lecture 21- immunology studyguide .pdf

The gastrointestinal immune system: Adaptive Immunity Mainly humoral immunity (via IgA) directed at microbes in the lumen Dominance of IgA because: 1. B cells in gut region class switch to IgA 2. IgA-expressing B cells home to the gut Abundant Treg cells act to control inflammatory reactions The spe...

The gastrointestinal immune system: Adaptive Immunity Mainly humoral immunity (via IgA) directed at microbes in the lumen Dominance of IgA because: 1. B cells in gut region class switch to IgA 2. IgA-expressing B cells home to the gut Abundant Treg cells act to control inflammatory reactions The speaker is discussing the role of the gastrointestinal (GI) immune system, specifically focusing on adaptive immunity. However, before delving into adaptive immunity, they mentioned innate immunity associated with the gastrointestinal tract. Although they didn't discuss it in detail, innate immunity is the first line of defense against pathogens and involves nonspecific mechanisms such as physical barriers (e.g., mucus, epithelial cells), chemical barriers (e.g., gastric acid, enzymes), and innate immune cells (e.g., macrophages, dendritic cells) that recognize and respond to pathogens. Moving on to adaptive immunity, which is the speaker's main focus, they mentioned that their discussion primarily pertains to the small intestine. The small intestine is a crucial site for immune responses due to its high exposure to antigens from food and commensal microorganisms. One key aspect of adaptive immunity in the GI tract discussed by the speaker is the production of immunoglobulin A (IgA). IgA is the predominant antibody class produced in the gut and plays a crucial role in mucosal immunity by preventing the attachment and invasion of pathogens, neutralizing toxins, and modulating the composition of the gut microbiota. The speaker likely discussed factors contributing to IgA production, such as specialized immune structures like Peyer's patches and mesenteric lymph nodes, as well as interactions between immune cells and gut 1 epithelial cells. Furthermore, the speaker touched upon the role of regulatory T cells (Tregs) in controlling inflammatory reactions in the gut. Tregs are a subset of T cells that suppress excessive immune responses, thereby preventing inflammation and maintaining immune tolerance to harmless antigens, including food and commensal microbes. Dysfunction of Tregs can lead to inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis. In summary, the speaker provided an overview of adaptive immunity in the gastrointestinal tract, highlighting the importance of IgA production and the regulatory function of Tregs in maintaining gut homeostasis and immune tolerance. These mechanisms are crucial for protecting against pathogens while preventing inappropriate immune responses to dietary antigens and commensal microbes. 1 Gut-antigen sampling: the role of M cells M cells transport microbes & antigens across epithelium to DCs and B cells Peyer’s patch mostly lymphocytes and APCs B:T ratio 5X higher than in systemic nodes The speaker is discussing the process of gut antigen sampling, particularly focusing on the role of specialized cells called M cells in the gut-associated lymphoid tissue, specifically within Peyer's patches. Here's a breakdown of the key points made by the speaker: 1.Introduction to Gut Antigen Sampling: The speaker introduces the concept of gut antigen sampling, which involves the immune system monitoring and responding to antigens passing through the gastrointestinal tract. These antigens can include pathogens, commensal microbes, or ingested food particles. 2.Peyer's Patches: Peyer's patches are specialized secondary lymphoid structures located in the gastrointestinal tract. These structures resemble lymph nodes but are not considered as such. They contain follicles, similar to those found in lymph nodes, which are involved in the activation and production of B cells and antibodies. 3.Composition of Peyer's Patches: The speaker explains that Peyer's patches are composed mainly of lymphocytes and antigen-presenting cells. Unlike typical lymph nodes found elsewhere in the body, Peyer's patches have a higher proportion of B lymphocytes compared to T lymphocytes. This high ratio of B cells is significant because it contributes to the production of immunoglobulin A (IgA), a key antibody in mucosal immunity. 4.M Cells: The speaker emphasizes the presence of specialized epithelial cells called M cells within Peyer's patches. 2 M cells are located on the luminal side of the epithelial sheet, which means they face the gut lumen. These cells play a crucial role in transporting antigens from the gut lumen to the underlying immune cells in Peyer's patches. 