The main protocol for this project is in active recruitment and accrual stages now. We continue to enroll a cohort of patients with severe atopic dermatitis (AD) alone, and those with AD in the context of immune deficiency. We have a substantial cohort of patients with genetic disorders, which include atopy as a part of the syndrome (now numbering over 400 patients total). The main findings that have occurred in this project within the past year are described in detail below. Finding 1: Severe atopic dermatitis in the absence of other syndromic features can be difficult to explain pathophysiologically. In collaboration with Erwin Gelfand, NJH, Andy Snow, USUHS and others, we identified heterozygous, hypomorphic, dominant interfering CARD11 mutations in four unrelated families with severe atopic dermatitis, with and without comorbid conditions including infection. Furthermore, we found that the mutations affected the NFKB pathway, as expected, but also the mTORC1 pathway, whose control is critical for preventing Th2 responses. Furthermore, addition of glutamine, thought to be critical for mTORC1 activation and reliant upon CARD11 for import, appeared to partially rescue a number of cellular phenotypes. The results suggest that there could be a monogenic cause for severe atopic dermatitis, and that this pathway may be a modifiable cause. A trial of glutamine supplementation in these patients is now in development. These findings were published in Nature Genetics Finding 2: Wiskott-Aldrich Syndrome (WAS) is known to be associated with atopic dermatitis and high IgE, but atopic disease had not been quantified in WAS. Further, the mechanistic work contributing to this allergic diathesis had not been performed at any detailed level. In collaboration with Scott Snapper and Edda Fiebiger, Harvard Medical School, we found that WAS patients have a marked increase in food allergy, on top of their eczema. Their rates of allergic sensitization were even higher. Despite that, anaphylaxis was not seen, and, similar to STAT3LOF patients, morphine skin testing of these patients suggested a blunted response, consistent with a failure of normal mast cell activation-- which had been demonstrated in WASP null mice previously. Consistent with that, we found that deletion of WASP in Tregs alone was sufficient to induce the allergic phenotype, in fact more severe than the systemic loss of WASP, likely due to the fact that mast cells were able to fully exert their effect function. We showed that the Treg defect was recapitulated in humans, in that GATA3 expression-- a key Th2 transcription factor usually suppressed in Tregs, was elevated in both mouse and human Tregs. These findings were published in the Journal of Clinical Investigation.
| Milner, Joshua D (2018) TCR Signaling Abnormalities in Human Th2-Associated Atopic Disease. Front Immunol 9:719 |
| Siegfried, Elaine C; Jaworski, Jennifer C; Eichenfield, Lawrence F et al. (2018) Developing drugs for treatment of atopic dermatitis in children (?3 months to <18 years of age): Draft guidance for industry. Pediatr Dermatol 35:303-322 |
| Dillen, Carly A; Pinsker, Bret L; Marusina, Alina I et al. (2018) Clonally expanded ?? T cells protect against Staphylococcus aureus skin reinfection. J Clin Invest 128:1026-1042 |
| Oh, Kyu-Seon; Gottschalk, Rachel A; Lounsbury, Nicolas W et al. (2018) Dual Roles for Ikaros in Regulation of Macrophage Chromatin State and Inflammatory Gene Expression. J Immunol 201:757-771 |
| Natarajan, Mukil; Hsu, Amy P; Weinreich, Michael A et al. (2018) Aspergillosis, eosinophilic esophagitis, and allergic rhinitis in signal transducer and activator of transcription 3 haploinsufficiency. J Allergy Clin Immunol 142:993-997.e3 |
| Lyons, Jonathan J; Milner, Joshua D (2018) Primary atopic disorders. J Exp Med 215:1009-1022 |
| 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 |
| Gaudinski, Martin Robert; Milner, Joshua D (2017) Atopic Dermatitis and Allergic Urticaria: Cutaneous Manifestations of Immunodeficiency. Immunol Allergy Clin North Am 37:1-10 |
| 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 |
Showing the most recent 10 out of 29 publications
