Lecture 20: Immunity Concepts - 2024

Lecture 20- November 20th Chapter 16- overall idea ◦In this chapter we discuss the first two lines of defense against pathogens, which we call the innate immunity defenses. The first line of defense is our skin and mucous membranes. The second line of defense consists of phagocytes,...

Lecture 20- November 20th Chapter 16- overall idea ◦In this chapter we discuss the first two lines of defense against pathogens, which we call the innate immunity defenses. The first line of defense is our skin and mucous membranes. The second line of defense consists of phagocytes, inflammation, fever, and antimicrobial substances produced by the body. The Concept of Immunity Immunity: also called resistance is the ability to ward off disease caused by microbes or their products and to protect against environmental agents such as pollen, harmful chemicals, and animal dander. Susceptibility: lack of resistance to a disease or lack of immunity. There are 2 types of immunity Ability off toward disease ◦Innate immunity: specific non ‣ defenses against any pathogen; rapid, present at birth. Responds to a pathogen. Innate immunity does not involve recognition of a specific microbe Doesn’t have memory of seeing and responding to the pathogen. ‣ They are always available to provide rapid responses to protect us against disease. Memorgis ‣ Further, innate immunity has no memory response, that is, a more rapid and stronger immune reaction to the same microbe at a later date. Eternity.intnfyEaggepppisicalbarrier ‣ Innate immunity first-line defenses include skin and mucous membranes, and the second-line defenses include natural killer cells, phagocytes, inflammation, fever, and antimicrobial substances. Overall ‣ Innate immune responses represent immunity’s early-warning system and are designed to prevent microbes from gaining access into the body and to help eliminate those that do gain access. ◦Adaptive immunity:oraquriedimmunity ‣ immunity or resistance to a specific pathogen once a microbe has breached the innate immunity defenses; slower to respond, has memory component that allows the body to more effectively target the same pathogens in the future. ‣ Is when we make a specific response to the pathogen, specific antibody response, or specific T cell response and than we remember it. ‣ Adaptive immunity involves lymphocytes (a type of white blood cell) called T cells (T lymphocytes) and B cells (B lymphocytes). Innate involves physical barriers like skin, we have chemicals like salt in sweat, cells that can phagocytize, inflammation is also part our natural innate immunity as well as fever and molecules like interferons is a antiviral compound that we make when were exposed to viruses and complement which are all non-specific for the pathogen, is also a cascade of proteins that interact with each other and important because it helps with inflammation and helps phagocytes find they’re target/ pathogen. Adaptive involves antibody producing cells and T cells which get help from phagocytes and responds specifically to a pathogen. Big Picture: Immunity Innate immune system No memory ◦is responsible for taking care of any pathogen or organism and isn’t specific to the organism, it also doesn’t remember seeing the organism. Our innate immune cells do work with the specific cells involved with adaptive or acquired immunity, theres also a memory component of adaptive immunity which we don’t have with innate. Skin- ◦protects us from all the microorganisms out there and if the skin is breached theres an opportunity for the microorganism to get deeper into our tissues and we can wind up with a mild infection. Mucous membranes- ◦The mucous being in our cavities protects the lining of the cavity from drying out because a lot of times that allows for an opening for microorganism to get in. Actsasaphysical barrier Anti microbial substances- ◦our cells make this. Inhibit the okill growth r microorganisms Inflammation/fever- ◦its our own immune system, the innate immunity is responding to the pathogen and hopefully getting rid of it and if it doesn’t than there’s adaptive or acquired immunity. First-Line Defenses part ofinnateimmunity ◦First-line defenses keep pathogens on the outside or neutralize them before infection begins. The skin, mucous membranes, and certain antimicrobial substances are part of these defenses. Second-Line Defenses Partofinnate immunity ◦Second-line defenses slow or contain infections when first-line defenses fail. They include proteins that produce inflammation, fever that enhances cytokine activity, and phagocytes and natural killer (NK) cells, which attack and destroy cancer cells and virus-infected cells. The defensive cells of innate immunity are shown in the following table. Third-Line Defenses ◦Third-line defenses, shown in the following table, include lymphocytes that target specific pathogens for destruction when the second-line defenses don’t contain infections. It includes a memory component that allows the body to more effectively respond to that same pathogen in the future. First- and second-line defenses are part of the innate immune system, whereas the third-line defenses are referred to as the adaptive immune system  skinmucousmembraneNkcellphago Cells of the innate immune system respond to pathogens and activate adaptive immunity. Responses of the innate system are activated by protein receptors in their plasma membranes. cellsneutrophils onmacrophages dendritic Located Among these activators are Toll-like receptors* (TLRs). mucosal censorsaine surfaces epithelial ◦These TLRs attach to various pattern recognition receptors (PRRs) commonly found on pathogens; these PRRs are called pathogen-associated molecular patterns (PAMPs). TLR'sonthe cells immune innate toPAMP'sonpathogeniccells attach ‣ Examples include the lipopolysaccharide (LPS) of the outer membrane of gram-negative bacteria, the flagellin in ofPAMP thisisatype the flagella of motile bacteria, the peptidoglycan in the cell wall of gram-positive bacteria, the DNA of bacteria, and the DNA and RNA of viruses. TLRs also attach to components of fungi and parasites. ◦When the TLRs on these cells encounter the PAMPs of microbes, such as the LPS of gram-negative bacteria, the TLRs induce the defensive cells to release chemicals called cytokines ‣ Cytokines - are proteins that regulate the intensity and duration of immune responses. One role of cytokines is to age Actress recruit other macrophages and dendritic cells, as well as other defensive cells, to isolate and destroy the microbes as part of the inflammatory response. Cytokines can also activate the T cells and B cells involved in adaptive immunity The innate immune system and adaptive function as a highly interactive and cooperative “supersystem” that produces a Act combined response that is more effective than either component can produce separately. Certain molecular and cellular components of the immune system serve important functions in both types of immunity. Physical Factors (1 of 3) Physical factors include barriers to entry and processes that remove microbes from the body’s surface. Skin Physicalbarrier ◦Dermis: inner and thicker portion made of connective tissue ◦Epidermis: outer thinner portion is in direct contact with the external environment and is made of continuous sheets of tightly packed epithelial cells with little or no material between the cells. ‣ The top layer of epidermal calls is dead and contains a protective protein called keratin. Shedding and dryness of skin inhibits microbial growth and removes microbes at the surface. Gets rid of pathogens that may be on skin surface. ◦ the dryness of the skin is a major factor in inhibiting microbial growth on the skin. When the skin is frequently moist, as in hot, humid climates, skin infections are quite common, especially fungal infections such as athlete’s foot. These fungi Footistn smell hydrolyze keratin when water is available. environment moist Skin is a formidable barrier to microbes Microbes rarely, if ever, penetrate the intact healthy epidermis. However, when the epithelial surface is broken as a result of burns, cuts, puncture wounds, or other conditions, a subcutaneous (below-the-skin) infection often develops. Physical Factors (2 of 3) can't enters Mucous membranes, the mucous