5. Function of M Cells: M cells transport antigens, including whole microbes or soluble antigens, from the gut lumen to the underlying immune cells in Peyer's patches. This transport process is not merely a means for antigens to sneak into the body but rather an organized ingestion process. Antigens transported by M cells are presented to antigen-presenting cells, such as dendritic cells and B cells, within Peyer's patches. 6.Immune Sampling in the Gut: The speaker highlights that gut antigen sampling allows the immune system to monitor the types of organisms and antigens present in the gut. This sampling process is essential for the immune system to mount appropriate responses to pathogens while maintaining tolerance to harmless antigens and commensal microbes. In summary, the speaker provides an overview of the specialized structures and cells involved in gut antigen sampling, with a focus on the role of M cells in transporting antigens from the gut lumen to the immune cells in Peyer's patches. This process is crucial for immune surveillance and maintaining gut homeostasis. 2 Gut-antigen sampling: intestinal dendritic cells “Pre-breach” “Post-breach” The speaker is discussing another mechanism by which the immune system in the gut samples antigens, specifically through intestinal dendritic cells. They describe two versions of this process: post-breach and pre-breach mechanisms. 1.Post-Breach Mechanism: In this scenario, antigens breach the tight junctions between epithelial cells, possibly due to imperfect sealing or damage to the epithelial barrier. As a result, antigens can pass through and be detected by dendritic cells located beneath the basement membrane of the epithelium. This mechanism is termed "postbreach" because it occurs after antigens have breached the epithelial barrier. 2.Pre-Breach Mechanism: In contrast, the pre-breach mechanism involves dendritic cells extending membrane protrusions between epithelial cells to directly sample antigens from the gut lumen without breaching the tight junctions. This allows dendritic cells to recognize, bind, internalize, and eventually present antigens to other immune cells. Unlike the post-breach mechanism, this process occurs before antigens breach the epithelial barrier. In both scenarios, dendritic cells play a crucial role in sampling antigens from the gut. Once dendritic cells capture antigens, they present them to T cells in the mucosal-associated lymphoid tissue (MALT), which includes structures like Peyer's patches, or to lymphocytes in underlying mesenteric lymph nodes. This antigen presentation is 3 essential for initiating immune responses and maintaining gut homeostasis. Overall, the speaker highlights the importance of intestinal dendritic cells in antigen sampling within the gut and emphasizes the existence of both pre-breach and post-breach mechanisms for detecting antigens. These mechanisms contribute to the immune system's ability to surveil and respond to potential threats in the gastrointestinal tract. 3 The gastrointestinal immune system: Humoral Immunity Major function => neutralize microbes in gut lumen via IgA (termed “secretory immunity”) IgA production 2/3’s of antibody by adult human each day 80% of plasma cells are associated with GI tract The speaker is discussing the functions of the adaptive immune system, particularly focusing on humoral immunity within the gastrointestinal (GI) tract. Here's a breakdown of the key points made by the speaker: 1.Overview of Adaptive Immunity: The speaker begins by explaining the overall function of the adaptive immune system, which includes both humoral and cell-mediated immunity. They emphasize that adaptive immunity can be broken down into antibody-based humoral immunity and T cell-based cell-mediated immunity. 2.Specialization of Humoral Immunity in the GI Tract: The speaker highlights the specialization of humoral immunity in the GI tract. They provide statistics indicating that a significant portion of antibody production in adults, specifically 2/3 of antibodies, is IgA, with the majority being produced in the gut and secreted into the gut lumen. Additionally, they mention that 80% of all plasma cells, which are antibody-secreting differentiated B cells, are associated with the GI tract. 3.Function of Humoral Immunity: The primary function of humoral immunity in the GI tract is to neutralize microbes present in the gut lumen via IgA antibodies. This process is often referred to as "secreted immunity." While similar mechanisms occur in other mucosal surfaces such as the respiratory and urogenital tracts, the bulk of secretory immunity is associated with the GI tract due to its large surface area. 4 4. Neutralizing Microbes in the Gut: The speaker emphasizes that the main goal of humoral immunity in the GI tract is to neutralize microbes present in the gut lumen before they can penetrate the epithelial barrier and enter the body. This function is crucial for maintaining a balance between responding to potentially pathogenic microbes while tolerating harmless commensal microbes. In summary, the speaker provides an overview of the functions of humoral immunity in the GI tract, highlighting its specialization in producing IgA antibodies and its role in neutralizing microbes present in the gut lumen. This process is essential for maintaining gut homeostasis and protecting against pathogens while tolerating commensal microbes. 