Finding 1: Patients with TGFBR mutations have many connective tissue abnormalities which overlap with those seen in STAT3LOF patients studied at the NIH. Furthermore, they also have a predisposition to allergic disease as well. We therefore sought to determine whether there was a mechanistic overlap between the two disorders. We found that STAT3 negatively regulates TGFB signaling via a protein called ERBIN. This negative regulation prevents excessive IL4R expression in lymphocytes, a critical mediator of atopic responses. We further showed that a family with loss-of-function in ERBIN had many of the symptoms seen in TGFBR mutations as well as STAT3LOF, and their cellular responses in vitro were also similar, including excessive upregulation of IL4R. The results were published in the Journal of Experimental Medicine. Finding 2: Because of our ongoing work in patients with STAT3 loss-of-function and STAT1 gain-of-function, we noted that the patients have a number of phenotypic similarities. In particular, the loss of Th17 cells and mucocutaneous candidiasis. We found that STAT3 appears to normally inhibit STAT1 function via SOCS3, and that when STAT3 function is reduced, STAT1 activation is exaggerated. The exaggerated STAT1 activation in both STAT1GOF and STAT3LOF patients, in turn, leads to increased PDL1 upreglation on T-cells. This PDL1 expression inhibits Th17 differentiation, since blockade of PDL1 in vitro, or breeding the STAT3LOF mouse to a PD-1 null mouse partially restores the capacity to generate Th17 cells. The findings help explain some of the phenotypic overlap between the two disorders and suggest a potential therapy for the consequences of low Th17 cells in both populations. The results were published in the Journal of Experimental Medicine. Finding 3: In studying patients with GATA3 haploinsufficiency, we wished to determine the cellular and phenotypic consequences of haploinsufficiency in such a key Th2-promoting gene highly associated with atopy. In collaboration with Dr. Steven Holland's lab (NIAID), we found that allergic sensitization could occur normally, and that there were minimal cellular changes associated with Th2 defects. Thus while the haploinsufficiency has a substantial effect on multiple organ systems including hearing and endocrine, there was little immunologic consequence. These findings have substantial implications for our studies allelic expression of gata3, as well as the impact of gene dose effects in gata3 on allergy risk. The results were published in the Journal of Allergy and Clinical Immunology. Finding 4: In our efforts to describe familial inheritance of allergic disease, we have identified over 50 families with an autosomal dominant inheritance of elevated basal tryptase levels in the absence of any signs of mastocytosis. Affected family members have cutaneous flushing, episodic gastrointestinal pain, food allergy and anaphylaxis, and, in a subset of patients, connective tissue abnormalties reminiscent of Ehlers-Danlos syndrome, hypermobility type. Patient basophils have a degranulation defect, perhaps due to anergy ex-vivo, and in the multiple families in whom bone marrow biopsies were done, there was a significant elevation in mast cell number, despite the complete lack of morphologic evidence or scale of mastocytosis. A report describing our experience with the first 9 families was published in the Journal of Allergy and Clinical Immunology. We have subsequently found that these families all have increased copy number of the alpha tryptase variant at TPSAB1 on a single allele. Those with triplications of this gene had worse symptoms than those with duplications, suggesting a gene dose effect. Patient mast cells secrete highly elevated levels of trytpase. Furthermore, we found that the duplications are actually present in perhaps 5% of the general population, and they explain the overwhelming majority of the 5% or so of the population that has elevated basal serum trytpase levels, and predispose to a variety of symptoms seen in the initial referral cohort. The results were published in Nature Genetics.
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