Aspergillosis, eosinophilic esophagitis, and allergic rhinitis in signal transducer and activator of transcription 3 haploinsufficiency Mukil Natarajan,

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Aspergillosis, eosinophilic esophagitis, and allergic rhinitis in signal transducer and activator of transcription 3 haploinsufficiency Mukil Natarajan, MD, Amy P. Hsu, BA, Michael A. Weinreich, MD, PhD, Yuan Zhang, PhD, Julie E. Niemela, MS, John A. Butman, MD, PhD, Stefania Pittaluga, MD, Janyce Sugui, PhD, Amanda L. Collar, BS, Jean K. Lim, PhD, Tirdad Zangeneh, DO, Tara Carr, MD, Andrew J. Oler, PhD, Morgan Similuk, ScM, Lindsey B. Rosen, BS, Jigar V. Desai, PhD, Alexandra F. Freeman, MD, Steven M. Holland, MD, Kyung J. Kwon-Chung, PhD, Joshua D. Milner, MD, Michail S. Lionakis, MD, ScD Journal of Allergy and Clinical Immunology Volume 142, Issue 3, Pages 993-997.e3 (September 2018) DOI: 10.1016/j.jaci.2018.05.009 Copyright © 2018 Terms and Conditions

Fig 1 Radiographic and histological features of the invasive sino-orbital-cerebral Aspergillus infection. A-D, Representative images of magnetic resonance imaging brain (T1 postgadolinium) showing the progression of the infection despite aggressive antifungal treatment. A, Initial infection diagnosis with early cavernous sinus involvement (arrow). B, One month after infection diagnosis, with involvement of Meckel's cave (arrowhead) and of the right orbit. C, Four months after infection diagnosis, with involvement of the middle cranial fossa and worsening of right orbital disease. D, Ten months after infection diagnosis, status-post right orbital exenteration with involvement of the posterior fossa (arrowhead). E and F, Representative histological images from Aspergillus-infected sinus tissue demonstrating necrosis, chronic inflammation, and invasive fungal hyphae by H&E (Fig 1, E) and GMS (Fig 1, F) stains. H&E, Hematoxylin and eosin; GMS, Grocott's methenamine silver. Magnification 20×. Journal of Allergy and Clinical Immunology 2018 142, 993-997.e3DOI: (10.1016/j.jaci.2018.05.009) Copyright © 2018 Terms and Conditions

Fig 2 A de novo STAT3 splice-site mutation results in NMD, STAT3 haploinsufficiency, and decreased STAT3 levels and phosphorylation without impairing TH17 responses. A, Pedigree of the patient. The patient is indicated in gray and by an arrow. The genotype of STAT3 alleles is indicated for each family member. B, Sequencing chromatograms of STAT3 from genomic DNA (upper panel) and cDNA (lower panel) at position c.*1671 in the 3′ untranslated region demonstrating loss of heterozygosity in the cDNA sequence, consistent with NMD. C, Sequencing chromatograms of STAT3 cDNA at the exon 12/13 junction (thick dotted line) from untreated cells (upper panel) and cells treated with an NMD inhibitor (cycloheximide; lower panel) demonstrating abnormal splicing after exon 12 in 1 allele and the introduction of a premature stop codon (*). The introduced sequence from intron 12 is listed below. D, Reduced total STAT3 protein expression by flow cytometry in cultured T cells compared with healthy controls. Representative histogram (left panel) and summary data of geometric mean fluorescence intensity (MFI) (right panel) from 3 independent experiments (n = 3 for our patient, 6 different healthy donors). E, Reduced pSTAT3 levels in memory T cells upon IL-6 stimulation. Representative histogram (left panel) and summary data of MFI (right panel) from 3 independent experiments (n = 3 for our patient, 6 different healthy donors). F, PBMCs were stimulated with the listed stimuli or were left unstimulated in RPMI medium as control and IL-17A (left panel) and IL-17F (right panel) protein levels were measured in the supernatant by Luminex assay. Results are from 2 independent experiments (n = 4 for our patient, n = 10 for healthy controls). G, IL-17A and IL-17F–expressing memory T cells were measured by flow cytometry. Representative flow cytometric plots (left panels) and summary data (right panels) of the percent of IL-17A and IL-17F–expressing cells from 3 independent experiments (n = 4 for our patient, 7 patients with HIES, 12 different healthy donors). ns, Not significant; UTR, untranslated region. *P < .05. Journal of Allergy and Clinical Immunology 2018 142, 993-997.e3DOI: (10.1016/j.jaci.2018.05.009) Copyright © 2018 Terms and Conditions