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Mucosal Immunology - Previous and Current Research

Antimicrobial peptide-producing Paneth cells at the bottom of crypts in the small intestine.

Lipid antigens in immunity
Chronic inflammation and tissue destruction are the basis for inflammatory bowel diseases (IBD) and autoimmune as well as viral hepatitis. These diseases are not only associated with debilitating clinical symptoms but are also key risk factors for the development of inflammation-associated malignancy. The development of novel therapeutic strategies that target these diseases is dependent on a detailed understanding of the cellular and molecular mechanisms underlying chronic inflammation. Of particular interest in this regard is the role of natural killer T (NKT) cells, an unconventional subset of T cells that responds to CD1d-restricted presentation of self and foreign lipid antigens and is associated with immediate innate-like effects on NK, T, and B cells thereby shaping and orchestrating immune responses. NKT cells are critical for antimicrobial immunity and genetic defects in lipid antigen presentation are associated with primary immunodeficiency in humans. However, recent studies have revealed that NKT cells are not only contributing to protective immunity but also play central roles in the pathogenesis of chronic inflammatory disorders. Thus, it was shown that ulcerative colitis, an inflammatory bowel disease (IBD), is characterized by NKT cell-dependent intestinal inflammation. Similarly, recent studies have revealed that NKT cells are centrally involved in the pathogenesis of autoimmune and infectious hepatitis.
In our recent work investigating the role of lipid antigens and NKT cells in intestinal and hepatic immunity, we could demonstrate that hepatocytes and intestinal epithelial cells can present lipid antigens via the non-classical MHC class I molecule CD1d to natural killer T cells thus providing the basis for protection from infectious hepatitis as well as intestinal inflammation (Zeissig et al., Nat. Med. 2012; Olszak et al., Nature 2014). Furthermore, this work revealed an essential role of the commensal microbiota and microbiota-derived lipid antigens in the control of homeostasis at mucosal surfaces and demonstrated that primary defects in lipid antigen presentation are associated with immunodeficiency in humans (An et al., Cell 2014; Olszak et al., Science 2012; Zeissig et al., J. Clin. Invest.; Zeissig et al., Nat. Immunol. 2014). Current ERC-funded work in the laboratory (ERC Starting Grant) is focused on the identification of lipid antigens which link metabolism and immunity in the liver and the intestine.

Monogenic forms of inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of disorders characterized by chronic intestinal and often systemic inflammation. In the vast majority of IBD patients, intestinal inflammation occurs through a complex and incompletely understood interplay of genetic and environmental factors. However, we and others have recently identified forms of mono- or oligogenic forms of IBD, in which one or few genetic defects significantly promote intestinal inflammation (Zeissig Y, Gut 2014; Zeissig S, Gut 2014). Patients with monogenic IBD often present with early-onset disease manifesting during childhood and exhibit severe and often treatment-refractory intestinal and systemic inflammation. The identification of a mono- or oligogenetic etiology in IBD patients thereby provided significant insight into the pathophysiology of IBD and forced, in a subset of these cases, a reconsideration of approaches for medical treatment. This translational research agenda is pursued in close collaboration with the Department of Pediatrics (Prof. Dr. Berner, Dr. LaaƟ) and the Institute of Clinical Molecular Biology (IKMB) Kiel (Prof. Dr. Schreiber, Prof. Dr. Franke). Genetic screening is offered to patients with early onset and/or familial IBD.

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