Immunology Study Guide Lecture 20 PDF

Complement activation depends on a proteolytic cascade IgG or IgM Proteolysis Signal amplification complement activation involves a proteolytic cascade, which refers to a series of enzymatic reactions that occur sequentially. This cascade leads to the activation of various complement proteins, ultim...

Complement activation depends on a proteolytic cascade IgG or IgM Proteolysis Signal amplification complement activation involves a proteolytic cascade, which refers to a series of enzymatic reactions that occur sequentially. This cascade leads to the activation of various complement proteins, ultimately resulting in several effector mechanisms. Here's a breakdown of the key points discussed in the text: 1.Proteolytic Cascade: Complement activation begins with the cleavage of one complement protein by an enzyme, leading to the activation of another complement protein. This process continues in a cascade fashion, amplifying the complement response. 2.Complement Proteins: Complement proteins circulate in the serum and extracellular fluid. They include various components such as C3, C4, C5, and so on. Each complement protein plays a specific role in the complement cascade. 3.Effector Mechanisms: Upon activation, complement proteins initiate several effector mechanisms: 1. Inflammation: Complement activation can trigger inflammation, which is a key aspect of the innate immune response. Inflammation helps recruit immune cells to the site of infection or injury. 2. Opsonization: Complement proteins can coat pathogens with opsonins, such as C3b, making them more susceptible to phagocytosis by immune cells such as macrophages and neutrophils. 1 3. Phagocytosis: Opsonized pathogens are engulfed and destroyed by phagocytes, a process known as phagocytosis. This helps eliminate pathogens from the body. 4. Membrane Attack Complex (MAC): The final step of complement activation involves the formation of the membrane attack complex (MAC). The MAC assembles on the surface of pathogens and creates pores in their membranes, leading to cell lysis and destruction. These effector mechanisms collectively contribute to the elimination of pathogens and the initiation of an appropriate immune response. Complement activation is crucial for host defense against infections and plays a significant role in immune surveillance and homeostasis. 1 Functions of complement (1) Activating signals neutrophils and macrophages The function of complement, specifically C3b, involves opsonization, which is the process of coating pathogens with opsonins to facilitate their recognition and ingestion by phagocytes. Here's a breakdown of the process: 1.C3b Deposition: During complement activation, the complement protein C3 is cleaved to form C3b. C3b binds covalently to the surface of pathogens, marking them for recognition by phagocytes. 2.Phagocyte Recognition: Phagocytes, such as macrophages and neutrophils, express receptors for C3b on their surface. These receptors, known as C3b receptors or complement receptors, recognize and bind to the C3b-coated pathogens. 3.Signaling and Phagocytosis: Binding of C3b to its receptor on the phagocyte initiates signaling processes within the cell. These signaling events trigger cytoskeletal rearrangements and membrane protrusions, allowing the phagocyte to engulf the opsonized pathogen. 4.Phagocytosis and Destruction: Once engulfed, the pathogen is contained within a phagosome, a vesicle formed 2 from the cell membrane. The phagosome then fuses with lysosomes, forming a phagolysosome. Within the phagolysosome, the pathogen is exposed to a variety of antimicrobial substances, including reactive oxygen species and hydrolytic enzymes, leading to its destruction. In summary, complement opsonization enhances the recognition and uptake of pathogens by phagocytes, promoting their destruction and clearance from the body. This process is essential for effective host defense against microbial infections. 2 Functions of complement (2) C3A AND C3b = “anaphylatoxins” Degranulation of mast cells relases multiple “vasoactive mediators” (example histamine) And activation of endotheilial cells The function of complement #2 involves the stimulation of inflammatory reactions, which is crucial for the host defense against pathogens. Here's a breakdown of the process: 1.C3b Binding and Proteolysis: When C3b binds to the surface of a microbe, proteolysis occurs, resulting in the generation of C3a and subsequent C5a. 2.Anaphylatoxins: C3a and C5a are referred to as anaphylatoxins because they can induce potent inflammatory responses. They act as signaling molecules that recruit and activate various cells involved in inflammation. 3.Recruitment and Activation of Leukocytes: Neutrophils and mast cells, key components of the innate immune system, express receptors for C3a and C5a. Binding of these anaphylatoxins to their receptors promotes the recruitment and activation of these leukocytes at the site of infection. 4.Activation of Endothelial Cells: C3a and C5a can also activate endothelial cells lining blood vessels. This activation leads to increased vascular permeability and the expression of adhesion molecules, facilitating the recruitment of additional immune cells to the site of infection. 