innate immune regulation of skin inflammation and pruritus
The goals of the Brian Kim Lab are to understand the regulatory mechanisms that control immune cell homeostasis at the skin barrier. Employing diverse models of allergic inflammation, autoimmunity and commensal microbial manipulation, research in the Kim Lab is examining how epithelial cell-derived signals and environmental factors influence the innate and adaptive immune response in the skin. Understanding these complex interactions will provide key insights into the mechanisms underlying multiple dermatologic diseases and may shed light on new therapeutic strategies.
Recent studies by the Kim Lab and others have identified that multiple immune cell populations including T cells, dendritic cells (DCs), basophils and innate lymphoid cells (ILCs) directly contribute to the pathogenesis of multiple inflammatory skin disorders including atopic dermatitis (AD), allergic contact dermatitis (ACD), psoriasis and graft-versus-host disease (GvHD). However, the exogenous factors that activate these host immune responses in the skin remain poorly defined. In recent years, two environmental factors have been clinically associated with skin inflammation in patients: (1) alterations in commensal microbiota and (2) the itch-scratch response. Although numerous studies show that the gut commensal microbiota powerfully impact the systemic immune response in mammalian hosts, the influence of skin microbiota remains poorly understood. Further, recent studies have identified itch-specific pathways that trigger scratching responses that result in exaggerated skin inflammation. Despite our increasing understanding of the role of immune cells, commensal microbiota and itch in pathogenesis of inflammatory skin disease, how these factors interact to regulate cutaneous inflammation remains poorly defined.
Currently, the Kim Lab has three fundamental questions that form the basis of independent projects:
How do innate lymphoid cells and basophils contribute to atopic dermatitis?
What is the role of skin and/or gut commensal bacteria in different inflammatory skin diseases?
How do immune cells and epithelial cells influence the itch response that underlies multiple inflammatory skin disorders?
To test the cellular and molecular mechanisms by which innate lymphoid cells and basophils contribute to atopic dermatitis, selective and conditional genetic deletion, pharmacologic manipulation, cellular depletion and adoptive cell transfer techniques are being employed. To examine the role of specific commensal populations in various skin diseases, targeted commensal microbial manipulation with antibiotics and germ-free mice are also underway. To determine the complex interactions between immune cells and keratinocytes in contributing to itch, in collaboration with neuroscientists in the Center for the Study of Itch, the Kim Lab is currently performing high-throughput functional screens for novel immune cell- and keratinocyte-derived factors that regulate itch. Finally, translational studies are currently underway employing 3D human organotypic co-culture systems to identify the effector mechanisms by which various innate immune cells mediate pathologic inflammation at the skin barrier in humans.
Kim B.S., Wang K., Siracusa M.C., Saenz S.A., Brestoff J.R., Monticelli L.A., Noti M., Tait Wojno E.D., Fung T.C., Kubo M., Artis D (2014). Basophils promote innate lymphoid cell responses in inflamed skin. Journal of Immunology, (In Press).
Noti M., Kim B.S., Siracusa M.C., Rak G.D., Kubo M., Moghaddam A.E., Sattentau Q.A., Comeau M.R., Spergel J.M., Artis D. (2014). Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis. Journal of Allergy Clinical Immunology, 133(5), 1390-1399. PMID: 24560412.
Margolis D.J., Kim B., Apter A.J., Gupta J., Hoffstad O., Papadopoulos M., Mitra N. (2014). Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis. JAMA Dermatology, 150(3):254-59. PMID: 24401911.
Wysocka M., Kossenkov A.V., Benoit B.M., Troxel A.B., Singer E., Schaffer A., Kim B., Dentchev T., Nagata S., Ise T., Showe L.C., Rook A.H. (2014). CD164 and FCRL3 are highly expressed on CD4+CD26- T cells in Sézary syndrome patients. Journal of Investigative Dermatology, 134(1):229-236. PMID: 23792457.
Siracusa M.C., Saenz S.A., Wojno E.D., Kim B.S., Osborne L.C., Ziegler C.G., Benitez A.J., Ruymann K.R., Farber D.L., Sleiman P.M., Hakonarson H., Cianferoni A., Wang M.L., Spergel J.M., Comeau M.R., Artis D. (2013). Thymic stromal lymphopoietin-mediated extramedullary hematopoiesis promotes allergic inflammation. Immunity, 39(6):1158-1170. PMID: 24332033.
Saenz S.A., Siracusa M.C., Monticelli L.A., Ziegler C.G., Kim B.S., Brestoff J.R., Peterson L.W., Wherry E.J., Goldrath A.W., Bhandoola A., Artis D. (2013). IL-25 simultaneously elicits distinct populations of innate lymphoid cells and multipotent progenitor type 2 (MPPtype2) cells. Journal of Experimental Medicine, 210(9):1823-1837. PMID: 23960191.
Noti M., Wojno E.D., Kim B.S., Siracusa M.C., Giacomin P.R., Nair M.G., Benitez A.J., Ruymann K.R., Muir A.B., Hill D.A., Chikwava K.R., Moghaddam A.E., Sattentau Q.J., Alex A., Zhou C., Yearley J.H., Menard-Katcher P., Kubo M., Obata-Ninomiya K., Karasuyama H., Comeau M.R., Brown-Whitehorn T., de Waal Malefyt R., Sleiman P.M., Hakonarson H., Cianferoni A., Falk G.W., Wang M.L., Spergel J.M., Artis D.(2013). Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis. Nature Medicine, 19(8):1005-13. PMID: 23872715.
Roediger G., Kyle R., Yip K.H., Sumaria N., Guy T.V., Kim B.S., Mitchell M.J., Tay S.S., Jain R., Forbes-Blom E., Chen X., Tong P.L., Bolton H.A., Artis D., Paul W.E., Fazekas de St. Groth B., Grimbaldeston M.A., Le Gros G., Weninger W. (2013). Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nature Immunology, 14(6):564-573. PMID: 23603794.
Kim B.S., Siracusa M.C., Saenz S.A., Noti M., Monticelli L.A., Sonnenberg G.F., Hepworth M.R., Van Voorhees A.S., Comeau M.R., Artis D. (2013). TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Science Translational Medicine, 5(170):170ra16. PMID: 23363980.
Hill D.A., Siracusa M.C., Abt M.A., Kim B.S., Kobuley D., Kubo M., Kambayashi T., LaRosa D.F., Renner E.D., Orange J.S., Bushman F.D., Artis D. (2012). Commensal bacterial-derived signals limit innate immune mechanisms of allergen-induced Th2 cell development. Nature Medicine, 18(4):538-546. PMID: 22447074.
Siracusa M.C., Saenz S.A., Hill D.A., Kim B.S., Headley M.B., Doering T.A., Wherry E.J., Jessup H.K., Siegel L.A., Kambayashi T., Dudek E.C., Kubo M., Cianferoni A., Spergel J.M., Ziegler S.F., Comeau M.R., Artis D. (2011). TSLP promotes interleukin-3-independent basophil hematopoiesis and type 2 inflammation. Nature, 477(7363):229-233. PMID: 21841801.