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Joshua David Milner, M.D., S.B.

Senior Investigator

Genetics and Pathogenesis of Allergy Section


Building 10, Room 5-3950
10 Center Drive
Bethesda, MD 20892


Research Topics

The Genetics and Pathogenesis of Allergy Section is a basic, translational, and clinical lab focused on understanding the immunology of atopic disease through 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, we hope to gain better insights into the mechanisms of immunodysregulation that lead to atopic inflammatory disease.

Josh Milner and an NIAID research team have found that wet wrap therapy combined with education on long-term skin care can dramatically improve the lives of children with severe eczema.

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.

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.

Search for Novel Genetic Diseases Associated With Atopy
AIU is also 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. One example is PLCG2-associated antibody deficiency and immune dysregulation (PLAID), which we recently described. Patients with PLAID have cold urticaria, atopy, immune deficiency, and autoimmunity. Research is ongoing into the pathophysiology of PLAID and into the role of the PLCG2 and its pathway in other related disorders.


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 in 2000. He was the recipient of the Pediatric Scientist Development Program Fellowship and did his fellowship in allergy and immunology at NIAID. He completed a postdoctoral fellowship with Dr. William Paul, NIAID, examining issues of mouse T-cell receptor repertoires. He was in the NIAID Clinical Research Transition Program immediately prior to being named chief of AIU as a clinical tenure-track investigator in NIAID.

Selected Publications

  1. Ombrello MJ, Remmers EF, Sun G, Freeman AF, Datta S, Torabi-Parizi P, Subramanian N, Bunney TD, Baxendale RW, Martins MS, Romberg N, Komarow H, Aksentijevich I, Kim HS, Ho J, Cruse G, Jung MY, Gilfillan AM, Metcalfe DD, Nelson C, O'Brien M, Wisch L, Stone K, Douek DC, Gandhi C, Wanderer AA, Lee H, Nelson SF, Shianna KV, Cirulli ET, Goldstein DB, Long EO, Moir S, Meffre E, Holland SM, Kastner DL, Katan M, Hoffman HM, Milner JD. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N Engl J Med. 2012;366(4):330-8.
  2. 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;138(1):187-99.
  3. Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, Lyons JJ, Engelhardt KR, Zhang Y, Topcagic N, Roberson ED, Matthews H, Verbsky JW, Dasu T, Vargas-Hernandez A, Varghese N, McClain KL, Karam LB, Nahmod K, Makedonas G, Mace EM, Sorte HS, Perminow G, Rao VK, O'Connell MP, Price S, Su HC, Butrick M, McElwee J, Hughes JD, Willet J, Swan D, Xu Y, Santibanez-Koref M, Slowik V, Dinwiddie DL, Ciaccio CE, Saunders CJ, Septer S, Kingsmore SF, White AJ, Cant AJ, Hambleton S, Cooper MA. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015;125(4):591-9.
  4. 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;133(5):1400-9, 1409.e1-5.
  5. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, Davis J, Hsu A, Asher AI, O'Shea J, Holland SM, Paul WE, Douek DC. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008;452(7188):773-6.
This page was last updated on July 31st, 2015