immune responses, the mechanisms that initiate Th2 pathology and disrupt tissue-specific homeostasis are less clear. Transforming growth factor beta (TGFb) is a multifunctional cytokine that plays a critical role in immunologic tolerance through its effects on the adaptive immune system. We have previously shown that patients with an autosomal dominant loss-of-function mutation in the genes encoding the receptor for TGFb are more likely to develop nearly all forms of allergic disease, including food allergy and eosinophilic esophagitis (EoE). EoE is characterized by the accumulation of an allergic infiltrate (eosinophils, mast cells, dendritic cells, T cells, and type 2 innate lymphoid cells (ILC2s)) uniquely in the esophagus, resulting in esophageal dysfunction that manifests as difficulty swallowing, food impaction, and poor growth. In preliminary studies, our lab has found that mice harboring a knock-in of an LDS allele (TgfbrIM318R/+) known to cause severe disease in humans also develop an allergic phenotype, including the spontaneous development of EoE with 100% penetrance. However, how impaired TGFb signaling leads to tissue-specific allergic inflammation is not clear. In FY21, we have continued our investigations into the role of epithelial cells in driving the recruitment of inflammatory cells to the esophagus and ultimately the development of EoE. We have additionally made significant progress in understanding how TGFb alters the phenotype and function of T cells in a manner that may promote the development of IgE-mediated pathology. TGFb is a multifunctional cytokine that plays a critical role in the development and function of nearly all cell types in the body. By understanding how TGFb regulates homeostasis in different tissues, we hope to gain insight into the pathways by which TGFb regulates cellular functions to promote allergic phenotypes, and the broader clinical consequences that may result from disruptions in TGFb signaling. In FY21, we collaborated with Dr. Jeff Kim from NIDCD on the first description of the audiologic and otologic phenotype of patients with LDS. In our cohort of 37 patients with genetically confirmed LDS, we found that 69% had an abnormal audiological finding, most commonly mild-moderate hearing loss. However, differences were seen across the different types of LDS. Patients with type 1 and 2 LDS, caused by mutations in genes encoding the receptor for TGFb, most commonly exhibited conductive hearing loss as well as bifid uvula and submucosal/hard cleft palates. Post-tympanostomy tympanic membrane perforations (TMP) were also common in these patients, affecting up to 45% of LDS type 1 and 2 patients. On the other hand, sensorineural hearing loss was only observed in patients with type 3 or type 4 LDS, caused by mutations in SMAD3 and TGFB2, respectively. Four cases of cholesteatoma were also noted (in patients with type 2 and 3 LDS). Overall, our findings underscore the importance of evaluating for audiologic and otologic pathology in patients with LDS, and the importance of considering the role of TGFb in wound healing processes and craniofacial development when choosing a medical and/or surgical approach for managing ear disease in this patient population. In FY21, we also collaborated with Dr. Janice Lee in NIDCR to publish a case report of two patients with LDS type 1 who exhibited rare cases of abnormal dentin manifesting as dentinogenesis imperfecta, which appears clinically as grayish or yellow-brown discoloration of the teeth. This condition can lead to weak teeth which are susceptible to fracture and breakage. Dentinogenesis imperfecta has been reported in other genetic diseases including osteogenesis imperfecta, but this is the first report in patients with LDS, pointing to a prominent role for TGFb in dentin development. Collectively, our studies in FY 21 have not only broadened our understanding about the role that TGFb plays in multiple systems in humans but has informed new ways we can improve the diagnosis and care of patients with LDS.