Download Genetics and Innate and Adaptive Immunity in IBD

Genetics and Innate and Adaptive
Immunity in IBD
Galliano Zanello, David Kevans, Ashleigh Goethel, Mark Silverberg,
Andrea Tyler and Kenneth Croitoru
Inflammatory bowel disease (IBD) is thought to be due to an abnormal inflammatory response within the gut in response to a trigger that
has yet to be identified. The strong family history in many patients,
especially those with Crohn’s disease suggests a genetic predisposition.
It has been hypothesized that the abnormal inflammatory response is
due in part to genetically determined alterations in the normal homeostatic processes in play at the gut mucosa that normally serve to ensure a
symbiotic relationship between the host and the ‘normal’ gut microbes.
Genetic studies in patient cohorts have identified an increasing number
of risk alleles that highlight a diverse series of molecular and cellular pathways that may be altered in these individuals. These pathways include:
defects in epithelial barrier function, genes involved in autophagy, a cellular pathway not previously considered in studies of IBD, receptors of
innate immune response, and immune and cytokine-related genes that
are involved in the effector and regulatory arms of the adaptive immune
response. Animal and human studies further highlight how altered innate
immune responses can be involved in intestinal inflammation and how
abnormal adaptive immune responses in IBD patients are directed against
the intestinal microbiota. The loss of the normal homeostatic mechanisms with activation of both innate and adaptive immune responses
may well be key to the initiation and propagation of IBD. The adaptive
immune response has long been the focus of study in understanding the
pathogenesis of IBD. Th1 and Th2 T cell subsets have been identified as
mediators of immune inflammation in early studies, and antigen-specific
responses key to their activation. Indeed, studies have shown bacterialderived antigens as initiators and drivers of T cell immune responses.
More recently, Th17, regulatory T cells and unconventional innate-like
T cells have been identified as important in the induction and regulation
of intestinal inflammation, and efforts are in place to define their role in
IBD. The seminal discoveries of pathogen recognition receptors including
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Toll-like receptors and nucleotide-binding oligomerization domain receptors have changed our understanding of how immune cells without antigen-specific receptors respond to microbes and can lead to the secretion
of inflammatory cytokines in the intestine. The role innate receptors
play in intestinal inflammation and homeostasis has been supported by
a number of animal studies; however, the role innate immune responses
and the various innate receptors play in the development and perpetuation of IBD remains to be determined. In conclusion, understanding the
role of genetically determined alterations in innate and adaptive immunity in patients with IBD will lead to new strategies for the prevention and
treatment of IBD.
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