Immune System and Phagocytes PDF

- - - - B cells: originate and mature in bone marrow - T cells: originate in bone marrow, but mature in thymus - Bone marrow and thymus are primary lymphoid organs - Each lymphocyte produces a unique protein that interacts with a single antigenic determinant - T cells: T cell receptors - B cells:...

- - - - B cells: originate and mature in bone marrow - T cells: originate in bone marrow, but mature in thymus - Bone marrow and thymus are primary lymphoid organs - Each lymphocyte produces a unique protein that interacts with a single antigenic determinant - T cells: T cell receptors - B cells: antibodies or immunoglobulins Phagocytes and microbial invasion - Innate immunity is primarily driven by the activities of phagocytes - Phagocytes recognize common structural features found on pathogens - Respond within minutes - Phagocyte-pathogen interactions: result in activation of genes and translation of proteins that eventually lead to the destruction of the pathogen - Not always effective in controlling infection - Certain phagocytes can activate adaptive immunity by processing and presenting antigens to receptors on T lymphocytes - Microbial invasion is the ability of a pathogen to enter host cells or tissues, multiply, spread, and cause disease Recruitment of phagocytes - Tissue damage, such as caused by puncture wound, can lead by invasion by microorganisms, - Resident leukocytes and damaged cells release cytokines and chemokines - a subclass of cytokines that attract circulating immune cells to the site of injury - Phagocytes, in response to the cytokine-chemokine gradient, are recruited to the site of injury and squeezed out of the blood capillaries, - The invading phagocytes are cleared by the phagocytes Pathogen recognition - Phagocytes must be able to recognize, capture, and destroy pathogens to clear infection and restore body tissue to a healthy state - Pathogen-associated molecular pattern: pathogens have structures and molecules not found in or on host cells (e.g., peptidoglycan, flagella, dsRNA (virus)) - Lipopolysaccharide of outer membranes of Gram negative bacteria is a common pathogen-associated molecular pattern - Pattern recognition receptors: leukocytes have membrane bound or soluble proteins that recognize pathogen-associated molecular pattern - Binding of pattern-associated molecular pattern by pattern-recognition receptors stimulates the phagocytes to engulf and destroy the pathogen - Toll-like receptors: a class of pattern recognition receptors - Each toll-like receptor on a human phagocyte recognizes and interacts with a specific pathogen-associate molecular pattern - Upon encountering a pathogen-associate molecular pattern, the toll-like receptor sends a signal to the nucleus Phagocyte signal transduction - Signal transduction in phagocyte: upon activation of toll-like receptors, a leukocyte will start a phosphorylation cascade to transmit the activation signal to the nucleus, - which will activate transcription factors to turn on genes in response to the activation signal - NFκB (nuclear factor kappa-light-chain-enhancer) is a key transcription factor that is activated in many different pathways Phagocytosis and phagolysosomes - Upon recognition of pathogen-associated molecular patterns by their toll-like receptors, phagocytes engulf the pathogens - Phagosome: the membrane-bound vesicle that surrounds the bacterium - The phagosome fuses a lysosome to form a phagolysosome - Phagocyte produces toxic reactive oxygen intermediates to kill the bacteria within a phagolysosome; - thus preventing damage to the phagocyte itself Phagocyte inhibition - Some pathogens can survive the phagolysosome - Mycobacteria tuberculosis: produces carotenoids to neutralize singlet oxygen and has a waxy cell wall that absorbs free radicals. This pathogen lives and divides within phagocytes - Some pathogens such as Streptococcus pyrogenes: produce leukocidins, which kill white blood cells. Dead white blood cells are found in pus - Some pathogens contain a capsule, which makes it difficult for the phagocyte to engulf them Inflammation: a nonspecific reaction to noxious stimuli (e.g., physical injury, toxins, and pathogens) - Local infection leads to inflammation in a small part of the body, followed by healing - Cytokines and chemokines released by injured cells and phagocytes draw white blood cells to a site of inflammation - Leukocytes at the site of infection release proinflammatory cytokines including interleukin-1 (IL-1) - The cytokines increase vascular permeability causing swelling, pain, and heat localized at site of infection - The pressure associated with swelling force fluids away from the blood vessels and into the lymphatic system - Strengthen immune response - Prevent the spread of pathogens to the bloodstream - Effective inflammatory response isolates and limits tissue damage, destroying damaged cells and pathogens Systemic inflammation and septic shock - Systemic inflammation: occurs when the inflammatory response fails to localize the pathogens and the reaction spreads throughout the body (leads to inflammation and disease throughout the body) - Inflammatory