Intestinal mucosal immunity

The intestinal epithelium

The first line of defense, the intestinal epithelial surface, comprises several different cell types, the majority of which are absorptive epithelia. Covering the epithelial cells is a layer of mucus that serves as the first line of defense. This mucus is secreted by goblet cells that are interspersed between the absorptive epithelia. These secretory cells synthesize and secrete glycoproteins, sometimes referred to as mucins ( Fig. 2.1 ).

As depicted in Fig. 2.1 , there is a crypt to villus gradient of epithelial cells, where cells in the crypt migrate to the villus tip. At the very base of the crypt are additional cells called the Paneth cells , which secrete antimicrobial peptides that protect against pathogenic agents that are injurious to the intestinal epithelial cells (IECs). These Paneth cells are strategically placed close to the mitotic region in the crypt where their secretions provide protection for the vulnerable but highly mitotically active cells that reside in the crypt region. Cells that migrate to the tip of the villus stop undergoing mitosis, continue to differentiate into functional absorptive epithelia, and are extruded from the tip of the villus in a process called anoikis , a form of programmed cell death.

In addition to their absorptive function, IECs directly participate in immune surveillance of the intestine. These cells act as a physical barrier and signal to other components of the mucosal immune system by producing cytokines and chemokines. The IECs express pattern recognition receptors (PRRs). A subset of these PRRs, the toll-like receptors (TLRs), play a vital role in the innate immune system by mediating signaling from microbial cell components such as lipoteichoic acid, flagellin, and lipopolysaccharide in the production of various cytokines and chemokines, which in turn propagates the inflammatory process. The inflammatory response can either protect against these pathogens or cause cellular injury if unregulated.

Another class of cells located in the intestinal epithelium, the innate lymphoid cells (ILCs), can be activated to produce cytokines, which play critical roles in inflammation. When ILCs are activated, they express cytokines that protect epithelial cells from injury.

Another unique set of cells, dendritic cells (DCs), recognize and eliminate exogenous pathogens. DCs act as gatekeepers, controlling the passage of antigens through the mucosal barrier to mucosal-associated lymphoid tissue. These cells open interepithelial tight junctions, enter the lumen, and with their branched projections, sense antigenic materials and phagocytose various microbes, including pathogens. DCs also act as messengers between the innate and adaptive immune systems, regulating intestinal immune tolerance by promoting the differentiation of CD4 ⁺ T cells toward regulatory T cells (Tregs).

Proinflammatory T helper (Th) cells eliminate pathogens during a host defense response. This is accomplished by destroying tissue via inducing tissue inflammation. Tregs are involved in immunologic homeostasis, preventing overactive inflammatory responses or loss of tolerance, which is thought to be an important component of autoimmunity such as seen in type 1 diabetes.

Lamina propria

The second major line of defense of the mucosal immune system is the lamina propria. This consists of cells that reside in the lower layer of the intestinal epithelium and is composed of B and T cells ( Fig. 2.2 ). The intestinal tract is continuously exposed to a large quantity of antigens, which places the epithelium under considerable stress. The mechanism that provides tolerance to the normal intestinal flora but still has the capability to respond to pathogenic organisms is found in the lamina propria. Imbalances in proinflammatory versus antiinflammatory microorganisms or other stimuli may lead to inflammation, such as seen in various forms of inflammatory bowel disease (IBD).