protects the cavity from drying it and being vulnerable. Actsasabarrierso pathogens ◦Epithelial layer that lines the gastrointestinal, respiratory, and genitourinary tracts ◦Mucus: the epithelial layer of a mucous membrane secretes a fluid called mucus, a slightly viscous (thick) glycoprotein produced by goblet cells of a mucous membrane. Is viscous glycoproteins that trap microbes and prevent tracts from that microbes other and dust particles drying out. Mucousmembranesecretesmucous isasticky which substance traps ‣ Some pathogens that can thrive on mucus are able to penetrate the membrane if they are present in sufficient numbers  ◦The mucous membrane of the nose also has mucus-coated hairs that filter inhaled air and trap particles. I ◦Lacrimal apparatus: (protects eye) drains tears; washes eye. Meant to keep on washing our eyes. This continual washing action helps keep microorganisms from settling on the surface of the eye. If an irritating substance or large numbers of microorganisms come in contact with the eye, the lacrimal glands start to secrete heavily, and the tears accumulate more rapidly than they can be carried away ◦IgA- is an antibody found in all of our cavities which can protect us Physical Factors (3 of 3) Ciliary escalator transports microbes trapped in mucus away from the lungs. The ciliary is always pushing things up and wanting to get out. ◦The cells of the mucous membrane of the lower respiratory tract are covered with cilia. By moving synchronously, these cilia propel inhaled dust and microorganisms that have become trapped in mucus upward toward the throat. ◦Coughing and sneezing speed up the escalator ◦SARS-CoV-2 infects cells of the respiratory tract and destroys cilia. Some substances in cigarette smoke are also toxic to cilia and can seriously impair the functioning of the ciliary escalator by inhibiting or destroying the cilia. Mechanically ventilated patients are vulnerable to respiratory tract infections because the ciliary escalator mechanism is inhibited. whentheciliaryescalatorisimpaired.thebodysabilitytoclearbacteri.aedebris motheringsed Epiglottis larynx asaflapoverthe Acts ◦Microorganisms are also prevented from entering the lower respiratory tract by a small lid of cartilage called the tract epiglottis, which covers the larynx (voicebox) during swallowing Ensuresthat food epathogensaredirectedintotheesophagusandnotintotherespirat.org l iquids Earwax prevents microbes from entering the ear ◦The external ear canal contains hairs and earwax (cerumen), which help prevent microbes, dust, insects, and water from entering the ear. Urine cleans the urethra via flow. Is flushing out things from the urinary tract so it doesn’t get established in the lining. When urine flow is obstructed—by catheters, for example—urinary tract infections may develop Vaginal secretions move microorganisms out of the vaginal tract. The secretions have antimicrobial agents and have a specific Ph that organism can’t grow in Peristalsis, defecation, vomiting, diarrhea- there aren’t pleasant experiences but its part of our innate system and gets the endotoxin out as fast as it can. ◦Peristalsis is a series of coordinated contractions that propels food along the digestive canal. Mass peristalsis within the large intestine propels its contents into the rectum, resulting in defecation. ◦ In response to microbial toxins, the muscles of the digestive canal contract vigorously, resulting in vomiting and/or diarrhea, which may also rid the body of microbes. ◦Tuft cells in the small intestine respond to helminth and protozoa parasites with production of cytokines that promote peristalsis, which helps expel the parasite. Tuft cells are named for their long microvilli extending into the intestine. Chemical Factors- physical factors alone do not account for the high degree of resistance shown by skin and mucous membranes against microbial invasion. Certain chemical factors also play important roles. Sebum forms a protective film over the surface of the skin and lowers the p H (3–5) of skin. Is formed when sebaceous (oil) glands of the skin produce an oily substance called sebum that prevents hair from drying and becoming brittle. ◦One of the components of sebum is unsaturated fatty acids, which inhibit the growth of certain pathogenic bacteria and fungi. The low pH of the skin, between pH 3 and 5, is caused in part by the secretion of fatty acids and lactic acid. The skin’s acidity probably discourages the growth of many other microorganisms.  Perspiration- the sweat glands of the skin produce this, which helps maintain body temp, eliminates certain wastes, and flushes microorganisms from the surface of the skin. Basicallysweat Lysozyme in perspiration, in tears, saliva, and urine destroys bacterial cell walls. Lyysozyme breaks up peptidoglycan layer in bacteria. Is an enzyme capable of breaking down cell walls of gram-positive bacteria and, to a lesser extent, gram- negative bacteria. ◦Lysozyme is also found in tears, saliva, nasal secretions, tissue fluids, and urine, where it exhibits its antimicrobial activity Low p H (1.2–3.0) of gastric juice destroys most bacteria and toxins.- ◦gastric juice is produced by the glands of the stomach Very Eaten organisms is it Low p H (3–5) of vaginal secretions inhibits microbes- ◦Vaginal secreations have a protective role, defending against bacteria in two ways. Glycogen produced by vaginal epithelial cells is broken down into lactic acid by Lactobacillus spp. This creates an acidic pH (3–5) that inhibits bacterial growth. Cervical mucus also has some antibacterial activity Earwax- is a physical barrier and functions as a chemical protectant. ◦It is a mixture of secretions from glands producing earwax as well as from the sebaceous glands, which produce sebum. The secretions are rich in fatty acids, giving the ear canal a low pH, between 3 and 5, which inhibits the growth of many pathogenic microbes. Earwax also contains many dead cells from the lining of the ear canal. Saliva- contains not only the enzyme salivary amylase that digests starch, but also a number of substances that inhibit microbial growth. The normal microbiota provide resistance to disease in three principal ways They are well adapted to the limited number of attachment sites on which they live. They have a competitive advantage over pathogenic microbes for these colonization sites because they dominate the available space and nutrients (competitive exclusion). This colonization resistance is especially effective against microbes such as Clostridioides difficile, Salmonella, Shigella, and Candida albicans. Normal Microbiota and Innate Immunity (1 of 2) the of inhibitgrowthpathogens microbiota Normal Normal microbiota compete with pathogens via microbial antagonism (competitive exclusion). Must be present in our body to try and prevent pathogen from taking over, normal microbiota sort of grabs onto they’re nutrients and not giving it space for a pathgoen to take over. The normal microbiota plays a role in our immunity to have a proper response to pathogen. ◦Competitive advantage for space and nutrients ‣ They are well adapted to the limited number of attachment sites on which they live. They have a competitive advantage over pathogenic microbes for these colonization sites because they dominate the available space and nutrients (competitive exclusion). This colonization resistance is especially effective against microbes such as Clostridioides difficile, Salmonella, Shigella, and Candida albicans. ◦Produce substances harmful to pathogens, release different anti microbial factors ‣ Normal microbiota produce substances that inhibit or kill pathogens. For example, Escherichia coli bacteria in the large intestines produce bacteriocins that inhibit or kill bacteria of the same or closely related species. Some normal microbiota, such as Lactobacillus in the vagina, produce hydrogen peroxide under anaerobic conditions. This has shown to be effective against infections caused by Chlamydia trachomatis, Gardnerella vaginalis, and Candida albicans.  ◦Alter conditions that affect pathogen survival ◦Prevent the overgrowth of harmful microbes ◦Play an important role in the development of the immune system ‣ Development of the immune system is dependent on the presence of microbiota even before birth. Babies are prone to have allergy’s later in life because they didn’t have normal flora interacting with the education of they’re immune system.The the educated more istheless flora toinfections prone Normal Microbiota and Innate Immunity (2 of 2) Commensalism: one organism benefits while the other (host) is unharmed. There’s organism that are on us, on our skin benefiting from us and don’t do nothing to us, they want to eat all of the oils and shedded skin cells. Example- staph epidermis ◦Most microbes that are part of the commensal microbiota are found on the skin and in the digestive canal. The majority of such microbes are bacteria that have highly specialized attachment mechanisms and precise environmental requirements for survival. Normally, such microbes are harmless, but they may cause disease if their environmental conditions change Opportunistic pathogens among the normal microbiota: must be doing something for us because we do tolerate them ◦E. coli (provides vitamin K), S. aureus, S. epidermidis, Enterococcus faecalis, Pseudomonas aeruginosa ◦Given the opportunity these organism will turn on us. Probiotics: live microbial cultures administered to exert a beneficial effect.Liveorganisms that benefits health provide Prebiotics: certain chemicals (nutrients) that selectively promote/induce the growth of beneficial bacteria. ◦Some can actually be useful but some aren’t. the stimulate Help and g rowth of activity goodbacteria Forced elements in blood partoblood Fluid f is plasmamostly like also water substances nutrients contains protein hormones Blood plasma- blood consists of this fluid, and is the liquid portion of blood in which the formed elements are suspended. Forced elements- cells and cell fragments suspended in blood plasma. In reference to blood, the erythrocytes, leukocytes, platelets, white blood cells, and red blood cells. These are the in blood plasma ◦ Formed elements are created in red bone marrow by blood stem cells in a process called hematopoiesis Hematopoiesis- the formation of blood cells. ◦It begins when a cell called a multipotent stem cell develops into two other types of cells called myeloid (bone marrow) stem cells and lymphoid stem cells. From these two stem cells, all of the formed elements develop. of cells formation blood The Figure 16-4 Hematopoiesis- cells that are part of our immune system The process begins in red bone marrow with a multipotent stem cell. into Divides myeloid and cell stem l ymphoid cell stem If you need a bone marrow transplant, you would get a restoration of the bone marrow by getting these multipotent stem cells will give you all of the different blood cells, monocytes are also part of myeloid stem cell lineage (ignore picture). Monocytes are immature phagocytic cells and they mature into some type of macrophage, they can be fixed and stay in a particular organ. Lymphoid dendritic cells are phagocytic Neutrophils are also phagocytic cells Eosinophils are useful to help attack large pathogens like worms because they break the worm up so phagocytic cells can go in and gobble up the rest of the worm parts.  Mast cells and basophils- play a role in blood vessel dilation so that macrophages and neutrophils can get out of blood, we need them to go into tissue when theres an infectious agent there. Lymphoid stem cell lineage- is made up of 3 cell types ◦T cell, B cell, and natural killer cells ‣ Natural killer cells- considered part of lymphoid stem cell lineage because of all the different proteins they have on the outside of there membrane, they fit into the lineage, but they do work non specifically. ◦B and T cells respond specifically to a pathogen Leukocytes are divided into two main categories based on their appearance under a light microscope: granulocytes and agranulocytes Formed Elements in Blood Granulocytes are leukocytes with large granules in their cytoplasm that are visible with a light microscope after staining. They are differentiated into four types of cells based on how the granules stain: ◦Neutrophils: phagocytic and motile; work in early stages of infection. First phagocytic cells on the scene/active in the initial stages of an infection, they don’t last long maybe 24 hours. They have the ability to leave the blood, enter an infected tissue, and destroy microbes and foreign particles. ◦Basophils: release histamine; which is important for our blood cells to dilate to get cells out to whatever tissue needs to see the macrophages, also work in allergic responses. Dilate theblood his bygreleasing cells tame site which allowsformacrophagesto out et the to ◦Eosinophils: phagocytic; toxic against parasites and helminths. Release things to break up the worms so they can be engulfed by the macrophages. Have the ability to leave the blood. Although eosinophils are physically too small to ingest and destroy helminths, they can attach to the outer surface of the parasites and discharge peroxide ions that destroy them. Their number increases significantly during certain parasitic worm infections and hypersensitivity (allergy) reactions such as eosinophilic asthma, a rare and severe type of asthma. ◦Mast cells- They are found in tissues throughout the body, especially the skin, but are not normally found in blood. Mast cells release chemicals that activate neutrophils and eosinophils during an infection. Release like factors to inflammation histaminet rigger Formed Elements in Blood- know monocytes and dendritic cells Agranulocytes are leukocytes with granules in their cytoplasm that are not visible with a light microscope There are three different types of agranulocytes: ◦Monocytes: mature into macrophages in tissues where they are phagocytic. They are not actively phagocytic until they leave circulating blood, enter body tissues, and mature into macrophages ◦Dendritic cells: found in the skin, mucous membranes, and thymus; phagocytic. They have long extensions that resemble the dendrites of nerve cells  ‣ Dendritic cells are especially abundant in the epidermis of the skin, mucous membranes, the thymus, and lymph nodes. Dendritic cells destroy microbes by phagocytosis and initiate adaptive immune responses by presenting antigens to lymphocytes ◦Lymphocytes: T cells, B cells, and Natural killer cells; play a role in adaptive immunity ‣ In fact, the proliferation (rapid increase) of lymphocytes is one factor responsible for the swelling of lymph nodes during an infection. As blood and lymph plasma that contain microorganisms pass through organs with macrophages, the microorganisms are removed by phagocytosis. Macrophages also dispose of worn-out blood cells. to Ability offadisease ward Cells Involved in Immunity- don’t need to to know description part/ know what it’s releasing and importance This is a list of cells we use when talking about innate immunity. Innate and both cells are part of our white blood cells that our of the myeloid lineage. Mast cells and basophils are important because the release histamines which dilate the blood vessels which helps things first atscene cell like macrophages and neutrophils to get out of our blood stream. Eosinophils- help us attack large parasites like worms,breakthem somacrophagescan them digest up Mast cells- release histamine and they can help present an antigen to the T and B cells which is part of adaptive/acquired immunity and blood matures phagocytictilted the Not nys egg Neutrophils and monocytes- the monocytes mature to our phagocytic cells. But the neutrophils and monocytes they engulf the organism and hopefully destroy it so that were rid of it and free from our system. andalertotherimmune by cells presentingthe themantige Dendritic cells- they are phagocytic cells and look like nerve cells.Act substances asmessengers harmful Detect B cells- make antibodies. Not phagocytic but play a key role in adaptive immunity. ◦Part of lymphoid cell lineage. They occur in lymphoid tissues of the lymphoid system and also circulate in blood. T cells- work on attacking cells one on one to kill the intracellular parasites like viruses because antibodies can’t get into virally infected cells but T cells will kill those cell.someTcellsattack orcoordinatethe directly immune by signalstoothercells response sending ◦Part of the lymphoid cell lineage. They occur in lymphoid tissues of the lymphoid system and also circulate