5.Release of Vasoactive Mediators: Mast cells, when activated by C3a and C5a, undergo degranulation, releasing vasoactive mediators such as histamine. These mediators promote vasodilation and increase vascular permeability, 3 allowing immune cells and molecules to access the site of infection more effectively. 6. Microbe Destruction: The inflammatory response initiated by complement activation ultimately leads to the destruction of microbes. Neutrophils, for example, engulf and destroy pathogens through phagocytosis, while mast cells release antimicrobial molecules to eliminate microbes. Overall, complement activation and the subsequent release of anaphylatoxins play a crucial role in initiating and amplifying inflammatory responses, which are essential for combating infections. However, excessive or dysregulated complement activation can contribute to inflammatory diseases and conditions such as anaphylactic shock, highlighting the importance of tight regulation of the complement system. 3 Functions of complement (3) Various bacteri ahave evolved thich cell walls or capsules that impede MAC formation MAC relsted tomprforin Creates o\pores in mivrobial cell membrane Poe\res allow movement of water into cell Function of complement #3 involves the formation of the membrane attack complex (MAC), which plays a critical role in directly killing target cells, particularly bacteria. Here's how the process unfolds: 1.C3b Binding and Activation: Initially, C3b binds to the surface of the bacterial cell, marking it for destruction. This binding event triggers the activation of other complement components, leading to the assembly of the membrane attack complex. 2.Assembly of the Membrane Attack Complex (MAC): The membrane attack complex consists of several complement proteins, including C5b, C6, C7, C8, and multiple molecules of C9. These components assemble into a pore-like structure on the surface of the bacterial cell membrane. 3.Pore Formation and Osmotic Lysis: Once assembled, the MAC inserts into the lipid bilayer of the bacterial cell membrane, forming a channel or pore. This pore disrupts the integrity of the bacterial membrane, causing an imbalance in ion concentrations and water influx. As a result, the bacterial cell swells and eventually ruptures, leading to osmotic lysis and cell death. 4.Role of Pore-forming Proteins: The pore-forming protein in the membrane attack complex, known as perforin, functions similarly to certain immune cells' proteins that create pores in target cell membranes. These pores 4 disrupt the target cell's osmotic balance, leading to cell lysis. 5. Bacterial Resistance Mechanisms: Some bacteria have evolved mechanisms to evade complement-mediated killing. For example, they may possess thick cell walls or capsules that impede MAC insertion, preventing osmotic lysis. This resistance allows certain bacteria to survive immune attack and cause infections. Overall, the membrane attack complex represents a potent effector mechanism of the complement system, directly targeting and destroying pathogens. However, bacterial resistance mechanisms highlight the ongoing evolutionary arms race between host immunity and microbial pathogens. 4 Regulation of complement Activation of complement is tightly regulated to: prevent activation on normal host cells limit duration of complement activation to prevent unintended damage Mediated by several circulating and cell membrane proteins => Each inhibits specific activity or assembly Certain microbes have evolved mechanisms to manipulate complement regulation Some recruit host complement regulatory proteins Others express proteins that mimic complement regulatory proteins Regulation of complement activation is crucial to prevent unintended damage to normal host cells and to limit the duration of complement activity. Here's how complement activation is regulated: 1.Complement Regulatory Proteins: These proteins circulate in the blood and other bodily fluids, while others are found on the surface of cells. They play a key role in inhibiting complement activation or preventing the assembly of the membrane attack complex (MAC). Depending on the specific regulatory protein, they may inhibit proteolytic activity of complement proteins or interfere with MAC formation. 2.Inhibition of Proteolytic Activity: Some complement regulatory proteins inhibit the proteolytic activity of certain complement proteins involved in the amplification pathway cascade. By doing so, they prevent excessive complement activation. 3.Prevention of MAC Formation: Other complement regulatory proteins interfere with the assembly of the membrane attack complex. This prevents the formation of pores in the membranes of normal host cells, protecting them from damage. 4.Microbial Evasion Mechanisms: Certain microbes, including bacteria, have evolved strategies to manipulate complement regulation to their advantage. Some bacteria can recruit complement regulatory proteins to their 5 surface, mimicking the protective mechanism seen in host cells. Additionally, certain pathogens express proteins that mimic complement regulatory proteins found in the host, effectively inhibiting complement activation and protecting the microbe from immune attack. Overall, complement regulation is essential for maintaining immune homeostasis and preventing excessive tissue damage. However, microbial evasion mechanisms highlight the ongoing arms race between host immunity and pathogens, emphasizing the complexity of host-pathogen interactions. 