Inflammation at mucosal barrier sites
Chronic inflammatory diseases, such as inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD) and asthma, constitute a significant global economic and public health burden. Epidemiologic, genetic and immunologic studies implicate dysregulated adaptive immune cell responses, driven by otherwise harmless environmental- or self-antigens, in the pathogenesis of these disorders. In order to maintain tissue health and homeostasis at mucosal barrier sites, such as the intestine and lungs, the adaptive immune system must be tightly regulated.
My research programme focuses on understanding the immune pathways that normally act to prevent inflammation at mucosal barrier tissue sites in health, while also dissecting how regulatory pathways become defective in the context of inflammation and disease. Cells of the innate system play key roles in interpreting cues from the tissue microenvironment in order to educate the adaptive immune system. In particular, innate lymphoid cells (ILCs) in mice and humans act as key regulators of inflammation, immunity and tissue repair at mucosal barrier surfaces through the production of effector cytokines and via antigen-presentation and other direct cell-to-cell interactions. Moreover, changes in the frequency and function of ILCs are associated with multiple chronic inflammatory disorders in humans, suggesting targeting of ILC pathways may be of clinical relevance.
The lab’s primary aims are to delineate the mechanisms that act to maintain tissue homeostasis in healthy individuals, and to identify the underlying processes that lead to loss of regulation in disease, using both basic and translational approaches. An improved understanding of these immune pathways will lead to the identification of novel therapeutic targets for chronic human inflammatory diseases in which tissue homeostasis is dysregulated, such as IBD and asthma.
Melo-Gonzalez F and Hepworth M.R. Functional and phenotypic heterogeneity of group 3 innate lymphoid cells. Immunology (2016) Dec 9. doi: 10.1111/imm.12697. [PMID: 27935637]
Withers D.R., Hepworth M.R., Wang X, Mackley E.C., Halford E.E., Dutton E.E., Marriott C.L., Brucklader-Waldert V, Veldhoen M, Elson C.O., Kelsen J, Baldassano R.N., Sonnenberg G.F. Transient inhibition of RORt differentially influences innate versus adaptive immunity to therapeutically limit intestinal inflammation. Nature Medicine (2016) Mar;22(3):319-23. doi: 10.1038/nm.4046 [PMID: 26878233]
Hepworth M.R., Fung T.C., Masur S.H., Kelsen J.R., MacConnell F.M., Dubrot J, Withers D.R., Hugues S, Farrar M.A., Reith W, Eberl G, Baldassano R.N., Laufer T.M., Elson C.O., Sonnenberg G.F. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science (2015) 29 May 2015: 1031-1035. doi: 10.1126/science.aaa4812. [PMID: 25908663]
Hepworth M.R., Monticelli L.A., Fung T.C., Ziegler C.G., Grunberg S, Sinha R, Mantegazza A.R., Ma H.L., Crawford A, Angelosanto J.M., Wherry E.J., Koni P.A., Bushman F.D., Elson C.O., Eberl G, Artis D, Sonnenberg G.F. Innate lymphoid cells regulate CD4+ T-cell responses to commensal bacteria. Nature (2013); Jun 6;498(7452):113-7 [PMID: 23698371]