in blood. ◦Not phagocytic but play a key role in adaptive immunity. Natural killer cells- patrol our body constantly and look for anything abnormal so if they see an abnormal tumor cell, a virus infected cell, a cell that might have chlamydia they go right up to the cell and inject different chemicals that destroy the cells, they work non specifically. They see something wrong with our cells and they respond specifically one on one with the aberrant cell. ‣ are found in blood, spleen, lymph nodes, and red bone marrow. NK cells have the ability to kill a wide variety of infected body cells and certain tumor cells. NK cells attack any body cells that display abnormal or unusual plasma membrane proteins. The binding of NK cells to a target cell, such as an infected human cell, causes the release of toxic substances from lytic granules in NK cells. Lytic granules are a secretory organelle unique to NK cells ‣ Some lytic granules contain a protein called perforin, which inserts into the plasma membrane of the target cell and creates channels (perforations) in the membrane. As a result, extracellular fluid flows into the target cell and the cell bursts, a process called cytolysis. NK cells also have other granules that release granzymes, which are protein- digesting enzymes that induce the target cell to undergo apoptosis, or self-destruction. This type of attack kills infected cells but not the microbes inside the cells; the released microbes, which may or may not be intact, can be destroyed by phagocytes. the Destroys the cell in p athogenis White blood cells- During many kinds of infections, especially bacterial infections, the total number of white blood cells increases as a protective response to combat the microbes; this increase is called leukocytosis. Y.hrdaintenefohieihfcytosis During the active stage of infection, the leukocyte count might double, triple, or quadruple, depending on the severity of the infection. ◦Diseases that might cause such an elevation in the leukocyte count include meningitis, infectious mononucleosis, appendicitis, pneumococcal pneumonia, and gonorrhea. ◦Other diseases, such as salmonellosis and brucellosis, and some viral and rickettsial infections may cause a decrease decrease in the leukocyte count, called leukopenia Leukopeniaisa cell when count an t here's infection blood white in ◦Leukopenia may be related to either impaired white blood cell production or the effect of increased sensitivity of white blood cell membranes to damage by complement, antimicrobial serum proteins Leukocyte increase or decrease can be detected by a differential white blood cell count, which is a calculation of the percentage of each kind of white cell in a sample of 100 white blood cells. The Lymphoid System- carries out specific immune response Consists of: The l ymphoid systemispartoftghqppdp.jpYYuYrs'Einfectionsodiseases yi which ◦Lymph plasma Lymnghiftmhfny.gg Fluidpartoflymph nodes filterharmful Lymph ◦Lymphatic vessels Tubes that transport lymph t hroughout body your from substances lymph ◦A number of structures and organs containing lymphoid tissue- is where the interaction happens with the pathogen with our B and T cells.It's also upofwhitebloodcells made ◦Red bone marrow- where blood stem cells develop into blood cells, including lymphocytes Lymphoid tissue contains large numbers of lymphocytes and phagocytic cells that participate in immune response. Lymph carries microbes to lymph nodes where B and T lymphocytes, macrophages, and dendritic cells encounter and destroy the pathogen IItihntelld.it wInveifyYnihng happens ◦Also within lymph nodes are reticular fibers, which trap microbes, and macrophages and dendritic cells, which destroy microbes by phagocytosis. Lymph nodes creates environment so that all the cells that need to work tg are finding each other bc there is a nice environment which lets the cells come together so they can interact. Immunology is the cells seeing the problem because they can recognize something specific on the pathogen and the cells can see that and than respond. A lot of cell to cell interaction. Figure 16-5- lymph noid- don’t need to know names of the area Lymphatic vessels begin as microscopic lymphatic capillaries located in spaces between cells The lymph noid allows the cells that need to work together come together, to be able to have a proper immune response. Macrophages and dendritic cells will bring the particular pathogen to the B cells and T cells that are in the lymph tissues and lymph nodes and they present an antigen or a pathogen to a B cell if we need to make antibodies to the pathogen or to the ares antibodies T cell if we need a T cell response to a virally infected cell. E re p The lymph tissue and vessels, and everything that belong to the lymph system is responsible for allowing the proper cells to interact and mount a good immune response. The lymphatic capillaries permit interstitial fluid derived from blood plasma to flow into them, but not out. Within the lymphatic capillaries, the fluid is called lymph plasma. Lymphatic capillaries converge to form larger lymphatic vessels. These vessels, like veins, have one-way valves to keep lymph plasma flowing in one direction only. At intervals along the lymphatic vessels, lymph plasma flows through bean-shaped lymph nodes. All lymph plasma eventually passes into the thoracic (left lymphatic) duct and right lymphatic duct and then into their respective subclavian veins, where the fluid is now called blood plasma. With the lymph nodes the fluid comes in one direction. Theissen the'ssights Lymphoid tissues and organs are scattered throughout the mucous membranes that line the digestive canal and the respiratory, urinary, and genital tracts. They protect against microbes that are ingested or inhaled. The spleen contains lymphocytes and macrophages that monitor the blood for microbes and secreted products such as toxins, much like lymph nodes monitor lymph plasma. The thymus serves as a site for T cell maturation. It also contains dendritic cells and macrophages. Phagocytosis Phagocytosis- is the ingestion of a microorganism or other substance by a cell Phagocytes- cells that perform phagocytosis. All are types of white blood cells or white blood cell derivatives Argulocyte When an infection occurs, both granulocytes (especially neutrophils, but also eosinophils) and monocytes migrate to the infected area.are mature macrophages Monocytes that leave the blood enlarge and develop into macrophages. Some macrophages, called resting (fixed) macrophages or histiocytes, are resident in certain tissues and organs of the body. ◦Resting macrophages are found in the liver (Kupffer’s cells), lungs (alveolar macrophages), nervous system (microglial cells), bronchial tubes, spleen (splenic macrophages), lymph nodes, red bone marrow, and the peritoneal cavity surrounding abdominal organs (peritoneal macrophages). Other macrophages are motile and are called wandering (free) macrophages; they roam the tissues and gather at sites of infection or inflammation. The monocytes and macrophages derived from monocytes constitute the mononuclear phagocytic (reticuloendothelial) system. During the course of an infection, a shift occurs in the type of white blood cell that predominates in the bloodstream. cellatsite first Granulocytes, especially neutrophils, dominate during the initial phase of bacterial infection, at which time they are actively phagocytic; this dominance is indicated by their increased number in a differential white blood cell count. However, as the infection progresses, the macrophages dominate; they scavenge and phagocytize remaining living bacteria and dead or dying bacteria. The increased number of monocytes (which develop into macrophages) is also reflected in a differential white blood cell count. The Mechanism of Phagocytosis (1 of 2) The phagocytic cells have to get to the organism it ingest Phagocytosis- is the ingestion of a microorganism or other substance by a cell. Divide phagocytosis into four main phases: chemotaxis, adherence, ingestion, and digestion: Chemotaxis Attraction ◦Chemotaxis allows phagocytes to migrate to infection sites and destroy invading bacteria. Timid cells pyetea.is orbacteria ◦Chemical signals attract/signal phagocytes to microorganisms. ◦Often the macrophages are