Regional immune systems include the mucosal immune systems, which protect the gastrointestinal, bronchopulmonary, and genitourinary mucosal barriers, and the cutaneous (skin) immune system. The gastrointestinal immune system is the largest and most complex. The intestinal mucosa of an adult human is estimated to contain approximately 50 × 109 lymphocytes (Table 1), and more antibody is made in the intestines than in all other parts of the immune system combined. The dedication of so many immune system resources to the gut reflects the large surface area of the intestinal mucosa, which has evolved to maximize the primary absorptive function of the tissue but must also resist invasion by trillions of bacteria in the lumen. The skin is also a barrier tissue with a vast surface area that must be protected from the environmental microbes that have ready access to the external lining. The total number of lymphocytes in the skin of an adult is estimated to be 20 × 109, about twice the total number of circulating lymphocytes (see Table 1). The different physical features of the mucosa (soft, wet, and warm) and the skin (tough, dry, and cool) favor colonization and invasion by different types of microbes. Therefore, it is not surprising that the immune system is specialized in different ways in these two types of tissues.
Table1. Estimated Numbers of Lymphocytes in Different Human Tissues
The immune systems at epithelial barriers share a basic anatomic organization, with an outer epithelial layer that prevents microbial invasion, underlying connective tissue containing various cell types that mediate immune responses to organisms that do invade through the epithelium, and local or more distant draining secondary lymphoid tissues where adaptive immune responses to invading microbes develop. The epithelial barrier may be several layers thick, as in the skin, or a single layer sitting on a basement membrane, as in the intestines. The underlying connective tissue, such as the dermis in the skin and the lamina propria in the gut, contains numerous scattered lymphocytes, dendritic cells (DCs), macrophages, and other cells that mediate innate immune responses and the effector phase of adaptive immune responses. Mucosal tissues also contain unencapsulated but organized secondary lymphoid tissues just under the epithelial barrier, which include B and T lymphocytes, DCs, and macrophages. These col lections of immune cells, often called mucosa-associated lymphoid tissue (MALT), are sites of development of some adaptive immune responses specialized for the particular mucosal tissue. Adaptive immune responses in epithelial barrier immune systems are also induced in draining lymph nodes that are located outside the barrier tissues. In skin and mucosal tissues, antigens outside the epithelial barrier are sampled by specialized cells within the epithelium and are delivered to draining lymph nodes or MALT.
Regional immune systems contain specialized cell types and molecules that may not be abundant in other sites. The cell types that are restricted to or more abundant in one or more regional immune systems include subsets of DCs (e.g., Langerhans cells in the skin), antigen transport cells (e.g., microfold [M] cells in the gut), specialized mucosal epithelial cells (e.g., tuft cells in the gut and lung), T lymphocytes (e.g., γδ T cells in epithelia), immunoglobulin A (IgA)-producing B cells and plasma cells in mucosal tissues, and various innate lymphoid cells (ILCs). The unique anatomic features and cell types in each tissue endow that tissue with special functional characteristics. For example, the sampling of antigens in the gut and their transport to secondary lymphoid organs rely on cell types and routes of lymphatic drainage that are different from what takes place in the skin or internal organs. Furthermore, the MALT structures in various regions of the gut and in other mucosal organs have distinct features.
The effector lymphocytes that are generated in the draining lymph nodes of a particular regional immune system (e.g., skin or small intestine) will enter the blood and preferentially home back to the same organ (e.g., dermis or lamina propria, respectively). The migration and localization of subsets of lymphocytes to different tissues is in part a result of tissue-specific homing mechanisms that direct these subsets from the blood into particular tissues, which we will discuss in detail later in this chapter.
Regional immune systems have important regulatory functions that prevent unwanted responses to nonpathogenic microbes and foreign substances that are likely to be present at different barriers. The clearest example is the gut-associated immune system, which must suppress responses to commensal bacteria that colonize the intestinal lumen, as well as to foreign food substances, but must respond to pathogenic bacteria, which will be present in much fewer numbers than the commensals. In fact, commensal luminal microbes in the gut are required to maintain a functional intestinal immune system that can defend against pathogens. The suppression of immune responses to nonpathogenic organisms and harmless foreign substances is also important in other sites of the body, including the skin, lung, and genitourinary tract, which are not sterile and are constantly exposed to the environment.
With this introduction, we will discuss the details of these various features in different regional immune systems, beginning with the largest.