4 Transcytosis of IgA The speaker is discussing the process of transcytosis of IgA antibodies within the gastrointestinal epithelial cells. Here's a breakdown of the key points made by the speaker: 1.Production of IgA: The speaker reiterates that IgA antibodies are primarily produced by plasma cells located in the lamina propria, which is the connective tissue layer underlying the epithelial cells of the gastrointestinal tract. IgA antibodies are dimeric, and the joining (J) chain links the two antibody molecules together to form dimers. 2.Polymeric Immunoglobulin Receptor (pIgR): The speaker introduces the Polymeric Immunoglobulin Receptor (pIgR), which is a protein present on the basolateral surface of epithelial cells. The pIgR is depicted as a string of spherical molecules in the figure provided by the speaker. 3.Transcytosis Process: The speaker describes the process of transcytosis, which involves the transportation of IgA antibodies from the basolateral surface of epithelial cells to the apical surface, where they can be released into the gut lumen. The following steps are involved: 4.a. Binding: The pIgR binds to the dimeric IgA antibodies secreted by plasma cells. 5.b. Endocytosis: The pIgR-bound IgA complex is internalized into the epithelial cell through endocytosis, forming an endocytic vesicle containing the IgA-pIgR complex. 5 6. c. Translocation: The endocytic vesicle containing the IgA-pIgR complex moves from the basolateral surface of the epithelial cell towards the apical surface. 7.d. Fusion and Cleavage: The endocytic vesicle fuses with the plasma membrane at the apical surface, leading to the release of the IgA antibodies into the gut lumen. During this process, a portion of the pIgR molecule is cleaved off, while the remainder stays associated with the epithelial cell membrane. 8.Functional Importance: The speaker emphasizes that transcytosis of IgA antibodies is a highly regulated and ordered process that allows for the transport of antibodies from inside the body (lamina propria) to the gut lumen. This process is essential for providing mucosal immunity within the gastrointestinal tract, where IgA antibodies can neutralize pathogens and antigens present in the gut lumen. In summary, the speaker provides a detailed explanation of the transcytosis process involved in transporting IgA antibodies across gastrointestinal epithelial cells, highlighting its significance in mucosal immunity within the gut. This process ensures that IgA antibodies produced by plasma cells in the lamina propria can effectively neutralize pathogens and antigens in the gut lumen, contributing to gut homeostasis and protection against infections. 5 The gastrointestinal immune system: T cell-mediated Immunity T cells found: within epithelia throughout lamina propria around and within Peyer’s patches in draining lymph nodes Most intraepithelial T cells are CD8+ Most in / around Peyer’s patches or GALTs are CD4+ Th or Tfh or Treg The speaker is discussing T cell-mediated immunity within the gastrointestinal (GI) tract, emphasizing the localization and function of T cells in different regions of the gut. Here's a breakdown of the key points made by the speaker: 1.Localization of T Cells: T cells are found in various locations within the GI tract, including: 1. Within the epithelium: These intraepithelial T cells are embedded within the epithelial sheet of the gut. They are often CD8-positive (CD8+), which means they are cytotoxic T cells (CTLs) or have the potential to become CTLs upon activation. Intraepithelial T cells play a role in surveillance and defense within the gut epithelial barrier. 2. Throughout the lamina propria: T cells are distributed throughout the connective tissue layer underlying the epithelial cells. In this region, T cells are typically CD4-positive (CD4+), representing T helper cells, T follicular helper cells involved in B cell activation, and regulatory T (Treg) cells responsible for regulating immune responses to maintain tolerance. 3. Within Peyer's patches and other gut-associated lymphoid tissues (GALTs): T cells present in these structures are primarily CD4+ T cells, which include T helper cells, T follicular helper cells, and Treg 6 cells. Peyer's patches are specialized lymphoid structures within the gut that contain B lymphocytes as well, contributing to immune surveillance and responses within the GI tract. 