Joshua D. Milner, M.D.
Rare, Inherited Autoimmune Disorder Identified
Chief, Genetics and Pathogenesis of Allergy Section, LAD
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.
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.
The section 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. Patients with histories highly suggestive of a familial/syndromic inheritance of their allergic symptomps—from urticarial to atopic dermatitis—are studied, their DNA sequenced, and their cell biology elucidated. 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.
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.
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.
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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 finished his residency in pediatrics at the Childrens National Medical Center in Washington, DC, in 2003. 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 the section as a clinical tenure-track investigator in NIAID in 2009. He received tenure in 2013.
John Barber, B.S. (Post-baccalaureate fellow)Guanping Sun, Ph.D. (Biologist)Shrimati Datta, Ph.D. (Postdoctoral fellow)Andrea Siegel, Ph.D. (Postdoctoral fellow)Monica Ghei Lawrence, Ph.D. (Clinical fellow)Michelle O’Brien, R.N. (Nurse study coordinator)Kelly Stone, M.D., Ph.D. (Staff clinician)
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.
Lyons JJ, Sun G, Stone KD, Nelson C, Wisch L, O'Brien M, Jones N, Lindsley A, Komarow HD, Bai Y, Scott LM, Cantave D, Maric I, Abonia JP, Rothenberg ME, Schwartz LB, Milner JD, Wilson TM. Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities. J Allergy Clin Immunol. 2014 May;133(5):1471-4.
Siegel AM, Stone KD, Cruse G, Lawrence MG, Olivera A, Jung M, Barber JS, Freeman AF, Holland SM, O’Brien M, Jones N, Wisch L, Kong HH, Desai A, Farber O, Gilfillan A, Rivera J, Milner JD. Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation. J Allergy Clin Immunol. 2013 Dec;132(6):1388-96.
Barber JS, Yokomizo LK, Sheikh V, Freeman AF, Garabedian E, van Dijk E, Sokolic R, Candotti F, Weng NP, Sereti I, Milner JD. Peptide library-based evaluation of T-cell receptor breadth detects defects in global and regulatory activation in human immunologic diseases. Proc Natl Acad Sci U S A. 2013 May 14;110(20):8164-9.
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 Jan 26;366(4):330-8.
Siegel AM, Heimall J, Freeman AF, Hsu AP, Brittain E, Brenchley JM, Douek DC, Fahle GH, Cohen JI, Holland SM, Milner JD. A critical role for STAT3 signaling in the development and maintenance of human T cell memory. Immunity. 2011 Nov 23;35(5):806-18.
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Last Updated November 07, 2014