Gut Immunity: brilliant educational animation from Nature Immunology

It is well-said that a picture is worth a thousand words. I have always found that a good, illustrative graphic can make a great impact upon the understanding of complex cellular pathways. And when one is visualizing dynamic processes, such as the processes occurring within the physiological system, newer technologies such as animations can be of a tremendous help. Of course, in order to be useful, it must be well-researched (so as to be scientifically accurate) as well as well-executed. This is why I was so excited about an animation depicting an immune process in the mammalian intestines presented by Nature Immunology.

The mucuous membrane or mucosa – the inner lining – of the intestines (‘gut’) contains a rich repertoire of immune cells, the largest immunological environment in the body. This organ has evolved this way probably because this mucosal layer continually encounters various microbes (either beneficial commensalic microbes or occasional pathogens), as well as antigens (either products of microbial pathogens or innocuous substances from the environment), coming into the body via or along with food. The immune defence system has a balanced mechanism to respond appropriately to pathogens, but tolerate commensals (which benefit the body) and harmless antigens. However, if this balance – a.k.a. homeostasis – is disturbed, the immune response may be wrongly activated or misdirected against these harmless antigens, giving rise to allergies to food items, or debilitating conditions such as Crohn’s disease or ulcerative colitis (collectively known as inflammatory bowel disease, in which the immune system attacks the intestinal tissue of the host’s own body). This wonderful animation from Nature Immunology introduces the key concepts associated with gut immunity.

The animated feature is appended below. What I have done in addition is that I have transcribed the 6-odd minutes of the feature, along with explanatory notes to facilitate understanding. Please let me know in the comments what you think.

Immunology in the gut mucosa:

The human gut can be the scene for devastating conditions such as inflammatory bowel disease, which arises through an improperly controlled immune response. The gut is often the body’s first point of contact with microbes; every mouthful of food is accompanied by a cargo of micro-organisms 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 [1], but a hardy few make it through to the intestines.

The intestinal surface is covered with finger-like protrusions called villi, whose primary function is the absorption of nutrients [2]. 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 are enriched in lymphoid tissue [3], making them key sites for coordinating immune responses to pathogens, whilst 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 [4] from both the Peyer’s Patches and the villi drain into the Mesenteric Lymph Node [5]. Within the villi is a network of loose connective tissue called the lamina propria, and at the base of the villi are the crypts which host the stem cells that replenish the epithelium.

Finally, the epithelium together with its thick overlying mucus forms an important barrier against microbial invasion. Embedded within the matrix of the Peyer’s Patches is a mix of immune cells including T- and B-lymphocytes, Macrophages, and Dendritic Cells [6]. 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 mucous layer, as well as specialized phagocytic cells, called M-cells, which can transport material across the epithelial barrier via a process 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 to lymphocytes. Sampling antigens in this way typically results in so-called tolerogenic activation, where the immune system initiates an anti-inflammatory response [7].

With their cargo of antigens, 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 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 migrate to lamina propria of the villi via the lymphatics. Here, the T-regs secrete a molecule called Interleukin (IL)-10, which exerts a suppressive action on immune cells within the lamina propria and upon the epithelial layer itself. IL10 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 into contact with bacteria is activated, leading to bacterial influx. Alarm molecules released by the epithelium activates immune cells, and T-regs in the vicnity scale down their IL10 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 IL6, IL12, and IL23. Effector T-cells also appear on the scene and these coordinate an escalation of the immune response by secreting their own inflammatory molecules, Tumor Necrosis Factor (TNF)-α, Interferon (IFN)-γ and IL17.

Soon after the effector T-cells are arrived, a voracious phagocyte called a neutrophil [8] is recruited. Neutrophils are critical for the clearance of the bacteria. One weapon in the neutrophil armory is the ability to undergo a dramatic form of self-destruction called necrosis [9]. This leaves behind a jumble of DNA saturated with enzymes, called the Neutrophil Extracellular Trap. Although this can effectively destroy the bacterial invaders and plug any breaches in the epithelial wall, it also causes collateral damage to tissues.

Slowly the tide begins to turn and the bacterial invasion is repulsed. Any remaining neutrophils die off by apoptosis, a non-inflammatory form of cell death, and are cleared by macrophages. Epithelial integrity is restored by replacement of any damaged cell 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 effective therapies for inflammatory bowel disease.

Notes:

1. Acidic environment of the stomach and gastric acid secretion: Cells in the gastric mucosa secrete highly concentrated (approximately 0.1N) hydrochloric acid (a.k.a. muriatic acid, the acidic substance used in bathroom cleaners!); the corrosive acid creates a favorable environment in which digestive enzymes can break down food proteins. There are other stomach-lining cells, which produce bicarbonate, a base, to balance the stomach pH [a measure of acidity] where necessary, and secrete mucus (a thick, viscous substance which acts as physical barrier to prevent the gastric hydrochloric acid from corroding the mucosal tissue). Cells in gut mucosa also have the ability to produce bicarbonate in sufficient quantity to neutralize remnants of gastric acid when the partially digested food moves along.
2. Villi: These finger-like projections increase greatly the available surface area of the intestinal mucosa, thereby providing more opportunity for the absorption of nutrients into the mucosal cells and thence to the blood vessels.
3. Lymphoid tissue: Connective tissue rich in a type of white blood cells, called lymphocytes, which are extremely important in defence processes associated with adaptive immunity.
4. Lymphatics: Just as blood vessels (arteries and veins) carry blood in the body, a parallel system called lymphatics carry lymph, a clear, watery fluid from spaces within tissues, containing various substances (including proteins, lipids, carbohydrates, and sometimes even microbes).
5. Mesenteric Lymph Nodes: Mesentery refers to folds of internal tissue which holds parts of the small intestine in place. It is richly supplied by blood vessel, lymphatics and nerves. Nodes are localized areas of lymphoid tissue.
6. T- and B-lymphocytes, Macrophages, and Dendritic Cells: These are all important immune effector cells. Macrophages and Dendritic cells are primary defence cells that can eat up (‘phagocytosis’) microbes and destroy them; they also can present parts of these microbes to lymphocytes. T-lymphocytes or T-cells help B-lymphocytes or B-cells recognize the antigen and form antibodies against it. Other types of T-cells can themselves kill microbes. All these cells also secrete various chemical substances, called cytokines and chemokines, which act as molecular messengers in recruiting various immune cells, coordinating and fine-tuning the immune response. Some of these cytokines are called Interleukins, shortened to IL.
7. Anti-inflammatory response: A type of immune response in which molecular messengers are used to scale down heavy-handed immune cell activity and switch off processes that recruit immune cells. This helps the body recognize and selectively tolerate beneficial substances such as commensalic microbes that live in the gut.
8. Neutrophils: These are highly versatile immune effector cells. Usually, they are one of the first cells recruited to the site of infection or tissue damage via message spread by molecular messengers. Neutrophils can themselves elaborate cytokines and chemokines, and have the ability to directly kill microbes.
9. Necrosis and Apoptosis: Necrosis of neutrophils involves loss of cell integrity and leakage of intracellular contents into the surrounding environment. It is a destructive process. Apoptosis, on the other hand, a.k.a. programmed cell death, involves the destruction of a cell in a controlled and directed manner, so that the surrounding tissues are unharmed, and remnants of apoptotic cells are cleared off by professional phagocytes.