Each chapter in this unique textbook contains boxed areas of text including for example case studies, techniques or recent developments worthy of the public's attention. The book also includes an associated website containing a range of support material for lecturers. Immunity: Mucosal Immunology in Health and Disease is an essential resource for BSc and MSc students and those studying for a PhD degree in departments of biology, biochemistry, biomedicine, medicine, veterinary sciences, and immunology. It has a strong appeal within the pharmaceutical industry.

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NCBI Bookshelf. New York: Garland Science; The immune system may be viewed as an organ that is distributed throughout the body to provide host defense against pathogens wherever these may enter or spread. Within the immune system, a series of anatomically distinct compartments can be distinguished, each of which is specially adapted to generate a response to pathogens present in a particular set of body tissues.

The previous part of the chapter illustrated the general principles underlying the initiation of an adaptive immune response in the compartment comprising the peripheral lymph nodes and spleen. This is the compartment that responds to antigens that have entered the tissues or spread into the blood.

A second compartment of the adaptive immune system of equal size to this, and located near the surfaces where most pathogens invade, is the mucosal immune system commonly described by the acronym MALT. Two further distinct compartments are those of the body cavities peritoneum and pleura and the skin.

Two key features define these compartments. The first is that immune responses induced within one compartment are largely confined in expression to that particular compartment. The second is that lymphocytes are restricted to particular compartments by expression of homing receptors that are bound by ligands, known as addressins, that are specifically expressed within the tissues of the compartment.

We will illustrate the concept of compartmentalization of the immune system by considering the mucosal immune system. The mucosal surfaces of the body are particularly vulnerable to infection. They are thin and permeable barriers to the interior of the body because of their physiological activities in gas exchange the lungs , food absorption the gut , sensory activities eyes, nose, mouth, and throat , and reproduction uterus and vagina.

The necessity for permeability of the surface lining these sites creates obvious vulnerability to infection and it is not surprising that the vast majority of infectious agents invade the human body through these routes. A second important point to bear in mind when considering the immunobiology of mucosal surfaces is that the gut acts as a portal of entry to a vast array of foreign antigens in the form of food.

The immune system has evolved mechanisms to avoid a vigorous immune response to food antigens on the one hand and, on the other, to detect and kill pathogenic organisms gaining entry through the gut. To complicate matters further, most of the gut is heavily colonized by approximately 10 14 commensal microorganisms, which live in symbiosis with their host.

These bacteria are beneficial to their host in many ways. They provide protection against pathogenic bacteria by occupying the ecological niches for bacteria in the gut. They also serve a nutritional role in their host by synthesizing vitamin K and some of the components of the vitamin B complex. However, in certain circumstances they can also cause disease, as we will see later. The mucosa-associated lymphoid tissues lining the gut are known as gut-associated lymphoid tissue or GALT.

The tonsils and adenoids form a ring, known as Waldeyer's ring, at the back of the mouth at the entrance of the gut and airways. They represent large aggregates of mucosal lymphoid tissue, which often become extremely enlarged in childhood because of recurrent infections, and which in the past were victims of a vogue for surgical removal. A reduced IgA response to oral polio vaccination has been seen in individuals who have had their tonsils and adenoids removed, which illustrates the importance of this subcompartment of the mucosal immune system.

The other principal sites within the gut mucosal immune system for the induction of immune responses are the Peyer's patches of the small intestine, the appendix which is another frequent victim of the surgeon's knife , and solitary lymphoid follicles of the large intestine and rectum.

Peyer's patches are an extremely important site for the induction of immune responses in the small intestine and have a distinctive structure, forming domelike structures extending into the lumen of the intestine see Fig. The overlying layer of follicle-associated epithelium of the Peyer's patches contains specialized epithelial cells. These have microfolds on their luminal surface, instead of the microvilli present on the absorptive epithelial cells of the intestine, and are known as microfold cells or M cells.

They are much less prominent than the absorptive gut epithelial cells, known as enterocytes, and form a membrane overlying the lymphoid tissue within the Peyer's patch. M cells lack a thick surface glycocalyx and do not secrete mucus.

Hence they are adapted to interact directly with molecules and particles within the lumen of the gut. M cells take up molecules and particles from the gut lumen by endocytosis or phagocytosis Fig.