5 Specialized Immunity Regional Immune Systems Privileged Tissues Regional immune systems refer to specialized immune responses that occur in specific parts of the body, tailored to the unique challenges and functions of those regions. There are two main categories of regional immune systems: 1.Mucosal Immune System: This system is primarily located in mucosal tissues, such as the gastrointestinal tract, respiratory tract, and urogenital tract. It is responsible for defending against pathogens that enter the body through these mucosal surfaces. The mucosal immune system includes specialized structures like Peyer's patches in the gut and tonsils in the respiratory tract, as well as secretory IgA antibodies that help neutralize microbes in mucosal secretions. 2.Cutaneous Immune System: This system is found in the skin and provides protection against pathogens that come into contact with the skin's surface. It includes various immune cells, such as Langerhans cells and dendritic cells, as well as antimicrobial peptides and other factors that help defend against infection. Regional immune systems play a crucial role in maintaining health and preventing infection in their respective tissues. They are specialized to respond rapidly and effectively to pathogens that may enter the body through these specific routes. Understanding the function and regulation of regional immune systems is essential for developing strategies to combat infections and promote overall health. 6 6 Regional immune systems Provide protection against microbial challenges encountered at certain locations Allow for appropriate balance with nonpathogenic commensal organisms Examples: Mucosal epithelial barriers: gastrointestinal, respiratory, urogenital Cutaneous (skin) Regional immune systems share certain basic features But each system contains specialized anatomic features, cell types, and molecules Regional immune systems refer to specialized immune responses that occur in specific anatomical regions of the body, such as mucosal epithelial barriers (e.g., gastrointestinal tract, respiratory tract, urogenital tract) and the skin. These systems are responsible for defending against pathogens that may enter the body through these particular routes. Key points about regional immune systems include: 1.Balancing Act: There is a delicate balance between mounting immune responses to pathogens and tolerating commensal organisms, which are normal inhabitants of these regions. The immune system must distinguish between harmful pathogens and harmless commensals to avoid unnecessary inflammation and tissue damage. 2.Specialized Features: Each regional immune system has unique characteristics and adaptations tailored to the specific challenges and functions of its respective tissue. For example, mucosal epithelial barriers produce mucus to trap and expel microbes, while the skin acts as a physical barrier against pathogens. 3.Shared Basic Features: Despite their differences, all regional immune systems share certain fundamental features, such as the presence of immune cells, production of antimicrobial peptides, and activation of inflammatory responses when necessary. 7 4. Location-Specific Functions: The types of pathogens and microbes encountered in each anatomical region vary, leading to location-specific immune responses. For instance, the gut is exposed to a diverse array of commensal bacteria, while the skin encounters environmental pathogens and microorganisms. Understanding the function and regulation of regional immune systems is essential for maintaining overall health and preventing infections in these vulnerable anatomical sites. These systems represent critical barriers that protect the body from external threats while maintaining a beneficial relationship with commensal organisms. 7 Challenges for GI immunity Large surface area to defend Abundance and diversity of nonpathogenic, commensal microbes Ongoing exposure to diverse food antigens Opportunistic infections and constant exposure to antigens Inflammation has negative impact on necessary GI functions => Must limit response to commensal and food antigens => But must still be able to detect small pathogen antigen “signals” amongst background The gastrointestinal (GI) immune system faces several challenges due to the unique environment of the gut: 1.Large Surface Area: The GI tract comprises a vast surface area, roughly equivalent to the size of a tennis court. Defending such a large area against pathogens and antigens requires robust immune defenses. 2.Abundance of Commensal Microbes: The gut is home to a diverse population of commensal microbes, which play essential roles in digestion and metabolism. However, the immune system must distinguish between harmless commensals and potentially harmful pathogens. 3.Constant Exposure to Antigens: The GI tract is constantly exposed to antigens from ingested food, commensal microbes, and other environmental sources. This continuous exposure requires the immune system to make decisions about whether to mount a response or maintain tolerance. 4.Opportunistic Infections: Some commensal microbes have the potential to cause opportunistic infections if the immune system is compromised. Balancing immune responses to prevent opportunistic infections while maintaining tolerance to commensals is crucial. 