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

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Although allergic diseases are among the most pervasive medical conditions to affect humans in the world, surprisingly little is known regarding the basic pathophysiologic mechanisms involved. In FY22, we made significant strides in understanding the mechanisms by which impaired TGFb signaling promotes allergic diseases. We have found that LDS mice and patients exhibit an exaggerated frequency of type 2 T follicular helper cells, which promote IgE production by B cells, and that the accumulation of these cells is the result of T cell-intrinsic defects. We are currently dissecting the underlying biochemical pathways involved. In FY22, we also further defined the mechanisms by which LDS mutations result in excessive proliferation and impaired differentiation of squamous epithelial cells in the esophagus and showed that these cell-intrinsic defects in epithelial cells were not only necessary but sufficient to drive the development of eosinophilic esophagitis (EoE), a chronic allergic disease characterized by the excessive accumulation of eosinophils in the esophagus. 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 FY22, we collaborated with Dr. Janice Lee from NIDCR to characterize the craniofacial manifestations of our patients with LDS and Shprintzen-Goldberg syndrome, a disorder caused by mutations in SKI (which encodes an inhibitor of TGFb signaling), that has significant phenotypic overlap with LDS. Using deep clinical phenotyping, three-dimensional (3D) facial photo surface analysis, and information obtained from cone-beam CT scans, we identified several developmental craniofacial abnormalities involving the orbit, maxilla, and mandible in these patient populations, as well as reduced pharyngeal airway in over half of the patients. In FY22, we also completed a study evaluating the effect of LDS mutations on skeletal health. We found that half of children and 9% of adults with LDS in our cohort had low bone density at one or more sites as measured by dual-energy x-ray absorptiometry (DXA). Sixty percent of patients had experienced 1 or more fractures, and 24% of patients who had spinal x-ray scans showed spinal compression fractures. Lower body mass index, asthma, male sex, and eosinophilic gastrointestinal disease were correlated with lower DXA Z-scores. We then created an algorithm to predict low bone density in LDS patients based on the presence or absence of 5 LDS-associated clinical features (scoliosis, pes planus, arachnodactyly, spondylolisthesis, and camptodactyly). Finally, we showed preliminary evidence that treatment with bisphosphonates may be beneficial in LDS patients with poor bone health.