Major Areas of Research
- Investigation of defects in T-cell receptor signaling and repertoires
- Clinical and pathophysiologic analysis of patients with known genetic diseases associated with atopy
- Search for novel genetic diseases associated with atopy
The Genetics and Pathogenesis of Allergy Section is a basic, translational, and clinical lab focused on understanding the immunology of atopic disease through study of patients with genetic diseases associated with atopic manifestations, patients with immune deficiency and atopy, and patients with severe atopic dermatitis. Through studies of patients and mouse models of their diseases, we hope to gain better insights into the mechanisms of immunodysregulation that lead to atopic inflammatory disease, rare and common.
Search for novel genetic diseases associated with atopy
The section is centrally focused on defining and understanding new genetic diseases of atopy in order to find novel pathways in the pathogenesis of allergy from these unique diseases. Patients with histories highly suggestive of a familial/syndromic inheritance of their allergic symptoms—from urticarial to atopic dermatitis—are studied, their DNA sequenced, and their cell biology elucidated. Examples include PLCG2-associated antibody deficiency and immune dysregulation (PLAID), which leads to cold urticaria, atopy, immune deficiency, and autoimmunity; PGM3 deficiency, which leads to severe allergy, infections, and neurologic symptoms; familial tryptasemia, which leads to a dominant inheritance of elevations in serum tryptase in the absence of mastocytosis, mast cell degranulation symptoms, and connective tissue abnormalities such as joint hypermobility; and gain of function mutations in STAT3, which lead to early onset autoimmunity, short stature, eczema, and other symptoms. Research is ongoing into the pathophysiology of these and other disorders, and patients with unknown syndromes that appear to be familial and have a major allergic component are actively recruited to elucidate their disorders.
Analysis of patients with known genetic diseases associated with atopy
Via the study of selected genetic diseases that have allergic symptoms as an associated manifestation, we hope to derive lessons in the pathophysiology of atopy from the known affected pathways. Examples of diseases studied include the autosomal dominant hyper-immunoglobulin (IgE) syndrome due to mutations in STAT3, Wiskott-Aldrich Syndrome, adenosine deaminase (ADA)-deficiency severe combined immunodeficiency disease (SCID) associated with high IgE and others.
Investigation of defects in T-cell receptor signaling and repertoires
Weak T-cell receptor (TCR)-mediated signaling of yet-undifferentiated naïve T cells can lead to inappropriate Th2 differentiation in mouse models. Insufficient TCR diversity can lead to impaired regulation of T cells by other T cells due to insufficient TCR specificity overlap of effector and regulatory populations or due to the absence of competition between T cells leading to the inappropriate emergence of weakly signaling TCRs specific for a given antigen. Our lab is developing and applying techniques to determine whether certain human disorders of atopy may be caused by defects in TCR diversity or signaling function.
Joshua Milner graduated with an S.B. in biology from the Massachusetts Institute of Technology (MIT) in 1995 and an M.D. with distinction in immunology from the Albert Einstein College of Medicine. He completed his residency in pediatrics at the Children’s National Medical Center in Washington, DC, and, as the recipient of the Pediatric Scientist Development Program Fellowship, did his fellowship in allergy and immunology at NIAID. He completed a postdoctoral fellowship with Dr. William E. Paul, NIAID, examining issues of mouse T-cell receptor repertoires before beginning as a clinical tenure-track investigator in the LAD. He was named chief of the LAD in 2017. He is an elected member of the American Society for Clinical Investigation and the Association of American Physicians, and is the recipient of the Phadia Allergy Research Forum Award, as well as the Drukier Prize in Pediatric Research from Cornell University.
Ma CA, Stinson JR, Zhang Y, Abbott JK, Weinreich MA, Hauk PJ, Reynolds PR, Lyons JJ, Nelson CG, Ruffo E, Dorjbal B, Glauzy S, Yamakawa N, Arjunaraja S, Voss K, Stoddard J, Niemela J, Zhang Y, Rosenzweig SD, McElwee JJ, DiMaggio T, Matthews HF, Jones N, Stone KD, Palma A, Oleastro M, Prieto E, Bernasconi AR, Dubra G, Danielian S, Zaiat J, Marti MA, Kim B, Cooper MA, Romberg ND, Meffre E, Gelfand EW, Snow AL, Milner JD. Germline hypomorphic CARD11 mutations in severe atopic disease. Nat Genet. 2017 Jun 19. doi: 10.1038/ng.3898. [Epub ahead of print].
Ma CA, Xi L, Cauff B, DeZure A, Freeman AF, Hambleton S, Kleiner G, Leahy TR, O’Sullivan M, Makiya M, O’Regan G, Pittaluga S, Niemela J, Stoddard J, Rosenzweig SD, Raffeld M, Klion AD, Milner JD. Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticarial, dermatitis, and diarrhea. Blood. 2017 Feb 2;129(5):650-653.
Lyons JJ, Liu Y, Ma CA, Yu X, O’Connell MP, Lawrence MG, Zhang Y, Karpe K, Zhao M, Siegal AM, Stone KD, Jones N, DiMaggio T, Darnell DN, Mendoza-Caamal E, Orozco L, Hughes JD, McElwee J, Hohman RJ, Frischmeyer-Guerrerio PA, Rothenberg ME, Freeman AF, Holland SM, Milner JD. ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans. J Exp Med. 2017 Jan 26. pii: jem.20161435.
Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, Ho N, Zhao M, Lui Y, O’Connell MP, Trivedi NN, Nelson C, DiMaggio T, Jones N, Matthews H, Lewis KL, Oler AJ, Carlson RJ, Arkwright PD, Hong C, Agama S, Wilson TM, Tucker S, Zhang Y, McElwee JJ, Pao M, Glover SC, Rothenberg ME, Hohman RJ, Stone KD, Caughey GH, Heller T, Metcalfe DD, Biesecker LG, Schwartz LB, Milner JD. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016 Dec;48(12):1564-1569.
Hox V, O’Connell MP, Lyons JJ, Sackstein P, Dimaggio T, Jones N, Nelson C, Boehm M, Holland SM, Freeman AF, Tweardy DJ, Olivera A, Metcalfe DD, Milner JD. Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis. J Allergy Clin Immunol. 2016 Jul;138(1):187-99.
Zhang Y, Yu X, Ichikawa M, Lyons JJ, Datta S, Lamborn IT, Jing H, Kim ES, Biancalana M, Wolfe LA, Dimaggio T, Matthews HF, Kranick SM, Stone KD, Holland SM, Reich DS, Hughes JD, Mehmet H, McElwee J, Freeman AF, Freeze HH, Su HC, Milner JD. Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment. J Allergy Clin Immunol. 2014 May;133(5):1400-1409.