CHAPTER 13 Barrier Immunity: The Immunology of Mucosa and Skin

A micrograph of mouse ileum shows circular green Peyer’s patches surrounded by a number of villi. — Digitally colorized scanning electron micrograph (SEM) of the mouse small intestine (ileum), with villi in blue and Peyer’s patches in green.

Learning Objectives

After reading this chapter, you should be able to:

Identify the barrier organs in the human body and describe the general strategies they use to maintain a homeostatic relationship with the commensal microbiome.
Describe two examples that demonstrate how the microbiome and the immune system influence each other in biological dialog.
Using the intestinal immune system as an example, describe the diversity of cell types in secondary lymphoid tissue that help barrier organs to maintain homeostasis.
Distinguish between homeostatic and inflammatory responses in barrier tissues and outline the general events that initiate type 1 and type 2 responses at these surfaces.
Outline distinctions and similarities in immune systems that monitor our intestinal and respiratory tracts as well as our skin.

The power of poop: “Eating poop pills can make you thinner!” “Probiotics: A diabetes cure?” “Parasitic worms may prevent Crohn’s disease.” Are any of these headlines based on fact? Can poop really benefit our health? Although healthy skepticism is critical, some of these claims, indeed, are supported by experimental evidence. And all are based on a relatively new understanding of our relationship with the vast community of microbes that live with us, on us, and in us. More specifically, they are based on our understanding of the dialog between our immune system and the microbes that live on the epithelial surfaces of our barrier organs—our intestinal, respiratory, and reproductive tracts, as well as our skin, all of which provide a boundary between the external world and our internal environment (Overview Figure 13-1). This chapter provides readers with a foundation not only to interpret the literature in this relatively new field of barrier immunity, but also to evaluate claims and coverage in the news.

OVERVIEW FIGURE 13-1

Barrier Immune Tissues

The surfaces of the human body—gastrointestinal tract (mouth and intestine), respiratory tract (airway), reproductive tract (cervix), and skin—are populated by microorganisms and monitored by barrier immune systems. Each is lined by one or more layers of epithelial cells, which interact with a variety of immune cells at and below these layers. The interaction between microbiome and innate and adaptive immune cells regulates the balance between tolerance and inflammation, and, ultimately, between health and disease.

The illustration shows a shaded outline of the human body with various parts zoomed out to display the barrier immune system in those organs. The parts of the body zoomed out are mouth, respiratory tract, intestine, cervix, and hand.

A zoomed out image from the mouth shows a layer of oral epithelial cells. The region below the epithelial layer has T R E G and I L C cells. An arrow from antigens, outside the cell, points toward the layer of epithelial cells. A zoomed out image from the respiratory tract shows a layer of airway epithelial cells. The region below the epithelial layer has mast cell, B cell, D C, I L C, T R E G, and T H 2 cells. An arrow from antigens, outside the epithelial layer, indicates that the antigens enter the epithelium. A zoomed out image from the intestine shows intestinal epithelium consisting of a layer of microbial community. The region above the epithelial layer is labeled lumen, and mucus is seen below the layer of epithelial cells. This layer also consists of dotted blocks of cells and a D C cell anchored to it. Below the layer, I LC, T R E G, B cell, T H 1, T H 2, and T H 17 are shown. Arrows from two D C s point to B cell and T subscript R E G. A zoomed out image from the palm of the hand shows the epidermis layer of the skin, consisting of C D 8 plus T cell and Langerhans cells. Underneath, the dermis has D C, mast cell, I L C, T H 1, T H 2, T H 17, and gamma delta T cell. A zoomed out image from the cervix shows a layer of cervical epithelial cells with a D C cells anchored to it. The region below the epithelial layer has I L C and T cells. An arrow from virus points to the surface of epithelial cells. Another arrow from D C points toward T cell.

At the bottom of human body outline, another illustration shows the mouth, intestinal region, and a hand with a cut. To the right of the three diagrams, a layer of epithelial cells is shown. Pathogens are shown entering the blood stream through the epithelial layer. The pathogens flow through the blood stream to the kidney. The presence of pathogens triggers the production of T H and T C cells in the thyroid and B cels in the bone marrow. These cells travel to the blood stream to the kidney. When the pathogens enter the kidney, they trigger the proliferation of T H cells, T C cells, and B cells, which in turn attack the pathogens. The B, T H, and T C cells flow through the blood stream to the heart, from where they are circulated to different parts of the body. These cells produce antibodies that attack pathogens entering the body.

Although introductory immunology courses have traditionally focused on cellular development and interactions in primary and secondary immune organs, a vast number of immune cells not only populate but also initiate immune responses at our body surfaces. In fact, the intestine alone harbors more immune cells than any other tissue, including 50 billion lymphocytes. We now recognize that our relationship with the microbes that inhabit our surfaces fundamentally influences our susceptibility and resistance to asthma, autoimmunity, cancer, and even mood and neurological disorders. The barrier immune systems mediate our relationship with microbes and are charged with both cultivating harmonious interactions with benign microbes and responding aggressively to harmful microbes.

The biologists Scott Gilbert and Jan Sapp and the philosopher Alfred Tauber recently reminded us that “we have never been individuals.”¹ Instead, we are better understood as superorganisms or “holobionts.” For example, approximately 40 trillion bacteria share our human bodies, which consist of about 30 trillion cells. Viruses, fungi, and worms are also important members of the community of organisms that co-exist in a healthy human body.

In this chapter, we begin by introducing common characteristics of barrier immune systems. Focusing primarily on the intestinal immune system, where our knowledge is most advanced, we introduce the cells, molecules, and microenvironments that help barrier immune communities maintain healthy relationships with our microbiome as well as respond to invasion.

We investigate the reciprocal relationship between the microbiome and the barrier immune system, which are in an authentic dialog, responding to and tuning each other during development and throughout our life span. We also touch on the surprising influence barrier immune responses have on distal organ function and systemic immunity.

The focus on intestinal immunity establishes a framework for our exploration of immune systems in other barrier organs, including the skin and respiratory tract. These barrier immune systems share many features, yet also have unique strategies that reveal the breadth and flexibility of our immune system.

Finally, we describe advances in our understanding of the relationship between barrier immunity and inflammatory disease associated with the intestine and skin. We also include three boxes, the first of which provides an overview of the many innate and adaptive immune cells that participate in barrier immunity. Next, a Clinical Focus box discusses the intriguing relationship between the intestinal response to the microbiome and brain activity—a two-way communication that may influence mood disorders, as well as susceptibilities to other neurological disorders, including schizophrenia. Last, an Advances box describes one of the first observations that differences in animals’ immune responses can be attributed to differences in their microbiomes.