In Fiscal Year (FY) 2019, we continued to advance our understanding of acquired and inherited genetic changes that promote mast cell reactivity and anaphylaxis; many of these disorders we had the opportunity to summarize in a comprehensive review in the Journal of Experimental Medicine in order to convey these new concepts to a broader population. In Sabato et al., we showed for the first time that both inherited and acquired genetic lesions affecting the mast cell compartment in an individual with severe clinical manifestations of mast cell activation. Given that both findings were rare, this report points to the concept that inherited increases in alpha-tryptase encoding copies of TPSAB1 may affect myeloid homeostasis. One putative mechanism of how this may occur was put forward in Le et al., where we demonstrated in collaboration with extramural investigators for the first time that increasing copies of alpha-tryptase encoding genes results in greater mass of alpha/beta-heterotetrameric tryptase with unique enzymatic and physiologic properties. We also reported the effects within the mast cell compartment of germline haploinsufficiency of GATA2. These patients have significant myeloid abnormalities and are at risk for myeloid leukemias. Absence of GATA2 in the mast cells of these patients - which in model systems has been shown to be critical for this lineage - was associated with impaired IgE-dependent reactivity owing to low levels of FceRI and KIT on the surface of these cells. Further, this defect could be recapitulated with a small molecule inhibitor of GATA2, suggesting a novel pathway to target for clinical allergy.
| 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 |
| Schussler, Edith; Yang, Amy; Lyons, Jonathan J et al. (2018) Persistent tryptase elevation in a patient with Gaucher disease. J Allergy Clin Immunol Pract 6:697-699 |
| Zhang, Yuan; Ma, Chi A; Lawrence, Monica G et al. (2017) PD-L1 up-regulation restrains Th17 cell differentiation inSTAT3loss- andSTAT1gain-of-function patients. J Exp Med 214:2523-2533 |
| Lyons, J J; Liu, Y; Ma, C A et al. (2017) ERBIN deficiency links STAT3 and TGF-? pathway defects with atopy in humans. J Exp Med 214:669-680 |
| Lyons, Jonathan J; Rosenberg, Helene F; Druey, Kirk M (2017) Editorial: Stressing out mast cells via CRF1. J Leukoc Biol 102:1284-1285 |
| Ma, Chi A; Stinson, Jeffrey R; Zhang, Yuan et al. (2017) Germline hypomorphic CARD11 mutations in severe atopic disease. Nat Genet 49:1192-1201 |
| Carlson, Ryan J; Bond, Michelle R; Hutchins, Shermaine et al. (2017) Detection of phosphoglucomutase-3 deficiency by lectin-based flow cytometry. J Allergy Clin Immunol 140:291-294.e4 |
| Lexmond, Willem S; Goettel, Jeremy A; Lyons, Jonathan J et al. (2016) FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy. J Clin Invest 126:4030-4044 |
| Lyons, Jonathan J; Yu, Xiaomin; Hughes, Jason D et al. (2016) Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet 48:1564-1569 |
| Lam, Christina; Ferreira, Carlos; Krasnewich, Donna et al. (2016) Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation. Genet Med : |
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