cells and mediators spread throughout the entire circulatory and lymphatic systems - Can lead to septic shock - SS: when increased vascular permeability resulting in a decrease of blood pressure, which can cause damage to multiple organs at the same time - Gram-negative bacteria: contain LPS, which triggers a proinflammatory cytokine response from leukocytes as their Toll-like receptors are activated - leads to a cytokine storm, which can be fatal. - Example: Salmonella species or Escherichia coli, which can be introduced into the peritoneal cavity or the bloodstream by a ruptured or leaking bowel Fever - Inflammatory response can induce fever because of released Cytokines, such as interleukin-1 and interleukin-6, - Fever: a condition of elevated body temperature - These cytokines stimulate the hypothalamus, the temperature control centre of the brain, to produce prostaglandins - Prostaglandins are chemical signals that raise the body temperature - Benefits of fever - Increases circulation rate, expedites leukocytes to get to the site of infection - Reduce the growth of pathogens because they do not tolerate the higher temperature - Increase in transferrins, which bind and sequester iron, thereby depriving pathogens of this important nutrient The complement system - Complement (C’) or the complement system: a set of circulating, inactive proteins that are sequentially activated in response to a pathogen - Functions to boost the efficiency of both the innate and adaptive immune responses for the destruction of pathogens - Three pathways: - a) The sequence, orientation, and activity of the components of the classical complement pathway. - b) The mannose-binding lectin pathway. - c) The alternative pathway - 3 OUTCOMES - Complement C3b coating the target making it easier for phagocytes to engulf it - Complement C3a diffuses to the surrounding area serving as a chemoattractant - Complement C5a binding to the target forming the membrane attack complex, resulting in cell lysis Natural killer cells: cytotoxic lymphocytes - Major Histocompatibility Complex I (MHC1 proteins): All nucleated cells have on their surface - Many virus-infected cells and tumour cells do not have MHC I proteins and produce a stress protein genes - When encountering a cell with stress proteins and without MHC I proteins, a natural killer cell will activate and destroy the target by producing: - Granzyme: an enzyme that induces apoptosis (programmed cell death) - Perforin: pokes holes in the target membrane Interferons: small cytokine proteins produced by virally infected cells - serve as a warning system and prevent viral replication by stimulating the production of antiviral proteins in uninfected cells once they receive the interferon signal from infected cells Lecture 19 – Adaptive immunity: highly specific host defense What is part of our cells n helps vs is acc immunity. - innate immunity: broadly targeted responses triggered by general features of microorganisms - Adaptive immunity: directed toward specific molecular components of the microbes mediated by a special class of antigen-reactive leukocytes called lymphocytes - B lymphocytes: from bone marrow and mature in bone marrow, produce antibodies (soluble in blood stream) that interact and protect against extracellular antigen - Conferring antibody-mediated immunity to the host - T lymphocytes (T cells): from bone marrow, mature in thymus. display antigen-specific receptors on their surface that defend against intracellular pathogens, such as viruses and some bacteria - Conferring cellular immunity to the host - Not based on soluble proteins Specificity: dependent on lymphocyte receptors interacting with individual antigen (from pathogen) - T lymphocytes (T cells) display antigen-specific receptors call T cell receptors - Each receptor specific to one antigen or limited type of antigen - All the receptors are identical on the lymphocyte - B lymphocytes display membrane-bound immunoglobulins on their surface - Same specificity to one time but also are antibodies (immunoglobulins) Memory: the first antigen exposure induces multiplication of antigen-reactive cells, resulting in multiple clones. Subsequent exposures to the same antigen result in rapid production of large quantities of antigen-reactive T cells or antibodies 1. Multiply like craz 2. All the cells exposed to same antigen, the memory cells interact with antigens = multiply = react Primary immune response: first exposure to an antigen in which antigen recognition by specific B or T lymphocytes leads to B and T cell activation, proliferation, and differentiation - Exposure = multiply & differentiate (primary response few days) - continuous exposure does not result in secondary response bc need refractory period, the cells need to become memory cells - Primary response not good enough for immunization, booster stimulates secondary response (strong response takes approx 3 months for humans) Secondary immune response: subsequent exposure to the same antigen activates clones from the primary immune response to generate stronger and faster response - Vaccination with killed or weakened pathogens, or their products, is