chemically attracted bc some of the cells that were damaged due to the pathogen release different chemicals, which can be compliment factors.TheacksEac cells at knitBhe maths haggged ast ite and macrophages are responding to the chemicals and some chemicals can even be released by the airsteen ◦Neutrophils pathogen itself and there an attraction to the cells. ◦Include microbial products, components of white blood cells, damaged cells, complement ‣ Among the chemotactic chemicals that attract phagocytes are microbial products, components of white blood cells and damaged tissue cells, cytokines released by other white blood cells, and, finally, peptides derived from complement—a system of host defense proteins discussed later in the chapter. Adherence Attachment ◦Attachment of the phagocytes plasma membrane to the surface of the microorganism ◦Once the macrophage is on site it has to attach to the pathogen. the TLR'son attach p hagocytes the toPAMPonmicrobe ◦Adherence is facilitated by the attachment of pathogen-associated molecular patterns (PAMPs) of microbes to receptors, such as Toll-like receptors (TLRs), on the surface of phagocytes. The binding of PAMPs to TLRs not only initiates phagocytosis, but also induces the phagocyte to release specific cytokines that recruit additional phagocytes. ◦On the surface membrane of the macrophage is toll like receptors which are protein receptors that recognize specific proteins or carbs that are on the pathogen, so a macrophage has multiple different toll receptors, one might recognize lps, another might recognize flagella protein, another might recognize a specific protein on the virus. The toll like receptors are recognizing specific protein, carb or DNA associated with the pathogen. ◦PAMPs (pathogen associated molecular patterns) on microbes attach to TLRs (Toll-like receptors) on phagocyte surfaces. ‣ Gets it name bc things like LPS and peptidglycan are repetitive structures and this is why its referred to as molecular patterns and that’s what the macrophage is recognizing. ◦sometimes the proteins are actually antibodies and they decorate the pathogen and the macrophage sees the antibody attached to the cell and they go to it and it starts ingesting that complex. ◦Microorganisms can be more readily phagocytized if they are first coated with certain serum proteins (opsonins) that promote attachment of the microorganisms to the phagocyte. This coating process is opsonization. The proteins that act as opsonins include some components of the complement system and antibody molecules ◦Opsonization: microorganism is coated with serum proteins, making adherence easierCY.de beantibodies ‣ Opsonins include complement components, antibodies.These the areon for allowing pathogen easier attachment ◦Organism that have capsules are anti phagocytic, the macrophages recognize the capsulate organism bc often theres antibodies attached to the capsule, we’ve seen the organism before and the antibody attached to the capsulated organs is now recognized by the macrophage. This is how our immune system gets around virulence factors of bacteria. The Mechanism of Phagocytosis (2 of 2) Once the phagocytic cells has attached because of the toll like receptors and the repetitive structures on the pathogen it gets ingested. Ingestion Engulfing ◦Pseudopods (cytoplasmic projections on the phagocyte) extend out and engulf the microorganism. Looks like a vesicle. ◦Engulfed microorganism is enclosed in a phagosome. Once the microorganism is surrounded, the pseudopods meet and fuse, surrounding the microorganism with a sac called a phagosome ◦Phagosome becomes acidic (p H 4)—activates hydrolytic enzymes. The membrane of a phagosome has enzymes that pump protons (H+) into the phagosome, reducing the pH to about 4. At this pH, hydrolytic (breakdown by water) enzymes are activated. Digestion ◦Next, the phagosome pinches off from the plasma membrane and enters the cytoplasm, where it contacts lysosomes that contain digestive enzymes and bactericidal substances. ◦Once inside the phagocytic cell there is the phagosome combining with lysosome which has nasty enzymes and even has oxygen radicals, the whole point is when they meet up into the phago-lysosome the organism gets destroyed and the waste products get excluded from the phagocyte. ◦Lysosomes fuse with phagosome forming phagolysosome. On contact, the phagosome and lysosome membranes fuse to form a single, larger structure called a phagolysosome Thehigher int Srmaphage c'EmMight lysosome Bembigee in ‣ Lysosomes provide numerous enzymes and toxic oxygen products (oxidative burst) The Baker ◦The contents of the phagolysosome brought in by ingestion are digested in the phagolysosome. ◦After enzymes have digested the contents of the phagolysosome brought into the cell by ingestion, the phagolysosome bodyis contains indigestible material and is called a residual body. Theleftoverwaste Residual pexpele mate phagocyte ◦This residual body then moves toward the cell boundary and discharges its wastes outside the cell. ◦Microorganism is digested inside a phagolysosome ◦Indigestible material forms a residual body that is removed from the cell by exocytosis In addition to providing innate resistance for the host, phagocytosis plays a role in adaptive immunity. Figure 16.8 The Phases of Phagocytosis The toll like receptors are on membrane of macrophages and the receptor is recognizing some feature on the pathogen whether it’s LPS, peptidoglycan.PAMP's Once it attaches the membrane surrounds the pathogen and brings it in as a phagosome and the phagosome will fuse with the lysosome and the digestion of the organism takes place, waste products can be expelled from the macrophages.Residua body The cells that resist phagocytosis, they have ways of preventing the fusion or neutralize it so the macrophages harbors the pathogen which is growing inside and the macrophage is circulating it making it systemic. Some bacteria can make leukocytein/leukostatin which inhibits the macrophage from engulfing or even kills the macrophage. cells Chemotaxisdamaged canreleasefactors The macrophage is attracted to the pathgoen because we’re releasing things from our cells so there’s an attraction to that area and the macrophage sees something and now will bring it in. Inflammation- hopefully can help us get rid of pathogen before damage Inflammation- damage to the body’s tissues triggers a local defensive response. Is another component of the second line of defense. The damage can be caused by microbial infection, physical agents (such as heat, radiant energy, electricity, or sharp objects), or chemical agents (acids, bases, and gases). Signs and symptoms: pain, redness, immobility, swelling (edema), heat. ◦Think of the acronym PRISH. ◦Pain due to the release of certain chemicals. ◦Redness because more blood goes to the affected area. ◦Immobility that results from local loss of function in severe inflammations. ◦Swelling caused by an accumulation of fluids. ◦Heat, which is also due to an increase in blood flow to the affected area. Inflammation has the following functions: ◦Destroys injurious agent if possible, and to remove it and its by-products from the body. ◦if destruction is not possible, to limits its effects on the body by confining or walling off the injurious agent and its by- itseffectsonthebody products Wallsofftolimit ◦Repairs and replaces tissue damaged by the injurious agents or its by products. Inflammation can be classified as acute or chronic, depending on a number of factor ◦Acute inflammation- the signs and symptoms develop rapidly and usually last for a few days or even a few weeks. It is usually mild and self-limiting, and the principal defensive cells are neutrophils. ‣ Examples of acute inflammation are a sore throat, appendicitis, cold or flu, bacterial pneumonia, and a scratch on the skin. ◦Chronic inflammation- the signs and symptoms develop more slowly and can last for up to several months or years. It is often severe and progressive, and the principal defensive cells are monocytes and macrophages. ‣ Examples of chronic inflammation are mononucleosis, peptic ulcers, tuberculosis, rheumatoid arthritis, and ulcerative colitis. During the early stages of inflammation, microbial structures, such as flagellin, lipopolysaccharides (LPS), and bacterial DNA stimulate