Laboratory of Allergic Diseases

Joshua D. Milner, M.D.

Chief, Allergic Inflammation Unit

Allergic Inflammation Unit

The Allergic Inflammation Unit is a basic, translational, and clinical lab focused on the nexus of immunodeficiency and atopy. Through studies of patients and mouse models of immunodeficiency associated with atopic phenotypes, we hope to gain better insights into the mechanisms of immunodysregulation that lead to atopic inflammatory disease.

Patients followed in the lab usually have a component of severe atopy—often in the form of eczema—as well as susceptibility to recurrent or severe infection. While known clinical entities such as the Hyper-Immunoglobulin E (IgE) Syndrome and Omenn’s Syndrome are examples of this phenotype, the primary focus of the lab is on syndromes with allergic/infectious phenotypes that have not yet been identified.

Several key interests in the lab revolve around a number of potential mechanisms by which immunodeficiency might lead to allergic disease in mouse models and humans, including the following:

1. Investigation of defects in T-cell receptor signaling. Weak TCR-mediated signaling of yet-undifferentiated naïve T cells can lead to inappropriate Th2 differentiation in mouse models and patients.
2. Measurement of T-cell receptor repertoires. Insufficient TCR diversity can lead to impaired host defense because of a lack of T cells with sufficiently high specificity for foreign antigens. It can also 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.
3. Assessment of STAT3 pathway genes. Mutations in STAT3 are associated with high IgE and immunodeficiency, as seen in the Hyper-IgE Syndrome (Job’s Syndrome). Disruption of other genes within the STAT3 pathway, such as the IL-21 receptor, rorgamma T, and IL-17, may prove to be critical in the pathogenesis of atopy, in addition to causing immunodeficiency.

Through investigation of these and other topics, we hope to develop novel diagnostic and management strategies for patients with atopy and recurrent infection. We also hope to apply lessons learned from this patient subset to broader atopic disease phenotypes, such as severe eczema, asthma food allergies, and others.

Selected Publications

For a complete listing, visit PubMed.

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 differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008 Apr 10;452(7188):773-6.

Milner JD, Fasth A, Etzioni A. Autoimmunity in severe combined immunodeficiency (SCID): lessons from patients and experimental models. J Clin Immunol. 2008 May;28 Suppl 1:S29-33.

Milner JD, Ward JM, Keane-Myers A, Paul WE. Lymphopenic mice reconstituted with limited repertoire T cells develop severe, multiorgan, Th2-associated inflammatory disease. Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):576-81.

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