2. Function of Intraepithelial T Cells: Intraepithelial T cells, particularly CD8+ T cells, play a role in cytotoxicity, targeting and eliminating virally infected or abnormal cells within the gut epithelium. These cells are strategically located within the epithelial barrier to provide immediate defense against intracellular pathogens. 3.Function of Lamina Propria and GALT T Cells: T cells within the lamina propria and GALTs, predominantly CD4+ T cells, serve various functions depending on their subtype. T helper cells assist in coordinating immune responses, T follicular helper cells aid in B cell activation and antibody production, and Treg cells regulate immune responses to prevent excessive inflammation and maintain tolerance to harmless antigens, including commensal microbes. 4.Localization-Function Relationship: The speaker highlights that the localization of T cells within different regions of the GI tract is associated with their specific functions. Intraepithelial T cells primarily focus on epithelial defense, while lamina propria and GALT T cells contribute to coordinating immune responses, antibody production, and immune regulation within the gut. Overall, the speaker provides an overview of T cell-mediated immunity in the GI tract, emphasizing the diverse roles and localization of T cells within different gut-associated structures and their contribution to gut immune surveillance and homeostasis. 6 Regulating immune responses in the gut Understanding remains incomplete but key factors include: Abundant regulatory T cells prevent inflammatory actions against commensals Inhibitory cytokines (especially IL-10) from Treg and other cells The commensal microbiome influences gut and systemic immune responses Several inflammatory diseases of the GI tract are related to unregulated responses to commensal organisms or to food antigens in genetically susceptible individuals The speaker is discussing the importance of regulating immune responses in the gut to maintain gut homeostasis and prevent negative consequences associated with excessive inflammation. Here's a breakdown of the key points made by the speaker: 1.Balancing Immune Responses: The speaker emphasizes the need for a balanced immune response in the gut. While it's essential for the immune system to respond to pathogenic organisms, constant activation against commensal microorganisms in the gut can lead to detrimental effects. 2.Regulation of Immune Responses: Several factors are involved in regulating immune responses in the gut: 1. Abundant Regulatory T Cells: Regulatory T cells (Tregs) play a crucial role in preventing inflammatory actions against commensal microorganisms. By limiting the responses of T cells and B cells, Tregs help maintain immune tolerance to harmless antigens. 2. Production of Inhibitory Cytokines: Inhibitory cytokines, such as interleukin-10 (IL-10), have immunosuppressive effects and help dampen inflammatory responses. Tregs are particularly adept at secreting IL-10, but other cells in the gut also produce this cytokine. 3. Influence of the Gut Microbiome: The gut microbiome, consisting of various microorganisms and their 7 metabolic products, can influence immune responses in the gut. The role of the gut microbiome in modulating immune function is an area of active research, and its impact on overall health and disease susceptibility is still being elucidated. 3. Association with Inflammatory Diseases: The speaker highlights that dysregulated immune responses in the gut are associated with inflammatory diseases such as celiac disease, Crohn's disease, and inflammatory bowel disease (IBD). These conditions are characterized by excessive inflammation and immune activation against commensal organisms or food antigens. Genetic susceptibility, along with environmental factors, plays a significant role in the development of these diseases. In summary, the speaker underscores the importance of regulating immune responses in the gut to maintain gut health and prevent inflammatory diseases. Factors such as the presence of regulatory T cells, inhibitory cytokines, and the influence of the gut microbiome contribute to immune regulation in the gastrointestinal tract. Understanding these regulatory mechanisms is crucial for managing gut immune responses and preventing immune-related disorders. 7 Specialized immunity of the respiratory tract Immune responses in alveoli tightly regulated to avoid impacting gas exchange Many similarities to GI mucosa: Relatively impermeable epithelial barriers Secretion of mucus and antimicrobials Localized lymphoid structures Secreted IgA (though not as much as GI) Specialized dendritic cells Reliance on regulatory T cells Wikipedia public domain The speaker is discussing the specialized immunity of the respiratory tract, highlighting similarities to the gastrointestinal mucosa. Here's a breakdown of the key points made by the speaker: 1.Tightly Regulated Immune Responses: Similar to the gut, immune responses in the respiratory tract are tightly regulated to avoid impacting gas exchange. The goal is to maintain homeostasis while still providing protection against pathogens. 