This material is then transported through the interior of the cell in vesicles to the basal cell membrane, where it is released into the extracellular space. This process is known as transcytosis. At their basal surface, the cell membrane of M cells is extensively folded around underlying lymphocytes and antigen -presenting cells, which take up the transported material released from the M cells and process it for antigen presentation. M cells take up antigens from the lumen of the gut by endocytosis.

The cell membrane at the base of these cells is folded around lymphocytes and dendritic cells within the Peyer's patches. Antigens are transported through M cells by the process of transcytosis more Because M cells are much more accessible than enterocytes to particles within the gut, a number of pathogens target M cells to gain access to the subepithelial space, even though such pathogens then find themselves in the heart of the adaptive immune system of the intestine, the Peyer's patches.

We will consider one of these pathogens in Section In addition to the organized lymphoid tissue in which induction of immune responses occurs within the mucosal immune system , small foci of lymphocytes and plasma cells are scattered widely throughout the lamina propria of the gut wall.

These represent the effector cells of the gut mucosal immune system. The life history of these cells is as follows. As naive lymphocytes, they emerge from the primary lymphoid organs of bone marrow and thymus to enter the inductive lymphoid tissue of the mucosal immune system via the bloodstream.

They may encounter foreign antigens presented within the organized lymphoid tissue of the mucosal immune system and become activated to effector status. From these sites, the activated lymphocytes traffic via the lymphatics draining the intestines, pass through mesenteric lymph nodes, and eventually wind up in the thoracic duct , from where they circulate in the blood throughout the entire body Fig.

They reenter the mucosal tissues from the small blood vessels lining the gut wall and other sites of MALT , such as the respiratory or reproductive mucosa, and the lactating breast; these vessels express the mucosal adressin MAdCAM In this way, an immune response that may be started by foreign antigens presented in a limited number of Peyer's patches is disseminated throughout the mucosa of the body.

This pathway of lymphocyte trafficking is distinct from and parallel to that of lymphocytes in the rest of the peripheral lymphoid system see Fig. Anatomy of mucosal immune responses. The left panel shows the afferent immune response. Antigen from pathogenic micro-organisms is presented beneath mucosal surfaces to naive lymphocytes within organized mucosal lymphoid tissue, for example Peyer's patches. The distinctiveness of the mucosal immune system from the rest of the peripheral lymphoid system is further underlined by the different lymphocyte repertoires in the different compartments.

The T cells of the gut can be divided into two types. These highly specialized T cells are abundant in the epithelium of the gut and have a restricted repertoire of T-cell receptor specificities. Unlike conventional T cells, many of these cells do not undergo positive and negative selection in the thymus see Chapter 7 , and express receptors with sequences that have undergone no or minimal divergence from their germline-encoded sequences.

These cells may be classified in phylogenetic terms as being at the interface between innate and adaptive immunity. This illustrates one of the key roles of T cells, which is to patrol and survey the body, destroying cells that express an abnormal phenotype as a result of stress or infection.

Infection or other injury to enterocytes, the epithelial cells lining the lumen of the gut, stimulates more This protein, which shows increased expression on activated monocytes and dendritic cells, presents endogenous lipid and glycolipid antigens to some types of T cell. This is closely analogous, although opposite in effect, to the polarization toward T H 2 cells induced by secretion of IL -4 by NK 1.

These cells can be found in the gut of mice lacking conventional MHC class I molecules, which shows that their development is not dependent on positive selection in the thymus by peptides bound to classical MHC class I molecules. These cells are likely to represent a further class of T cells that have a major role in maintaining the integrity of the gut mucosa by recognizing and destroying injured mucosal cells.

The dominant antibody isotype of the mucosal immune system is IgA. This class of antibody is found in humans in two isotypic forms, IgA1 and IgA2. The expression of IgA differs between the two main compartments in which it is found—blood and mucosal secretions. In mucosal secretions, IgA is almost exclusively produced as a dimer and the ratio of IgA1 to IgA2 is approximately A number of common intestinal pathogens possess proteolytic enzymes that can digest IgA1, whereas IgA2 is much more resistant to digestion.

The higher proportion of plasma cells secreting IgA2 in the gut lamina propria may therefore be the consequence of selective pressure by pathogens against individuals with low IgA2 levels in the gut. The mechanism of isotype switching to IgA is discussed in Section There are special mechanisms for the secretion of polymeric IgA and IgM antibody into the gut lumen see Section Polymeric IgA and IgM are synthesized throughout the gut by plasma cells located in the lamina propria and are transported into the gut by immature epithelial cells located at the base of the intestinal crypts.

