role of the immunoproteasome inflammatory bowel disease
vorgelegt von pl. Biochemikerin Nicole Schmidt
Di
zur Erlangung des akademischen Grades Doktorin der Naturwissenschaften (Dr. rer. nat.) vonderFakulta¨tIII-Prozesswissenschaften derTechnischenUniversita¨tBerlin genehmigte Dissertation
Promotionsausschuss: Vorsitzender: Prof. Dr. J. Kurreck Berichter: Prof. Dr. R. Lauster Berichter: PD Dr. U. Steinhoff
Tag der wissenschaftlichen Aussprache: 16.04.2010
Berlin 2010
D83 1
in
2
Anybody who has been seriously engaged is scientific work of any kind realizes
that over the entrance to the gates of the temple of science are written the words:
Entz¨undungdarstellt.HierbeiwurdenzweiexperimentelleAns¨atzeverfolgt:(i)DieEn-twicklung von dextran sulfate sodium (DSS)-induzierter Kolitis wurde inlmp7−/−Ma¨suen
untersucht, die eine Defizienz in der Immunoproteasom Untereinheit LMP7 aufweisen. (ii)
Der Einsatz der Proteasominhibitoren MG132 oder Bortezomib wurde an DSS-behandelten
propia. A layer of mucus which is secreted by specialized epithelial cells named goblet
cells, covers the epithelium [1].
Figure 2.1:The anatomy of the intestine.The intestine is composed of three layers: the outer muscularis, the submucosa and the mucosa, which is in contact with the lumen (Figure is adapted from [2]).
The intestine is home of a dense and diverse community of microorganisms, which com-prise 1011-1012organisms. Therefore the gastrointestinal (GI) immune system has to keep
a balance between tolerance towards commensal microflora and responsiveness towards
invading pathogens. This balance is maintained by a complex network of innate and
adaptive mucosal immune mechanisms [3].
In this context the intestinal epithelium is not only responsible for the uptake of nu-
trients, but also participates in the immune defense of the gut. The intestinal epithelium,
2
INTRODUCTION
8
including the mucus layer, functions as a physical barrier between the luminal microen-
vironment and the GI mucosa. Further, intestinal epithelial cells (IECs) contribute to
the mucosal immunity by producing antimicrobial peptides, which help to control the
growth of luminal bacteria. In addition, IECs can release proinflammatory cytokines
in response to invading pathogens that are recognized by pattern-recognition receptors
(PRRs). Therefore IECs display a first line of defense by three major mechanisms, a phys-
ical barrier, a direct antimicrobial activity and the function to alert the immune system
in response to infection [4]. Besides IECs, the epithelial layer also contains intraepithelial
lymphocytes (IELs), which are mainly T cells [5].
The lamina propia, which underlies the epithelium, contains a large number of T
cells, B cells, macrophages and dendritic cells (DCs). Thereby, specialized intestinal
DCs express tight-junction proteins and extend their dendrites between epithelial cells
to directly sample the luminal microenvironment [6]. Plasma cells of the lamina propia
constantly release Immunoglobulin (Ig) A, which is transported through IECs into the
intestinal lumen as a defense mechanism against penetrating intestinal commensal bacteria
and invasive pathogens [7].
Further, the intestine is associated with several lymphoid organs referred to as gut-
associated lymphoid tissues (GALT). Whereas Peyer’s patches (PPs) in the small intestine
and isolated lymphoid follicles (ILFs) in the colon are located within the mucosa itself,
intestinal lymph also drains into the mesenteric lymph nodes. The GALT not only allows
a rapid immunity but also restrict the response to the gut