2.Similarities to Gastrointestinal Mucosa: The speaker lists several similarities between the respiratory and gastrointestinal mucosa: 1. Relatively impermeable epithelial barriers: Both mucosal surfaces have epithelial barriers that prevent the entry of pathogens and toxins. 2. Secretion of mucus and antimicrobials: Mucus and antimicrobial substances are secreted to trap and neutralize pathogens, aiding in immune defense. 3. Localized lymphoid structures: Similar to Peyer's patches in the gut, the respiratory tract has specialized lymphoid structures that contribute to immune surveillance and responses. 4. Secretion of IgA: While IgA is the primary antibody in the gastrointestinal tract, it is also present in the 8 respiratory system, albeit in smaller amounts. Specialized dendritic cells: Like in the gut, the respiratory tract has specialized dendritic cells that sample microbes in the airways and lungs, initiating immune responses as needed. 6. Reliance on regulatory T cells: Regulatory T cells play a role in limiting excessive immune responses to antigens in the respiratory tract, helping to maintain immune balance. 1.Conceptual Similarities: The speaker emphasizes that while there are differences in the specific mechanisms and components involved, conceptually, the immune responses in the respiratory tract share similarities with those in the gastrointestinal tract. Both systems prioritize protection against pathogens while minimizing immune-mediated damage to the surrounding tissues. In summary, the speaker highlights the parallels between the immune responses in the respiratory and gastrointestinal mucosa, underscoring the importance of tight regulation to maintain homeostasis and ensure effective immune defense without compromising essential physiological functions. 5. 8 Specialized immunity of the respiratory tract Differences from GI regional immunity: Innate immunity Surfactant proteins suppress inflammatory responses Ciliated epithelial cells clear mucus and expel trapped microbes Adaptive immunity IgE and Th2 cells involved in responses to various antigens and allergens IgA often works in collaboration with abundant mast cells The speaker is discussing the specialized immunity of the respiratory tract, highlighting key differences from the gastrointestinal tract. Here's a breakdown of the key points made by the speaker: 1.Surfactant Proteins: Surfactant proteins present in the respiratory tract serve to reduce surface tension and facilitate gas exchange in the lungs. Additionally, some surfactant proteins have the ability to suppress inflammatory responses, helping to regulate immune activity in the respiratory tract. 2.Ciliated Epithelial Cells: The respiratory tract is lined with ciliated epithelial cells that possess cilia on their surface. These cilia beat in coordinated motions, pushing mucus and trapped microbes upwards towards the throat. This mechanism helps to clear the respiratory tract of debris and pathogens, preventing respiratory infections. 3.Role of IgE in Adaptive Immunity: In addition to IgA, the respiratory tract also utilizes IgE in adaptive immune responses. TH2 cells, associated with IgE production, are involved in responses to certain antigens that trigger inflammatory reactions, such as allergies. Mast cells, which are abundant in the respiratory tract, collaborate with IgE to initiate inflammatory and allergic responses when necessary. 4.Collaboration between IgA and Mast Cells: Unlike in the gastrointestinal tract, where IgA primarily interacts with 9 other immune cells, in the respiratory tract, IgA often collaborates with mast cells. Mast cells play a crucial role in allergic reactions by releasing histamines and other inflammatory mediators upon activation by IgE-bound antigens. 5. Specialized Differences: The speaker underscores that while there are similarities between the immune systems of the gastrointestinal and respiratory tracts, there are also specialized differences. These differences reflect the unique functions and challenges faced by each mucosal surface. Understanding these distinctions is crucial for comprehensively understanding mucosal immunity and its role in health and disease. In summary, the speaker highlights the specialized aspects of immunity in the respiratory tract, focusing on mechanisms such as surfactant proteins, ciliated epithelial cells, and the role of IgE and mast cells in allergic responses. These adaptations reflect the respiratory tract's unique needs for maintaining homeostasis and protecting against pathogens and allergens. 