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 among the most pervasive medical conditions affecting humans world-wide, the basic pathophysiologic mechanisms involved remain poorly understood. We previously demonstrated that Loeys-Dietz syndrome (LDS) is associated with an elevated risk of allergic disease in both patients and in a mouse model of the disease. In FY25, we continued to investigate the basic processes by which dysregulated TGFb signaling promotes the development of eosinophilic esophagitis (EoE), a chronic allergic disease characterized by esophageal dysfunction and the accumulation of eosinophils in the esophageal tissue. In FY25, we also continued our studies of patients and mice with Myhre syndrome, an autosomal dominant disorder caused by mutations in SMAD4, which encodes a critical signaling molecule in the TGFβ pathway. Myhre patients and mice often exhibit low antibody levels and/or inadequate antibody titers in response to vaccines. In contrast to LDS, Myhre patients also tend to have low IgE antibody levels and a low prevalence of allergic disease. Our ongoing studies are focused on understanding how SMAD4 regulates antibody responses using both patient samples and a murine model. The primary cause of early morbidity and mortality in LDS patients results from rupture of arterial aneurysms and aortic dissection. Given that COVID-19 vaccination and illness have been reported to confer an elevated risk for cardiovascular events (CVE), in FY25 we collaborated with our colleagues at Johns Hopkins to investigate whether patients with LDS and other vascular connective tissue disorders, including Marfan Syndrome and vascular Ehlers Danlos syndrome (EDS), are at higher risk for these adverse events because of their underlying cardiovascular disease. We conducted a cross-sectional web-based survey between Nov 22, 2021, and March 15, 2022. 325 individuals with a self-reported vascular connective tissue disorder responded. We found that COVID-19 illness was associated with a higher rate of new abnormal heart rhythm within 30 days following infection. However, given the self-reported nature of this outcome, further studies are needed to determine whether this represents a true increase in pathologic arrhythmias or more benign and short-lived situational palpitations or tachycardia caused by fever and illness. No increase in any other category of CVEs was noted following COVID-19 illness, and no CVE events were increased within 30 days following COVID-19 vaccination. The frequency of expected adverse events following vaccination reported by patients with vascular connective tissue orders was similar to the general population. Despite their predisposition for allergic disease, patients with LDS did not report a higher than expected rate of allergic reactions to the vaccine. Taken together, these data support the safety of COVID-19 vaccination in patients with underlying vascular connective tissue disease. Using the same study design, in FY25 we also evaluated adverse events, including cardiovascular events, after COVID-19 illness and vaccination in patients with hypermobile Ehlers-Danlos syndrome (EDS). Hypermobile EDS is an inherited connective tissue disease characterized by joint hypermobility and multi-system co-morbidities including pain, fatigue, sleep and gastrointestinal issues, anxiety, and poor health-related quality of life. A total of 368 individuals responded to the survey. We observed a higher than expected rate of new abnormal heart rhythm within 30 days following SARS-CoV2 infection, which again may represent short-lived situational tachycardia during acute illness. No increase in CVEs was observed within 30 days after COVID-19 vaccination. However, all categories of expected adverse events were more common in patients with hypermobile EDS following vaccination than in the general population. Overall, 87.2% of respondents who received at least one vaccine dose reported at least one expected adverse event. Allergic reactions were associated with 20.9% of doses, palpitations and/or dizziness with 21.7%, hypotension with 10%, and loss of consciousness with 2%. Additionally, 3.1% of respondents reported being hospitalized after a vaccine dose due to an adverse reaction. Overall, we conclude that vaccination is generally safe in patients with hypermobile EDS; however, expected adverse events are common, consistent with the high baseline prevalence of similar symptoms in this patient population. Through a collaboration with Dr. Janice Lee’s group in NIDCR, we have been studying the dental phenotype of LDS and previously showed that these patients are prone to enamel defects, particularly those with mutations in TGFBR2. In FY25, we continued this collaboration and found that LDS mice harboring a mutant Tgfbr2 knock-in allele exhibited normal production and mineralization of enamel, but enamel rod decussation was disrupted, resulting in impaired biomechanical properties. Similarly, deciduous teeth from patients with LDS type 2 had normal enamel thickness and normal to mildly reduced mineral density but showed disrupted enamel ultrastructure and biomechanical properties. These enamel changes appear to result from abnormal movement of ameloblasts, enamel-producing cells, during matrix deposition. Ongoing studies aim to understand the mechanisms by which dysregulated TGFb signaling disrupts coordinated ameloblast movement.