These express the polymeric immunoglobulin receptor on their basolateral surfaces. This receptor binds polymeric IgA or IgM and transports the antibody by transcytosis to the luminal surface of the gut. Upon reaching the luminal surface of the enterocyte, the antibody is released into the secretions by proteolytic cleavage of the extracellular domain of the polymeric IgA receptor. Secreted IgA and IgM bind to the mucus layer overlying the gut epithelium where they can bind to and neutralize gut pathogens and their toxic products Fig.

The major antibody isotype present in the lumen of the gut is secretory polymeric IgA. This is synthesized by plasma cells in the lamina propria and transported into the lumen of the gut through epithelial cells at the base of the crypts.

Polymeric IgA more We are continuously exposed to a huge array of foreign antigens in the form of foods, but these do not normally induce an adaptive immune response. For example, IgA antibodies with high affinity to food antigens do not normally develop. This lack of response occurs despite the fact that the repertoire of lymphocyte antigen receptors has not been negatively selected to remove those specific for food antigens. This is because, like any other foreign antigen, food antigens do not play a part in the central mechanisms of lymphocyte tolerance to self, which are established in the thymus and bone marrow see Chapter 7.

The feeding of foreign antigens leads typically to a state of specific and active unresponsiveness, a phenomenon known as oral tolerance. Thus, no antibody response follows the feeding of a foreign protein such as ovalbumin, although a strong antibody response to this protein can be induced by injecting it subcutaneously, especially if an adjuvant is given as well.

However, the feeding of ovalbumin is followed by a prolonged period during which the administration of ovalbumin by injection, even in the presence of adjuvant, elicits no antibody response. This suppression is antigen -specific, because antibody responses to other injected antigens are not affected. These experiments show that there are antigen-specific mechanisms for suppressing peripheral immune responses to antigens delivered by mouth.

The mechanisms of oral tolerance are partly understood but, before considering them, we will first discuss the contrasting immune responses that are seen in response to bacterial infections of the gut. We each harbor more than species of commensal bacteria , which are present in the largest numbers in the colon and ileum. Despite the fact that these bacteria collectively weigh approximately 1 kg and outnumber us by approximately 10 14 to 1, for most of the time we cohabit with our intestinal bacterial flora in a happy symbiotic relationship.

One protective activity of our normal gut flora is that of competition against pathogenic bacteria for space and nutrients, preventing their colonization of the gut see Fig. This activity is dramatically illustrated by one of the adverse effects of antibiotics.

Taking an antibiotic kills large numbers of commensal gut bacteria and thereby offers an ecological niche to bacteria that would not otherwise be able to compete successfully with the normal flora and grow in the gut.

One example of a bacterium that grows in the antibiotic-treated gut and can cause a severe infection is Clostridium difficile ; this produces two toxins, which can cause severe bloody diarrhea associated with mucosal injury Fig. Treatment with antibiotics causes massive death of the commensal bacteria that normally colonize the colon. This allows pathogenic bacteria to proliferate and occupy an ecological niche that is normally occupied by harmless commensal bacteria.


Immunology: Mucosal and Body Surface Defences

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Immunology : mucosal and body surface defences

NCBI Bookshelf. New York: Garland Science; The immune system may be viewed as an organ that is distributed throughout the body to provide host defense against pathogens wherever these may enter or spread. Within the immune system, a series of anatomically distinct compartments can be distinguished, each of which is specially adapted to generate a response to pathogens present in a particular set of body tissues. The previous part of the chapter illustrated the general principles underlying the initiation of an adaptive immune response in the compartment comprising the peripheral lymph nodes and spleen.


Immunology: Mucosal and Body Surface Defences

After an introduction to the basic structure of the immune system, the book looks at two important families of signalling molecules: cytokines and chemokines, before covering the workings of the mucosal immune system. It continues by examining immunity against the four major groups of pathogens - viruses, bacteria, fungi and parasites, and concludes by looking at disorders of the immune system, mucosal tumour immunology and the process of vaccination. Students across a range of disciplines, including biology, biochemistry, biomedicine, medicine and veterinary sciences, will find this book invaluable, both as an introduction to basic immunology and as a guide to mucosal immune defence mechanisms. Immunology : Mucosal and Body Surface Defences.

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