9 Immune privilege - protection from immune response Occurs in tissues where inflammation carries high risk of organ damage / failure Examples: eye, brain, testes Not well understood but some common contributing mechanisms: Blood-tissue barrier: tight junctions seal endothelial cells of vasculature Secretion of anti-inflammatory factors / signals that inactivate T cells Reduced dendritic cells, and/or higher threshold for macrophage activation Reduced vasculature and draining lymphatics The speaker is discussing the concept of immune privilege, which refers to the protection from immune responses in certain tissues or organs of the body. Here's a breakdown of the key points made by the speaker: 1.Brain and Testicles: Immune privilege is observed in tissues such as the brain and testicles, where inflammation can lead to significant damage or loss of function. Inflammation in the brain, for example, can result in brain damage, while inflammation in the eye can lead to rapid loss of vision. 2.Mechanisms of Immune Privilege: 1. Blood-Tissue Barrier: The speaker mentions the concept of the blood-tissue barrier, which includes tight junctions sealing endothelial cells in the vasculature of certain tissues like the brain or the eye. This barrier prevents immune cells from exiting the bloodstream and entering the tissue, thereby reducing the likelihood of inflammation. 2. Secretion of Anti-inflammatory Signals: Some tissues secrete molecules that inhibit inflammatory responses or deactivate T cells locally. This limits the extent of immune activation within the tissue. 3. Reduced Numbers of Dendritic Cells: Certain tissues have fewer dendritic cells, which are crucial for antigen detection and presentation. With reduced dendritic cell numbers, there is less initiation of 10 immune responses. Higher Thresholds for Activation of Innate Immune Cells: Some tissues have higher activation thresholds for innate immune cells like macrophages, making them less responsive to immune signals. 5. Reduced Vasculature and Lymphatics: Immune-privileged tissues may have fewer blood vessels and lymphatic drainage, limiting the movement of immune cells into and out of the tissue. 1.Ongoing Research: The speaker emphasizes that immune privilege is still not fully understood and remains an area of active research. While it was previously thought that immune cells had minimal interactions with certain tissues like the brain, recent studies have revealed more complex mechanisms at play. In summary, immune privilege refers to the protective mechanisms that limit immune responses in specific tissues to prevent damage or dysfunction. These mechanisms include barriers to immune cell entry, secretion of anti-inflammatory signals, reduced numbers of immune cells, and limited vascular and lymphatic supply. Ongoing research seeks to further elucidate the intricacies of immune privilege and its implications for health and disease. 4. 10 Immune privilege - protection from immune response Fetal immune privilege Fetus expresses paternally-inherited genes foreign to the mother Not well understood but possible mechanisms include: reduced antigen presentation reduced expression of costimulators active regulatory T cells The speaker discusses immune privilege in the context of protecting from immune responses against paternally inherited genes or foreign antigens present in the fetus. Here's a breakdown of the mechanisms involved: 1.Reduced Antigen Presentation: There is some evidence suggesting that there is reduced antigen presentation of paternally inherited genes to the mother's immune system. This means that these antigens are not presented as effectively, potentially reducing the likelihood of immune recognition and response. 2.Reduced Expression of Co-stimulators: Co-stimulators are molecules involved in the activation of antigenpresenting cells (APCs), which then activate T cells and B cells. In the context of immune privilege, there may be reduced expression of co-stimulators in response to antigens from the fetus. This diminishes the activation of the immune response against these antigens. 3.Role of Regulatory T cells (Tregs): Regulatory T cells play a crucial role in suppressing immune responses and maintaining immune tolerance. In the context of immune privilege associated with paternally inherited genes or fetal antigens, active regulatory T cells may help suppress the immune response, preventing excessive reactions against foreign antigens. These mechanisms collectively work to limit the immune response against paternally inherited genes or foreign 11 antigens present in the fetus, thereby contributing to immune privilege and protecting the developing fetus from maternal immune attack. While not fully understood, these mechanisms represent ways in which the maternal immune system is regulated to maintain tolerance towards the fetus. 11