Gut immunity – What are the keys to protection?
Transcripción
Gut immunity – What are the keys to protection?
Gut immunity – What are the keys to protection? Christopher Chase, DVM, PhD, Diplomate ACVM South Dakota State University, Brookings, South Dakota Introduction The mucosal immune system provides the first immune defense barrier for over 90% of potential pathogens in the gastrointestinal tract. It must not only protect against harmful pathogens but also tolerize the immune system to dietary antigens and normal microbial flora (Figure 1). The mucosal immune system is very rudimentary in the newborn pig and gradually develops in four stages over the first 6 weeks of life1 (Table 1). Secretory IgA plays an important role in immunity at mucosal surfaces by making infectious agents stick together, preventing attachment of infectious agents to epithelial cells, and neutralizing toxins. Other components of the immune response may also be important in protection against various types of infection at mucosal surfaces. For example, neutrophils in the pig can migrate into the intestinal lumen in large numbers in response to antigen-antibody complexes. Gut associated lymphoid t issue Mucosal immunity, particularly the gut associated lymphoid tissue (GALT), is greatly influenced by environmental factors on the surface of the mucosal (Figure 1).3 The GALT of the pig is poorly developed and undergoes a rapid period of development and expansion that is not completed when pigs are weaned commercially at 14-24 days. The two most important critical control points for environmental influences are immediately after birth and at weaning. Colostrum is important for gut development and growth and non-antigen specific immune development. Colostrum is also important for providing pathogen specific immunoglobulin (Ig). Colostrum contains high levels of transforming growth factor β (TGF-β that has anti-inflammatory effects and accelerates the switch to IgA antibody along with preventing expression of active immune responses and promoting the development of tolerance against nutrient antigens (Bailey et al 2005a). The presence of commensal microbial flora is absolutely essential for the development of GALT in the neonatal pig. The second major environmental control point for GALT is weaning. At weaning, the pig can make active immune responses. The weaning period is characterized by diet change, low feed intake, poor growth and development, diarrhea and increased risk for disease from enteric pathogens. Unfortunately the maternal milk factors that modulate the immune response (TGF-β and provide specific immunity in the newborn (Ig) are no longer available and the balance between tolerance and active immunity at weaning is disturbed. The magnitude and severity of this “weaning” GALT crisis is dependent Table 1: The development of the mucosal immune response in the neonatal pig.† Stage Pig age Immune status 1 The newborn pig Rudimentary Peyers patches Small numbers of mucosal APCs and T-cells 2 1 Day - 2 weeks Non-specific expansion of Peyer’s patches and B-cells Appearance of some conventional, activated, helper T-cells Influx of MHCII+ cells in lamina propria 3 2 weeks-4 weeks Appearance of mature helper T-cells in lamina propria; IgM+ B cells in intestinal crypt areas 4 4 weeks-6 weeks Expansion of B-cell repertoire to IgA+ B cells in intestinal crypt area Appearance of memory cytotoxic T-cells in the epithelium (intraepithelial T cells) and in lamina propria † Adapted from Veterinary Immunology and Immunopathology, Bailey M, Haverson K, Inman C, Harris C, Jones P, Corfield G, Miller B, Stokes C, The influence of environment on development of the mucosal immune system, 108:189-198, 2005, with permission from Elsevier. American Association of Swine Veterinarians 407 2015 AASV Annual Meeting: Beyond Our Oath: Integrity, Intensity, Professionalism on how much the immune system was expanded during the preweaning period. Unfortunately the point where the production system determines the weaning age and the point where the immune system is ready for “weaning” are not the same and managing the immune system for optimal disease prevention at early weaning ages will continue to be problematic. Stress, immunosuppression, and immunity There is ample evidence that both physical and psychological distress can suppress immune function in animals, leading to an increased incidence of infectious disease. Excess heat or cold, crowding, mixing, weaning, limitfeeding, shipping, noise, and restraint are stressors that are often associated with intensive animal production and have been shown to influence immune function in various species. Also social status, genetics, age and the duration of stress (chronic vs. acute) have been shown to be important in the pig’s response to stress. Weaning is stressful event for the young pig. Research indicating that weaning before 3 weeks results in long term negative effects on immune system and mucosal development. Weaning at 2, 3, or 4 wk of age (but not at 5 wk of age) has been shown to decrease response of piglets to initiate an immune response. Early weaning results in increases in mast cells resulting in intestinal mucosa dysfunction. However, successful vaccination strategies at the time of weaning are frequently reported in the field. Nutritional influences on i mmunity The immune system does not get a free ride when it comes to nutrition. The immune requires energy, protein, vitamins and trace minerals. Both malnutrition and overfeeding may result in impairment of immune function and increased susceptibility to disease due to a deficiency or excess of proteins or calories, or a relative imbalance in vitamin or trace mineral content. Animals under intensive production conditions typically have a completely controlled diet. Therefore, it is very important that the diet, especially the vitamin and trace mineral