5.Inflammation and Gastrointestinal Function: Excessive inflammation in the gut can disrupt normal gastrointestinal function and lead to conditions such as inflammatory bowel disease (IBD), Crohn's disease, and 8 celiac disease. The GI immune system must carefully regulate its responses to prevent inflammation-related damage. Overall, the GI immune system faces the challenge of maintaining a delicate balance between protecting against pathogens and tolerating commensal microbes and dietary antigens. Failure to properly regulate immune responses can lead to inflammatory disorders and compromise gastrointestinal function. 8 The gastrointestinal immune system Barrier Peyers patch - Organized secondary lympjoid tissue - Ontains B cells and t cells, DCs and macrophages Connective tissue innate and adaptive cells lympathics blood vesslees “mucosal-associated lymphoid tissue” = MALT “gut-associated lymphoid tissue” = GALT The gastrointestinal (GI) immune system consists of several key components that work together to protect the body from pathogens while maintaining tolerance to harmless antigens such as commensal bacteria and dietary molecules. Here's an overview of the basic components: 9 1. Mucosal Epithelium: The mucosal epithelium lines the inner surface of the GI tract and serves as a physical barrier to prevent the entry of pathogens into the body. It is reinforced by tight junctions between epithelial cells. 2.Mucus Layer: Situated atop the mucosal epithelium, the mucus layer provides an additional protective barrier. It helps trap and eliminate pathogens, and it also contains antimicrobial molecules to inhibit microbial growth. 3.Lamina Propria: Beneath the mucosal epithelium lies the lamina propria, a connective tissue layer 9 that supports the epithelial barrier. The lamina propria contains various types of immune cells, including innate immune cells (e.g., macrophages, mast cells) and adaptive immune cells (e.g., T cells, B cells). 4. Peyer's Patches: Peyer's patches are specialized structures of organized secondary lymphoid tissue found in the lining of the small intestine, particularly in the ileum. They contain B cells, T cells, dendritic cells, and macrophages, resembling lymph nodes. Peyer's patches play a crucial role in initiating immune responses to antigens encountered in the 9 gut. 5. Mucosal-Associated Lymphoid Tissue (MALT): MALT refers to the collective lymphoid tissue associated with mucosal epithelia throughout the body. In the context of the GI tract, it specifically includes structures like Peyer's patches and other mucosa-associated lymphoid aggregates. 6.Mesenteric Lymph Nodes: Located in the mesentery, which attaches the intestines to the abdominal wall, mesenteric lymph nodes are conventional lymph nodes deeper within the body. They receive lymphatic drainage from the GI tract 9 and serve as sites for immune cell activation and antigen presentation. Overall, the GI immune system is intricately organized to effectively combat pathogens while maintaining tolerance to harmless antigens. Specialized structures like Peyer's patches and the presence of diverse immune cell populations in the lamina propria contribute to the system's ability to mount appropriate immune responses in the gut. 9 The gastrointestinal immune system: Innate Immunity 1. Barrier aspects Mucus secreted by Goblet cells Defensins secreted by Paneth cells Epithelial sheet sealed by tight junctions Basement membrane (ECM) In the gastrointestinal (GI) immune system, innate immunity plays a critical role in providing immediate defense against pathogens and maintaining tissue homeostasis. Here are some key aspects of innate immunity in the GI tract: 1.Epithelial Barrier: The mucosal epithelium of the GI tract acts as the first line of defense against pathogens. It forms a physical barrier that prevents the entry of microorganisms into the underlying tissues. Specialized epithelial cells, such as goblet cells, produce mucus that traps and removes pathogens, while enterocytes express tight junctions that seal the intercellular spaces and prevent microbial translocation. 2.Pattern Recognition Receptors (PRRs): Epithelial cells and resident immune cells in the lamina propria express PRRs, such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs). These receptors recognize conserved microbial structures, known as pathogen-associated molecular patterns (PAMPs), present on the surface of pathogens. Activation of PRRs triggers signaling pathways that induce the production of antimicrobial peptides, cytokines, and chemokines, promoting inflammation and recruitment of immune cells to the site of infection. 3.Antimicrobial Peptides (AMPs): The GI tract produces various AMPs, such as defensins, cathelicidins, and lysozyme, which exhibit broad-spectrum antimicrobial activity against bacteria, fungi, and viruses. These peptides 10 are secreted by epithelial cells and immune cells, contributing to the maintenance of microbial balance and protection against pathogens. 