the Toll-like receptors of macrophages to produce cytokines, such as tumor necrosis factor alpha (TNF-α). isanattractant This Figure 16.9a-b The Process of Inflammation a) Damage to otherwise healthy tissue—in this case, skin. (b) Vasodilation and increased permeability of blood vessels allows phagocyte migration. Phagocytosis by macrophages and neutrophils removes bacteria and cellular debris. Macrophages develop from monocytes. When we have a problem and breach in our skin and the organisms are now deeper into our tissue, the first thing is a lot of the skin cells that were damaged start releasing things like histamine and, prostaglandins and kinins and the blood vessels outthe wemove to bloodcenssite are starting to dilate and they start leaking because the macrophages have to squeeze out which is diapedesis and they start grabbing on to the cell lining of the blood vessel, this happens in response to the release of the chemicals that released during the injury of the cells in our tissue. The macrophages and neutrophils are sneaking out and going to the site. There can also be blood clots which is an important feature or inflammation. Ultimately, we want the macrophages and the neutrophils, to get out, to grab, and go through the process of phagocytosis. In the meantime, we do have an inflammatory response. So we will see swelling in the area, fluid is coming out of our blood vessels, but that's to take care of the infection. When our lungs have reached the point where they’re loaded with the macrophages that are infected what our body can do is to wall off the focal point where macrophages are infected and its wrapped around with collagen and that creates the tubercle, now with the area walled off the macrophages can’t escape and go into circulation, this is a granulona or for tuberculosis its tubercle, this can last for years but if someone becomes immunocomprimised the tubercle can be broken down and all of a sudden have an active infection again. Figure 16.9c The Process of Inflammation Ultimately, we would have a scab forming to cover up that hole and ultimately repair the site. And that's all part of the inflammation response. Neutrophilsmacrophages Increased permeability permits defensive substances normally retained in the blood to pass through the walls of the blood vessels and enter the injured area. The increase in permeability, which permits fluid to move from the blood into tissue spaces, is responsible for the edema (accumulation of fluid) of inflammation. The pain of inflammation can be caused by nerve damage, irritation by toxins, or the pressure of edema. oEkiteEuid FYIfma jb  thepermeability Regulates ofbloodvessels Table 16-2 Summary of Vasoactive Mediators of Inflammation Vasodilation and the increase in permeability of blood vessels are caused by a number of chemicals released by damaged cells in response to injury. These chemicals are called vasoactive mediators. One such substance is histamine, a chemical present in many cells of the body, especially in mast cells in connective tissue, circulating basophils, and blood platelets. Histamine is released in direct response to the injury of cells that contain it; it is also released in response to stimulation by certain components of the complement system. Phagocytic granulocytes attracted to the site of injury can also produce chemicals that cause the release of histamine. Histamine is dilating our blood vessels so macrophages and neutrophils can get out to where they need to go Kinins- Are another group of substances that cause vasodilation and increased permeability of blood vessels. Kinins are present in blood plasma, and once activated, they play a role in chemotaxis by attracting phagocytic granulocytes, chiefly Attraction neutrophils, to the injured area. Prostaglandins- help create higher temp. Are substances released by damaged cells, intensify the effects of histamine and kinins and help phagocytes move through capillary walls. Despite their positive role in the inflammatory process, prostaglandins are also associated with the pain related to inflammation. Leukotrienes- are substances produced by mast cells (cells especially numerous in the connective tissue of the skin and respiratory system, and in blood vessels) and basophils. Leukotrienes cause increased permeability of blood vessels and help attach phagocytes to pathogens. Cytokines- Activated resting macrophages also secrete cytokines that contribute to vasodilation and increased permeability. Another function of cytokines in inflammation is to stimulate cells to produce yet more cytokines. This positive feedback loop occasionally gets out of control, resulting in a cytokine storm that can cause significant tissue damage. A cytokine storm can lead to pneumonia, pulmonary edema, multiorgan dysfunction, and acute respiratory distress syndrome (ARDS), immune excessive response the causative syndrome in about 70% of COVID-19 fatalities. Cytokinestorm These things are all attractants that help the macrophage to get to the site of infection. Vasodilation and the increased permeability of blood vessels also help deliver clotting elements of blood into the injured area. The blood clots that form around the site of activity prevent the microbe (or its toxins) from spreading to other parts of the keep helps Clotting from infection spreading the body. ◦As a result, there may be a localized collection of pus, a mixture of dead cells and body fluids, in a cavity formed by the breakdown of body tissues. This focus of infection is called an abscess. Common abscesses include pustules and boils. Phagocyte Migration and Phagocytosis Generally, within an hour after the process of inflammation is initiated, phagocytes appear on the scene As the flow of blood gradually decreases, cytokines alter adhesion molecules on cells of the endothelium (lining) of blood vessels. This alteration causes the phagocytes (both neutrophils and monocytes) to begin to stick to the endothelium. This sticking process in response to local cytokines is called margination. (Margination is also involved in red bone marrow, cin where cytokines can release phagocytes into circulation when they are needed.)YIE.ie IEIii i fi i iiminin Then the collected phagocytes begin to squeeze between the endothelial cells of the blood vessel to reach the damaged area. This migration, which resembles ameboid movement, is called diapedesis; it can take as little as 2 minutes. The phagocytes then begin to destroy invading microorganisms by phagocytosis. As the inflammatory response continues, monocytes follow the granulocytes into the infected area. Once the monocytes are contained in the tissue, they undergo changes in biological properties and become free macrophages. The granulocytes predominate in the early stages of infection but tend to die off rapidly. Macrophages enter the picture during a later stage of the infection, once granulocytes have accomplished their function. They are several times more phagocytic than granulocytes and are large enough to phagocytize tissue that has been destroyed, granulocytes that have been destroyed, and invading microorganisms. After granulocytes or macrophages engulf large numbers of microorganisms and damaged tissue, they themselves eventually die. As a result, pus forms, and its formation usually continues until the infection subsides. At times, the pus pushes to the surface of the body or into an internal cavity for dispersal. On other occasions the pus remains even after the infection is terminated. In this case, the pus is gradually destroyed over a period of days and is absorbed by the body. As effective as phagocytosis is in contributing to innate resistance, there are times when the mechanism becomes less functional in response to certain conditions. For example, with age, there is a progressive decline in the efficiency of phagocytosis. Recipients of heart or kidney transplants have impaired innate defenses as a result of receiving drugs that prevent the rejection of the transplant. Radiation treatments can also depress innate immune responses by damaging red bone marrow. Even certain diseases such as AIDS and cancer can cause defective functioning of innate defenses. Finally, individuals with certain genetic disorders produce fewer or impaired phagocytes. Tissue repair The