4- Immunology- Pt 1B.docx

- **Innate Immunity: Pathogen Recognition** - **PAMPs (pathogen associated molecular patterns)** are components that are shared between different types of pathogens and present a molecular composition that differs from self. - They are only found in microbes and a...

- **Innate Immunity: Pathogen Recognition** - **PAMPs (pathogen associated molecular patterns)** are components that are shared between different types of pathogens and present a molecular composition that differs from self. - They are only found in microbes and are not normally within the normal body cells. - PAMPs play the role of recognizing pathogens. - **DAMPs (damage associated molecular patterns)** are released when cells die (intracellular DAMPs) or are generated when connective tissue is damaged (extracellular DAMPs). - DAMPs play a role in recognizing damage to your own cells. - **PRRs (pattern recognition receptors)** are receptors of innate immunity that recognize PAMPs and DAMPs. - PRRs can be soluble, or membrane bound. - They are found in various areas of the body (intracellular or membrane bound). - PRRs can be phagocytic or play a signaling role. - Signaling: PRRs signal cytokine production and granule release. - If phagocytic, PRRs are located on the cell surface. - **Sentinel Cells** - Sentinel cells are cells that have high quantities of PRRs, which allow them to have a better "surveillance" for PAMPs and DAMPs. - Sentinel cells are majorly involved in immune surveillance and threat recognition. - Examples of sentinel cells include: dendritic cells, macrophages, and mast cells. - All of these cells recognize the PAMPs and DAMPs, they activate pro-inflammatory and antimicrobial mediators (responses). - These cells (mast cells, dendritic cells, and macrophages) are the sources of the following mediators: histamine, cytokines, and prostaglandins. - **Innate Immunity: Inflammation** - Inflammation happens once sentinel cells are exposed to PAMPs, DAMPs, or pr-inflammatory cytokines. - Inflammation needs to be strictly regulated to only 1 site, rather than becoming systemic. - **Systemic inflammation** will always occur from any inflammation; however, uncontrolled systemic inflammation is problematic. - Inflammation of the hypothalamus can lead to fever, anorexia, sleepiness, and depression. - Inflammation of the liver can lead to increased synthesis of acute-phase proteins, and iron sequestration. - Inflammation of the bone marrow can lead to increased white cell production. - Cell activation results in the upregulation of antimicrobial defenses, and the release of pro-inflammatory chemokines, lipid mediators, and cytokines. - The more pathogens that are bound to PAMPs and DAMPS, the more mediators that get produced, and the longer the cycle of inflammation continues. - Without pathogen presence, no stimulation will occur, and therefore, the cycle of inflammation will never start, or would stop the cycle if it had already been started. - **Mast cells** are vasoactive molecules that release histamines and serotonin. - The release of these things will cause vasodilation and increased vascular permeability, allowing neutrophils to leave the blood vessels and travel towards the microbes. - The more leukocytes arriving, the easier it is to migrate to the tissue. - **Chemokines** are a type of cytokine that guides and directs leukocyte migration towards pathogens/microbes. - Chemokines bind to neutrophil receptors and alters the cytoskeleton of the neutrophil which propels the neutrophil to move in the direction of the microbe (following the concentration gradient). - **Inflammation: Leukocyte Kinetics** - Step 1: Neutrophils predominate during acute inflammation, using phagocytosis to kill pathogens. - This is an innate immune response. - Step 2: Monocytes/Macrophages predominate at the later stages of inflammation. - This is an innate immune response - Monocytes are present in the blood. - Macrophages are the form of monocytes once they are out of the blood. - Step 3: Lymphocytes are present once the adaptive immune system is engaged in the response. - This is an adaptive immune response. - The lymphocytes include: B cells, cytotoxic T cells, and helper T cells. - **Innate Immunity: Phagocytosis** - Phagocytosis is an active process of capturing and ingesting foreign objects/microbes by phagocytes such as neutrophils and macrophages. - Phagocytosis involves the destruction of microorganisms, damaged cells and cellular debris, and foreign objects. - Phagocytosis induced cytokine production. - Phagocytosis involved processing and presentation of antigens. - Processing: breaking the microbe down - Presentation: Showing antigens (on the surface of macrophages) to T cells. - **Phagocytosis: Steps** - Step 1: The phagocyte detects and binds to their target. - Step 2: It surrounds the captured object with pseudopodia and engulfs the object via endocytosis. - Step 3: The endocytosed object becomes enclosed in the phagosome. - Step 4: The phagosome fuses with the lysosome to form a phagolysosome. - Step 5: The contents of the lysosome are released into the phagolysosome. - **Phagocytosis: Intracellular Killing Mechanisms** - Phagocytosis utilizes an **oxidative pathway**. - **Respiratory burst** is when the use of oxygen and glucose increases several fold. - Phagocytosis keeps ROS (reactive oxygen species) and RNS (reactive nitrogen species) contained, preventing them from spreading toxins to other parts of the body. - Phagocytosis utilizes a **non-oxidative pathway** which is dependent on the actions of the toxic substances present in lysosomes. - Cationic proteins: damage the bacterial cell wall - Lysozyme: damaged the mucopeptides in the bacterial cell wall - Lactoferrin: sequestrates iron, thus inhibiting bacterial growth - Proteolytic and hydrolytic enzymes: digest killed bacteria - **Innate Immunity: Complement System** - The complement system is a collection of circulating ans membrane-associated proteins, with activation that occurs in a sequential manner. - Many complement proteins are proteolytic enzymes. - 3 possible activation pathways: Alternative pathway, Classical pathway, and Lectin pathway - All of the above activation pathways will have the same outcome, however, they way they start varies. - The alternative and lectin pathways are both activated by microbe interaction, making them part of the innate immune response. - **Alternative pathway** - This pathway involves complement proteins being activated on microbial surfaces (because complement regulatory proteins are not present on microbes, only host cells). - **Lectin pathway** - This pathway involves activation when a carbohydrate-binding plasma protein, MBL (mannose-binding lectin), binds to terminal mannose residues on the surface glycoproteins. - **Classical pathway** - This pathway involves activation by antibodies that bind to microbes or other antigens. - This pathway requires antibody presence, making it part of the adaptive immune system. - **Immune System: General Info** - The **MAC (membrane attack complex)** breaches the cell membrane of microbes, allowing water to rush into the cell, and causes destruction by osmotic lysis. - **NK (natural killer) cells** are apart of the innate immune system. - Healthy host cells will always have **MHC1**, while infected or mutated cells will either have an altered MHC1 or activating ligands. - NK cells go around the body, checking for MHC1. - Viruses and cancer tend to remove MHC1, so when NK cells see that it is missing, they take action to eliminate that cell. - Inhibitory receptors for NK cells.