4. Phagocytic Cells: Macrophages and dendritic cells residing in the lamina propria are crucial phagocytic cells that engulf and eliminate invading pathogens. Macrophages play a key role in scavenging debris, producing pro-inflammatory cytokines, and presenting antigens to adaptive immune cells. Dendritic cells sample luminal antigens and migrate to secondary lymphoid organs to initiate adaptive immune responses. 5.Inflammatory Mediators: In response to infection or tissue damage, innate immune cells release pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) and chemokines that recruit neutrophils, monocytes, and other immune cells to the site of inflammation. These mediators enhance phagocytosis, promote tissue repair, and contribute to the elimination of pathogens. 6.Natural Killer (NK) Cells: NK cells are innate lymphoid cells that play a role in immune surveillance and cytotoxicity. They can directly kill infected or transformed cells without prior sensitization, contributing to the elimination of intracellular pathogens and tumor cells in the GI tract. Overall, innate immunity in the GI tract orchestrates rapid and effective responses to microbial challenges, helping to maintain gut homeostasis and protect against infections. These innate immune mechanisms work in concert with adaptive immunity to provide comprehensive immune surveillance and defense in the GI mucosa. 10 The gastrointestinal immune system: Innate Immunity TLR’s and other PAMP / DAMP receptors on various cells trigger innate immune response to pathogens BUT inflammatory response to commensals is limited by multiple mechanisms: TLRs on basolateral surface of epithelial cells TLRs IN GI tract requires high threshold for activation phagocytes secrete IL-10 (inhibitory cytokine) In the gastrointestinal (GI) immune system, it's crucial to balance the response to pathogens while avoiding excessive inflammation in response to commensal microbes. Toll-like receptors (TLRs) play a key role in detecting pathogens and triggering immune responses. However, several mechanisms exist to limit inflammatory responses to commensal microbes: 1.Localization of TLRs: TLRs on epithelial cells are primarily located on the basolateral surface, facing away from the lumen of the gut. This positioning ensures that TLRs only become activated when microorganisms breach the epithelial barrier and reach the underlying tissue. The apical surface, which directly interacts with the gut lumen, lacks TLR expression, preventing unnecessary activation by luminal contents. 2.Higher Activation Threshold: TLRs expressed in the GI tract have higher activation thresholds compared to those in other tissues. This means that they require a higher concentration of microbial products (PAMPs) to trigger a response. By setting a higher threshold, the immune system ensures that only significant microbial challenges provoke a response, reducing the risk of overreacting to harmless commensals. 3.Phagocyte-Mediated Regulation: Phagocytes, such as macrophages, play a dual role in the gut immune response. While they are capable of killing microbes, they also produce inhibitory cytokines that dampen 11 inflammation. This unique feature of gut-resident phagocytes helps to suppress excessive inflammatory responses even during microbial encounters. Overall, these mechanisms allow the GI immune system to discern between pathogenic threats and harmless commensals, thereby minimizing unnecessary inflammation and preserving gut homeostasis. If you have any further questions or need clarification on specific points, feel free to ask! 11 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 T reg cells act to control inflammatory reactions In the gastrointestinal (GI) immune system, adaptive immunity plays a crucial role, particularly through the production of antibodies, primarily Immunoglobulin A (IgA), and the presence of regulatory T cells (Tregs). 1.Production of IgA: IgA is the predominant antibody produced by the GI-associated immune system. B cells in the gut region undergo class switching to produce IgA under the conditions specific to the gut environment. This class switching allows B cells to switch from producing other types of antibodies (e.g., IgM, IgG) to IgA. Additionally, IgAexpressing B cells that leave the gut tend to return to the gut due to chemotaxis, further contributing to IgA production in the gut-associated lymphoid tissue. 2.Role of IgA: IgA antibodies produced in the gut are directed against microbes present in the gut lumen. These antibodies help to neutralize and eliminate pathogens, as well as prevent the adherence and colonization of harmful microbes on the epithelial surfaces of the gut. 3.Regulatory T Cells (Tregs): The GI tract contains a relatively abundant population of Tregs compared to other locations in the body. Tregs play a critical role in controlling inflammatory reactions within the gut. They suppress 12 the activity of other immune cells, particularly effector T cells, helping to maintain immune tolerance and prevent excessive inflammation in response to commensal microbes and dietary antigens. Overall, the production of IgA and the presence of Tregs are key components of adaptive immunity in the GI tract. IgA antibodies contribute to the defense against pathogens and maintenance of gut homeostasis, while Tregs help to regulate immune responses and prevent inflammatory damage to the gut tissue. If you have any further questions or need clarification on specific points, feel free to ask! 12