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. We had recently identified heterozygous, hypomorphic, dominant interfering CARD11 mutations in four unrelated families with severe atopic dermatitis, with and without comorbid conditions including infection. Since the publication, in collaboration with Bodo Grimbacher, Matthew Cook and Andrew Snow, we identified more than 20 new families with rare or novel mutations in CARD11, from whom 10 new dominant negative mutations were confirmed. In that context, we found mutations in CARD14 in three families with similar presentations of severe atopic dermatitis and viral and bacterial skin infection. These mutations, like the CARD11 mutations, were dominant negative with varying degrees of expressivity in the families. CARD14 is highly homologous to CARD11, and binds MALT1 and BCL10 with activation, as part of the CARD11-BCL10-MALT1 (CBM) complex, but its expression is largely restricted to keratinocytes. In collaboration with Dr. Eli Sprecher's lab, we showed that keratinocyte NFkB activation was impaired when expressing CARD14DN mutations, as was antimicrobial peptide expression. The keratinocyte host defense defect could therefore substantially contribute to the pathogenesis of atopic dermatitis in these patients and points to such barrier host defense as critical in preventing allergic disease. The results were published in the Journal of Allergic and Clinical Immunology. Finding 2: In collaboration with Dr. Raz Somech, we showed that patients with MALT1 loss of function can develop significant atopic disease and IgE elevation, and that, similar to patients with mutations in MALT1 binding partner CARD11, mTORC1 activation is impaired. The results suggest that CARD11, CARD14 and MALT1 mutations might all affect the mTORC1 pathway in addition to the NFkB pathway, opening new venues for treatment and understanding of pathogenesis. The results were published in the Journal of Clinical Immunology. Finding 3: In collaboration with Dr. Pam Guerrerio, we showed that total immunoglobulin E (IgE) elevations, such as those seen in our cohort of severe atopic dermatitis, require a reinterpretation of specific IgE levels that would be used for predicting the odds for passing or failing food challenges in food allergic individuals. The findings were published in Annals of Allergy, Asthma and Immunology.
| 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 |
| 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 |
| 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