final stage of inflammation is tissue repair, the process by which tissues replace dead or damaged cells. Repair begins during the active phase of inflammation, but it cannot be completed until all harmful substances have been removed or neutralized at the site of injury. The ability to regenerate, or repair, depends on the type of tissue. For example, skin has a high capacity for regeneration, whereas cardiac muscle tissue has a low capacity to regenerate. A tissue is repaired when its stroma or parenchyma produces new cells. The stroma is the supporting connective tissue, and the parenchyma is the functioning part of the tissue. For example, the capsule around the liver that encloses and protects it is part of the stroma because it is not involved in the functions of the liver; liver cells (hepatocytes) that perform the functions of the liver are part of the parenchyma. If only parenchymal cells are active in repair, a perfect or near-perfect reconstruction of the tissue occurs. A familiar example of perfect reconstruction is a minor skin cut, in which parenchymal cells are more active in repair. However, if repair cells of the stroma of the skin are more active, scar tissue is formed. As noted earlier, some microbes have various mechanisms that enable them to evade phagocytosis. Such microbes often induce a chronic inflammatory response, which can result in significant damage to body tissues and disrupt tissue repair. The most significant feature of chronic inflammation is the accumulation and activation of macrophages in the infected area. Cytokines released by activated macrophages induce fibroblasts in the tissue stroma to synthesize collagen fibers. These fibers aggregate to form scar tissue, a process called fibrosis. Because scar tissue is not specialized to perform the functions of the previously healthy tissue, fibrosis can interfere with the normal function of the tissue. Fever- While inflammation is a local response of the body to injury, there are also systemic, or overall, responses. One of the most important is fever, an abnormally high body temperature, a third component of the second line of defense. The most frequent cause of fever is infection from bacteria (and their toxins) or viruses. Macrophages are involved with resetting our temp and are responding to part of the pathogen and releasing cytokines which reset the hypothalamus for a higher temp. Abnormally high body temperature Hypothalamus (sometimes called the body’s thermostat) is normally set at 37°C. It is believed that certain substances affect the hypothalamus by setting it at a higher temperature. The fever helps our cells to work more efficiently. when phagocytes ingest gram-negative bacteria, the lipopolysaccharides (LPS) of the cell wall are released. LPS causes the phagocytes to release the cytokines interleukin-1 and TNF-α. Cytokines cause the hypothalamus to release prostaglandins that reset the hypothalamus to a higher temperature ◦When the temp gets too high theres a risk. ◦Chills often predict the onset of a fever. They are caused by rapid muscle contractions and relaxations and are the body’s way of generating heat to raise body temperature. The body maintains the higher temperature until the cytokines are eliminated As the infection subsides, heat-losing mechanisms such as vasodilation and sweating go into operation. This phase of the fever, called the crisis, indicates that body temperature is falling. ◦As body temperature falls (crisis), is vasodilation and sweating occurs Fever Fever can be considered a defense against the disease ◦Phagocytes and T cells work better at a slightly higher temperature (1-2 degrees C) raised ◦Higher temperatures intensifies the effect or production of other antimicrobial substances (such as interferons, transferrins). Because the high temperature speeds up enzymatic reactions, it may stimulate production of immune proteins ◦ Interleukin-1 helps step up the production of T cells, and a high body temperature intensifies the effect or production of other antimicrobial substances (discussed shortly), including antiviral interferons and transferrins that decrease the iron available to microbes. ◦Higher temperatures may slow growth of pathogens that thrive at normal body temp ◦Increased metabolic rate speeds tissue repair processes Complications of fever ◦Tachycardia (rapid heart rate), acidosis, dehydration, seizures, coma Phdrops ◦Body temperature Antimicrobial substances The body produces certain antimicrobial substances, a final component of the second line of defense, in addition to the chemical factors mentioned earlier. Among the most important of these are the proteins of the complement system, interferons, iron-binding proteins, and antimicrobial peptides. The Complement System- complex set of proteins that work as a cascade of proteins interacting with other proteins in the compliment system Complement system- consists of over 30 proteins produced by the liver that circulate in blood serum and within tissues throughout the body. The system is so named because it “completes,” or enhances, cells of the immune system in destroying microbes. The complement system is not adaptable, never changing over a person’s lifetime. Therefore it is no memory considered part of the innate immune system. However, it can be recruited into action by the adaptive immune system ◦Together, proteins of the complement system destroy microbes by cytolysis, opsonization, and inflammation It is◦Serum proteins produced by the liver that enhances the immune system in destroying microbes ‣ Act in a cascade in a process called complement activation Complement is essential to have to get a normal immune response. in takin Blighter.es FagtMsnairtnkimYbsEnc'E Involved with inflammation and helping macrophages. It punches holes in membranes of pathogens to destroy it. Proteins are designated with uppercase C and numbered in order of discovery. The proteins are inactive until they split into fragments (products). These fragments carry out the destructive actions As the complement proteins interact with one another they are cleaved at a certain point into fragments and when they’re cleaved they’re given a lowercase letter (c) its until notactivated cleaved ◦Activated fragments are indicated with lowercase a and b The splitting of inactive complement proteins into activated fragments results from events within one of three pathways of complement activation canbecomeactiveby3ways There are 3 ways of triggering the compliment cascade. ◦The classical pathway ◦The alternative pathway ◦The lectin pathway The reactions within these pathways occur in a cascade in which one reaction triggers another, which in turn triggers another. More product is formed with each succeeding reaction in the cascade, amplifying the effects. All three pathways of complement activation end in the activation of C3. The Classical Pathway Antibodiesneedtobe the Sowe'veseen present by reaction The classical pathway begins with an antigen–antibody reaction. These are compliment proteins found in our blood and produced in liver and they are essential to have healthy immune system C1 (compliment 1) protein recognizes an antibody attached to a pathogen. Must have antibodies in our system in order to recognize the specific pathogen. Antibodies bind to antigens, Antibodies attach to antigens (for example, proteins or large polysaccharides on the surface of a bacterium or other cell), forming antigen–antibody complexes. The antigen–antibody complexes bind to and activate C1. Next, activated C1 activates C2 and C4 by splitting C2 into fragments C2a and C2b, and C4 into C4a and C4b. C1 splits and activates C2 and C4 C2a and C4b combine and activate C3 by splitting it into C3a and C3b fragments. ◦C3a functions in inflammation ◦C3b functions in cytolysis and opsonization typake heh tyke Figure 16.10a Pathways of Complement Activation- need to know how the cascade is involved with innate immunity C1 is recognizing some specific region on the antibody. C1 attaches and once it attaches, C2 come in and C4. C2 is split and theres also a cleavage of C4 and this has to happen for C3 to be split into C3a and C3b, and there are essential components that drive all the compliment pathways. So since this system is driven by antibodies, it assumes that we’ve seen the