a means of conferring immunity Tolerance: the acquired ability to make an adaptive response to discriminate between host (self) and foreign (nonself) antigens - How to distinguish self vs foreign - Failure to develop tolerance may result in reactions against self, called autoimmunity - Precursor T cells travel from the bone marrow to the thymus, they mature, and are put under both positive and negative selective pressure - How to know which cells to keep? - First: Positive selection – T cells that recognize MHC peptides are retained - Must recognize Major Histocompatibility Complex proteins on surface - If not, they don't multiply - Second: Negative selection – T cells that pass the positive selection and strongly bind to self-antigens are selected against - If they react too strongly with MHC, they don’t pass - Clonal deletions – more than 99 percent of T cells that enter the thymus do not survive the selection process; remaining T cells react strongly with foreign antigens B cell selection and tolerance ONLY when they see an antigen do they go thru selec. - Enormous diversity of antigen-reactive B cells - Positive B cell selection occurs when the B cell receptors encounter an antigen that they recognize: - Proliferate, make more copies (with the help of T helper cells) - Differentiate into antibody-producing plasma cells (many) and memory cells (few) - Negative B cell selection occurs in the bone marrow, where self-reactive B cells are deleted (clonal deletion), or silenced because they lack a T cell help signal Antigens: substances that react with antibodies or T cell receptors - Not all antigens are immunogenic Immunogens: substances that elicit an immune response Intrinsic factors that determine immunogenicity include: - Size: haptens, which are small molecules, are not immunogens but they may induce an immune response if attached to a larger carrier molecule - Complexity: complex proteins and carbohydrates are good immunogens, while molecules with simple repeating units (e.g., DNA, mRNA: too similar to make unique structure to be recognized bc they r simply af) are poor immunogens - Vaccines often attached to protein (immunogenic) - Physical form: insoluble molecules or aggregates are usually excellent immunogens Extrinsic factors that determine immunogenicity include - Dose: micrograms to a gram - Route: injection is more effective than oral exposure - A large, oral dose of an immunogen may induce tolerance rather than immunity Antibodies do not interact with an entire antigen, but only with a distinct portion of the molecule called an antigenic determinant or epitope - Where they can bind: antigenic determinant or epitope - Antigens typically contain several different epitopes, each capable of reacting with a different antibody - May include sugars, short peptides of four to six amino acids, and other organic molecules that are components of a larger immunogen - T cell receptors recognize epitope only after the antigen has been processed (partially degraded) - example: antigen-presenting cells such as Macrophages, B lymphocytes etc. - They chew up antigens and put them on the surface as a couple of proteins? Active vs Passive immunity B lymphocyte (B cell): each B cell has ~100,000 identical antibodies on its surface called B cell receptors - B cells interact with antigen and T helper (Th) cells to produce antibodies - B cell receptors bind to antigen (pathogen), internalize, and digest it - The pathogen-derived peptides are affixed to Major Histocompatibility Complex II proteins and display on the surface of the B cell (antigen-presenting cell) - The antigen-presenting B cell interacts with an antigen-specific T cell, T helper cell - T helper cell secretes cytokines to activate the B cell to produce clones that differentiate into plasma cells (producing antibodies) and memory cells Antibodies (or immunoglobulins, Igs): either soluble or cell surface antigen receptors - bind to toxins or viruses to neutralize them - Toxin bound by antitoxin antibody is neutralized and doesn’t bind bind to foreign cells and make them easier to engulf by phagocytes Structure and function of immunoglobulin G (IgG) - Five major classes of antibodies: IgG, IgA, IgM, IgD, and IgE - differences in amino acid sequence of their heavy chain - different structural features, expression patterns, and functional roles - IgG is the most common antibody circulating in the body - Four polypeptide chains: two heavy and two light chains - The two heavy and two light chains are held together covalently by disulfide bond. - One heavy and one light chain interact to form an antigen-binding unit. - each IgG molecule has two antigen-binding sites. - The constant domain is identical for all IgG - The Fc stem binds receptors on phagocytes to facilitate phagocytosis - The variable domains bind antigen igG used in soluble secrtion, part of secondary Primary and secondary antibody responses in serum - Primary antibody response: produces short-lived plasma cells that live for less than a week; mostly IgM - Low concentration - Secondary antibody responses (subsequent exposures): response quicker - Memory cells do not need T cell help