content, be optimally formulated. Key vitamins and minerals for optimal immune function include vitamins A, C, E, and the B complex vitamins, copper (Cu), zinc (Zn), magnesium (Mg), manganese (Mn), iron (Fe), and selenium (Se). The balance of these constituents is especially important since excess or deficiency in one component may influence the availability or requirement for another. The route of vaccination The route of vaccine administration can be important when attempting to induce mucosal immunity. To induce 408 secretory IgA production at mucosal surfaces, it is best for the vaccine to enter the body via a mucosal surface. This can be accomplished by feeding the vaccine to the animal, aerosolizing the vaccine so the animal will inhale it, or by intramammary exposure. If a sow is exposed to an infectious agent in her intestinal tract, she may respond by producing secretory IgA not only in her own intestinal tract, but also in her mammary gland. The sow passes the IgA against the infectious agent to the piglet when it suckles, thus protecting the piglet from infectious agents present in the sow’s intestine. This protection will only last as long as the piglet continues to suckle. Enteric infections by many organisms are not controlled by the presence of IgG and IgM in the bloodstream or by a systemic cell-mediated immune response. If a modified live vaccine is given by injection, but goes to a mucosal surface to replicate, it may also induce a secretory IgA response. In addition, killed vaccines for some respiratory pathogens, such as M. hyopneumoniae and SIV are capable of stimulating an IgA response to c hallenge. The common mucosal system The acquired immune response is the target of vaccination.2 Its myriad of B cells, T cells, cytokines, and antibodies provides the pathogen-specific memory with continued duration of protective immunity (Figure 1). The acquired response is the target for vaccines to generate memory and protection. In the mucosal lymphoid tissues (Figure 2), mature T cells and B cells that have been stimulated by antigen and produce IgA will leave the submucosal lymphoid tissue and reenter the bloodstream. These lymphocytes will exit the bloodstream into the submucosa of other mucosal associated lymphoid tissue (MALT), many that are associated with the respiratory tract (Figure 2). Many of these cells will return to the same mucosal surface from which they originated but others will be found at different mucosal surfaces throughout the body. This homing of lymphocytes to other MALT sites throughout the body is referred to as the “common immune system” (Figure 2). The predominant Ig secreted by the mucosal immune system is IgA. IgA is secreted by plasma cells in the submucosa and is transported to the mucosal surface of the epithelial cell. The epithelial cell add a secretory component to IgA that is important for protecting the IgA molecule from proteolytic enzymes and also serves to anchor the IgA into the mucous layer forming a protective coating on the mucosal surface (Figure 1). IgA plays an important role in immunity by making infectious agents clump together, preventing attachment of infectious agents to epithelial cells, and neutralizing toxins. Intraepithelial T lymphocytes are important mediators of immunity at mucosal American Association of Swine Veterinarians Figure 1: Mucosa immune system of the gut epithelium. The lamina propria (LP) contains scattered T-cells and epithelium contains intraepithelial lymphocytes (IELs). B-cells are scattered in the LP but more often in the crypt regions along with plasma cells that produce IgA that is transported and secreted into the lumen. M cells facilitate antigen uptake and delivery to the organized lymphoid tissues. T-cells activated in the Peyer’s patch and medistinal LN express the integrin α4β7 interacts with cell-adhesion molecule MADCAM1, on the high endothelial vessels (HEVs). This homes these T-cells to the mucosal LP. The chemokine ligand CCL25 produced by epithelial cells recruits lymphocytes with CCR9 receptor to the LP. Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Immunology, Cheroutre H, Madakamutil L. Acquired and natural memory T cells join forces at the mucosal front line 4:290-300,2004. surfaces (Figure 1). This is especially true for respiratory infections. Pigs have high numbers of intraepithelial lymphocytes that are predominantly T cells (many are cytotoxic T cells that kill virus-infected cells). Summary Management of the pig’s mucosal immune system is not a simple process. Stressors and nutrition often compromise immunity. It is important that vaccinations be given at optimal times and that vaccination is not overused. Vaccination can never overcome poor management. References 1. Bailey M, Haverson K, Inman C, Harris C, Jones P, Corfield G, Miller B, Stokes C. 2005. The influence of environment on development of the mucosal immune system. Veterinary Immunology and Immunopathology, 108:189–198. 2. Chase CCL, JK Lunney. 2012. Chapter 16 Immune System. In Diseases of Swine, 10th edition. Eds Karriker L, KJ Schwartz, A Ramirez, GW Stevenson, JJ Zimmerman. Wiley-Blackwell, Ames IA, p p.227–250. 3. Cheroutre H, Madakamutil L. 2004. Acquired and natural memory T cells join forces at the mucosal front line. Nature Reviews Immunology 4:290–300. American Association of Swine Veterinarians 409 2015 AASV Annual Meeting: Beyond Our Oath: Integrity, Intensity, Professionalism Figure 2: Lymphocyte circulation and common mucosal immune system of the pig. As illustrated on the left side of the figure, the pig has unique lymphocyte circulation with lymphocytes entering the lymph nodes by afferent lymphatics but exiting via blood vessels rather than efferent lymphatics. The common mucosal system involves the circulation of B- and T-cells between lymphoid tissues on mucosal s urfaces. 410 American Association of Swine Veterinarians