The human guts can be the scene for devastating conditions such as inflammatory bowel disease which arises through an improperly controlled immune response.
The guts is often the body’s first point of contacts with microbes.
Every mouth full of food is accompanied by a cargo of microorganisms that go on to encounter the mucosa,the innermost layer of the gut.
Most microbes are destroyed by the harsh acidic environment in the stomach, but a hardy few make it through to the intestine.
The intestinal surface is covered with finger-like protrusions called villi whose primary function is the absorption of nutrients.
However, these structures and the underlying tissues also host the body’s largest population of immune cells.
Scattered along the intestinal mucosa are dome-like structures called peyer’s patches.
These enriched in lymphoid tissue, making them key sites for coordinating immune responses to pathogens was promoting tolerance to harmless microbes and food.
The villi contain a network of blood vessels to transport nutrients from food to the rest of the body.
Lymphatics from both the peyer’s patches and villi drain into the mesenteric lymph node.
Within the villi is a network of loose connected tissue called the lamina propria and at the base of the villi are the crypts which host stem cells that replenish the epithelium.
Finally, the epithelium together with it stick overlying mucus, forms an important barrier against microbial invasion.
Embedded within the matrix of the peyer’s patch is a mix of immune cells including T and B lymphocytes, macrophages and dendritic cells.
A key function of the peyer’s patch is the sampling of antigens.
In this case, mostly bacteria and bits of food.
To facilitate this, the peyer’s patch has a much thinner mucus layer as well as specialized phagocytic cells called M cells which can transform material across the epithelial barrier, bioprocess called transcytosis.
Finally, dendritic cells are able to extend dendrites between epithelial cells to sample antigens that are then broken down and used for presenting lymphocytes.
Sampling antigens in this way typically results in so called tolerogenic activation where the immune system initiates an anti-inflammatory response.
With their cargo of antigen, these dendritic cells then traffic to the T cell zones of the peyer’s patch.
Upon encounter with specific T cells, the dendritic cells convert them into an immunomodulatory cell called a regulatory T cell or T-reg.
Defects in the function of these cells are associated with inflammatory bowel disease in both animals and humans.
These T-regs then migrate to the lamina propria of the villi, by a lymphatics.
Here, the T-regs secretes a molecule called IL-10 which exerts to suppressive action on immune cells within the lamina propria and upon the epithelial layer itself.
IL-10 is therefore critical in maintaining immune quiescence and preventing unnecessary inflammation.
However, a breakdown in this process of immune homeostasis results in gut pathology and when this occurs over a prolonged period and in an uncontrolled manner, it can lead to inflammatory bowel disease.
Chemical, mechanical or pathogen triggered barrier disruption coupled with particular genetic susceptibilities may all combine to set off inflammation.
Epithelium coming in to contact with bacteria is activated, leading to bacterial influx.
Alarm molecules released by the epithelium activate immune cells and T-regs in the vicinity scale down their IL-10 secretion to enable an immune response to proceed.
Dendritic cells are also activated by this environment and start to release key inflammatory molecules such as IL-6, IL-12 and IL-23.
Affected T cells also appear on the scene and these coordinates escalation of the immune response by secreting their own inflammatory molecules, tumor necrosis factor alpha, interferon gamma and IL-17.
Soon after the affected T cells that are arrived, a veracious phagocyte called a neutrophil is recruited.
Neutrophils are critical for the clearance of bacteria.
One weapon in the neutrophil armory is the ability to undergo dramatic form of self-destruction called apoptosis.
This leaves behind a jumble of DNA saturated with enzymes called a neutrophil extracellular trap.
Although this can effectively destroy bacterial invaders and plug any breaches in the epithelial wall, it also causes collateral damage to tissues.
Slowly the time begins to turn and the bacterial invasion is repulsed and even remaining neutrophils die off by apoptosis, unknown inflammatory form of cell death and cleared by macrophages.
Epithelial integrity is restored by replacement of any damaged cells with new ones from the intestinal crypts.
Finally, T-regs are recruited once again to calm the immune response.
Targeting the molecules involved in gut pathology is leading to affected therapies for inflammatory bowel disease.