Finding 1: 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, including mucocutaneous candidiasis, immune dysregulation and increased neoplastic disease. We had previously 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 upregulation on T-cells inhibiting Th17 differentiation. Further study has now shown that these patients also fail to produce Th9 cells, which are important for the pathogenesis of allergic and autoimmune disease, but also for anti-tumor host defense. We found that the enhanced STAT1 signal in both patient types inhibits Th9 differentiation by overproducing the transcription factor T-bet. Further, we found that IL-21 production was low during differentiation cultures and that exogenous IL-21 could rescue the poor Th9 differentiation at least in part by acting upon residual STAT3 activity to upregulate SOCS3 and suppress STAT1 activation. The results help describe further overlap between the two syndromes and pathways. Further, given the anti-cancer effects of exogenous IL-21, these patients provide a potential set of molecular defects which would be most likely to respond to IL-21 therapy in patients requiring such treatment. The results were published in the Journal of Allergy and Clinical Immunology. Finding 2: We had recently described Hereditary alpha tryptasemia syndrome (HATS), initially identified in 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 abnormalities 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 tryptase. 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 tryptase levels, and predispose to a variety of symptoms seen in the initial referral cohort. The results were published in Nature Genetics. There were then several follow up studies we performed. The first showed that there were a series of CACNA1H variants which were in partial linkage with the TPSAB1 CNV. These variants led to a functional gain of function of the Calcium channel. Because CACNA1H has been implicated in pain and other phenotypes we also saw in patients with the TPSAB1 CNV, we wished to see if the presence of the variants might affect phenotypes in control and hereditary alpha tryptasemia patients. We did not find any associations using the NIH Clinseq control cohort or our cohort of HATS patients. The results were published in Genomics in Medicine. We then also described, along with Didier Ebo and Vito Sabato in Belgium, that the family they had initially reported with familial hypertryptasemia actually had HATS, due to a never before described quintuplication in TPSAB1. One of the patients had associated clonal mast cell disease suggesting that the CNV could contribute to the risk for developing clonal mast cell disease. The results were published in the Journal of Clinical Immunology.

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2018
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Sabato, Vito; Chovanec, Jack; Faber, Margaretha et al. (2018) First Identification of an Inherited TPSAB1 Quintuplication in a Patient with Clonal Mast Cell Disease. J Clin Immunol 38:457-459
Lyons, Jonathan J; Stotz, Stephanie C; Chovanec, Jack et al. (2018) A common haplotype containing functional CACNA1H variants is frequently coinherited with increased TPSAB1 copy number. Genet Med 20:503-512
Milner, Joshua D (2018) TCR Signaling Abnormalities in Human Th2-Associated Atopic Disease. Front Immunol 9:719
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Ma, Chi A; Xi, Liqiang; Cauff, Brian et al. (2017) Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea. Blood 129:650-653
Schwerd, Tobias; Twigg, Stephen R F; Aschenbrenner, Dominik et al. (2017) A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis. J Exp Med 214:2547-2562

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