Previous and Current Research
We are interested in the immunological mechanisms which govern homeostasis at mucosal surfaces and the pathways contributing to disruption of homeostasis under conditions of inflammation and malignancy. Our work is particularly focused on basic research aiming towards a better understanding of the role of lipid antigens at the intersection of metabolism and immunity as well as translational research investigating the pathogenesis of inflammatory bowel disease (IBD).
Lipid antigens in immunity, inflammation, and cancer
Inflammation at mucosal surfaces is associated with tissue destruction and predisposes to malignancy. The development of novel therapeutic strategies that target mucosal inflammation in diseases such as IBD is dependent on knowledge of the 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 which recognizes self and foreign lipid antigens in the context of CD1d and which regulates inflammation and tumor development.
We could recently demonstrate that parenchymal cells of the intestine and the liver can present lipid antigens to NKT cells, which provides the basis for protection from infectious hepatitis and 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 microbial-derived lipid antigens in the control of homeostasis at mucosal surfaces and demonstrated that primary defects in lipid antigen presentation are associated with immunodeficiency (An et al., Cell 2014; Olszak et al., Science 2012; Zeissig et al., J. Clin. Invest. 2010; Zeissig et al., Nat. Immunol. 2014). In current ERC-funded work in the lab (ERC Starting Grant), we are combining analytical tools such as lipidomics with immunological approaches to study the nature of lipid antigens at the the interface of metabolism, immunity, and cancer. These studies shall provide the basis for the development of novel therapeutic strategies that target inflammatory and malignant diseases at their origin.
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, using exome sequencing and functional studies we and others have recently identified forms of IBD, in which selected genetic defects promote intestinal inflammation in a mono- or oligogenic manner (Zeissig Y, Gut 2014; Zeissig S, Gut 2014). These studies have provided significant insight into the mechanisms involved in the regulation of immunological homeostasis at mucosal surfaces and the genetic pathways associated with disruption of homeostasis in IBD. Ongoing efforts focus on the immunological characterization of monogenic defects in IBD and the discovery of novel forms of monogenic IBD.
Future Projects and Goals
The aims of our ongoing and future research are
- To provide a better understanding of the immunological mechanisms involved in control of homeostasis at mucosal surface
- To delineate the genetic and immunological basis of chronic inflammatory diseases such as IBD and autoimmune hepatitis
- To study the role of lipids at the intersection of metabolism, immunity, and cancer
Methodological and Technical Expertise
- Mouse models of intestinal inflammation and cancer
- CD1 lipidomics (with Andrej Shevchenko, MPI-CBG)
- T cell receptor sequencing
- Antigen presentation
Olszak T, Neves JF, Dowds CM, Baker K, Glickman J, Davidson NO, Lin CS, Jobin C, Brand S, Sotlar K, Wada K, Katayama K, Nakajima A, Mizuguchi H, Kawasaki K, Nagata K, Müller W, Snapper SB, Schreiber S, Kaser A, Zeissig S*, Blumberg RS*.
Protective mucosal immunity mediated by epithelial CD1d and IL-10.
Nature. 2014 May 22;509(7501):497–502.
An D, Oh SF, Olszak T, Neves JF, Erturk-Hasdemir D, Lu X, Zeissig S, Blumberg RS, Kasper DL.
Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells.
Cell. 2014 Jan 16;156(1-2): 123–33.
Zeissig S, Murata M, Sweet L, Publicover J, Hu Z, Kaser A, Bosse E, Iqbal J, Hussain MM, Balschun K, Röcken C, Arlt A, Günther R, Hampe J, Schreiber S, Baron JL, Moody DB, Liang JT, Blumberg RS.
Hepatitis B virus-induced alterations in hepatocyte CD1d lipid antigens activate natural killer T cells and contribute to protective immunity.
Nat. Med. 2012. Jul;18(7):1060–8.
Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, Glickman JN, Siebert R, Baron RM, Kasper DL, Blumberg RS.
Microbial exposure during early life has persistent effects on tissue-associated iNKT cells and their function.
Science. 2012 Apr 27;336(6080):489–93.
Zeissig S, Dougan SK, Barral D, Junker Y, Chen Z, Kaser A, Ho M, Mandel H, McIntyre A, Kennedy SM, Painter, GF, Veerapen N, Besra GS, Cerundolo V, Yue S, Beladi S, Behar SM, Chen X, Gumpertz JE, Breckpot K, Raper A, Baer A, Exley MA, Hegele RA, Cuchel M, Rader DJ, Davidson NO, Blumberg RS
Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function.
J Clin Invest. 2010 Aug 2;120(8):2889–99.