pathogen before. tcomplexes.CI heantibodies sticktoapathogenand Startsoff when antibody sees protein thisand binds form antigen and T active his a ctivates C2 CY toitanditcleaves becomes C1 C2 get andc2b Ca Ca cleaved combine effectiveat IgMis activating The Alternative Pathway- p athwayif this r it1st useeing time can use The alternative pathway begins by contact between certain complement proteins and a pathogen; it doesn’t involve antibodies. The alternative pathway is activated by contact between certain complement proteins and a pathogen. We want to be able to turn on complement system, even if we don’t have antibodies present, which can be done in the alternative pathway. Can turn compliment cascade on without requiring antibodies present or seeing the pathogen before. We have proteins in our body that make B, D, P which recognizes something on the pathogen but its not antibodies, so we turn on compliment cascade and get down all the way where we need to be. ◦Serum proteins called factor B, factor D, and factor P (properdin) bind to a microbe’s surface. Then C3 is activated when it binds to factors B, D, and P. ◦Once the complement proteins combine and interact, C3 splits into fragments C3a and C3b. As in the classical pathway, C3a participates in inflammation, and C3b functions in cytolysis and opsonization. C3 present in the blood combines with factors B, D, and P on microbe surface C3 splits into C3a and C3b, functioning the same as in the classical pathway Figure 16.10b Pathways of Complement Activation The Lectin Pathway- When macrophages ingest bacteria, viruses, and other foreign matter by phagocytosis, they release cytokines that stimulate the liver to produce lectins, proteins that bind to carbohydrates Macrophages ingest pathogens, releasing cytokines that stimulate lectin production in the liver Mannose-binding lectin (MBL) is a form of lectin that binds to the carbohydrate mannose, which is found in bacterial cell walls and on some viruses. MBL is able to bind to these pathogens because MBL molecules recognize a distinctive pattern of carbohydrates that includes mannose. Tagsit ◦As a result of binding, MBL functions as an opsonin to enhance phagocytosis, and activates C2 and C4. C2a and C4b activate C3, As with the other two mechanisms, C3 splits into fragments: C3a participates in inflammation, and C3b functions in cytolysis and opsonization. Figure 16.10c Pathways of Complement Activation We make protein, mannose binding which is just a sugar binding protein that recognizes the sugar of certain pathogens which triggers the compliment proteins to get us down there which is essential. EEi i ii iii iiain iistacteria 2EE i wIIEiiin in ie Outcomes of Complement Activation The classical, alternative, and lectin pathways result in complement cascades that activate C3. Activation of C3, in turn, can lead to cytolysis, opsonization, and inflammation. The complement can fork MAC, some of the compliment protein can bind to pathogens and now the phagocyte sees the compliment attached to the pathogen and internalizes it (opsonization). Cytolysis ◦Cytolysis of microbial cells involves the formation of a membrane attack complex (MAC) ◦Activated complement proteins create a membrane attack complex (MAC) ‣ The MAC creates a hole on a pathogen’s cell membrane and makes transmembrane channels, allowing for flow of extracellular fluid into the pathogen. The fluid inflow bursts the microbial cell tein'canedmacformsonthesurfaceofthepathogenditmakeholesin.it Activated C3 splits into C3a and C3b. CYIYEI.fi nwdeneagpyp8s the starts ttheppgthogenand assemblyofmac bing.int Etnagen C3b splits C5 into C5a and C5b. C5b through C8 and the multiple C9 fragments form the MAC. ‣ Plasma membranes of the host cell contain proteins that protect against lysis by preventing the MAC proteins from attaching to their surfaces. ‣ Gram-negative bacteria are more susceptible to cytolysis because they have only one or very few layers of peptidoglycan to protect the plasma membrane from the effects of complement. Gram-positive bacteria have many layers of peptidoglycan, which limit complement’s access to the plasma membrane and thus interfere with cytolysis. Bacteria that are not killed by the MAC are said to be MAC resistant  Opsonization ◦Promotes attachment of a phagocyte to a microbe ◦Activated C3 splits into activated C3a and C3b. ◦C3b binds to the surface of a microbe, and receptors on phagocytes attach to the C3b. Inflammation ◦Activated C3 splits into C3a and C3b. ◦C3a and C5a bind to mast cells and cause them to release histamine, cytokines, and other chemicals during inflammation. C5a also functions as a very powerful chemotactic factor that attracts phagocytes to the site of an infection. ◦Activated complement proteins bind to mast cells, releasing histamine. Some compliment proteins increase inflammation and are attraction for the macrophages. Basically compliment activation results in all 3 of these important features of innate immunity. Figure 16.12 Outcomes of Complement Activation A) we see that these two red complement that were a breakdown of C3, starts responding to another complement and its cleaved. And now we ultimately form a core of these C6, C7, C8, and C9. They form a core. And it just opens up a whole membrane and the cell lysis, this is considered cell lysis. We also know that C3B will non specifically bind to pathogens. On the macrophage it has a C3b receptor that it sees. So it lets the macrophage see the pathogen because its decorated with the protein that it can see. B) Maybe this pathogen has a capsule, but now it's C3B, the patch of the capsule, all of a sudden the macrophage recognizes it. And that's what we refer to as opsonization. C) And then we know the complement C5A and B, they stimulate mast cells to release histamine so that the macrophages can get to the site. And the macrophages themselves are attracted to C5A. And so that's why the macrophages are going to that site and we're having a typical inflammatory response. C5a is a tracking macrophages, and neutrophils, and C5a is causing histamine to be released. Figure 16.13 Inflammation Stimulated by Complement Figure 16-8b shows everything and how compliment is critical for us to have a healthy immune system Can turn on complement system 3 different ways- this only shows classical way All of these complement factors are interacting. We see the macrophage has a receptor C3b, which can bind to the organism, and the macrophage is internalizing it. We refer to this as opsonization. We see how the C3a and C5a are part of the inflammatory response. If these factors keep on going down the cascade, we ultimately make the membrane attack complex. Genetically, if we're missing one of these complement factors, we're basically immunocompromised, because you can see the role it plays in our immune system and the innate immunity. *need to know for example why C3b is so important in C5a. reTEE.aiht.in Regulation of Complement Once complement is activated, its destructive capabilities usually cease very quickly, thereby minimizing the destruction of host cells. This is accomplished by various regulatory proteins in the host’s blood and on certain cells, such as blood cells. The regulatory proteins are present at higher concentrations than the complement proteins. The proteins bring about the breakdown or inhibition of activated complement. One example of a regulatory protein is CD59, which prevents the assembly of C9 molecules to form the MAC. Complement and Disease In addition to its importance in defense, the complement system assumes a role in causing disease as a result of inherited deficiencies. C1, C2, or C4 deficiencies cause collagen vascular disorders that result in hypersensitivity (anaphylaxis); deficiency of C3, though rare, results in increased susceptibility to recurrent infections with pyogenic (pus-producing) microbes; and C5 through C9 defects result in increased susceptibility to Neisseria meningitidis and N. gonorrhoeae infections. Complement may play a role in diseases with an immune component, such as systemic lupus erythematosus, asthma, various forms of arthritis, multiple sclerosis, and inflammatory bowel disease. Complement is also implicated in Alzheimer’s disease and other neurodegenerative disorders. The complement system is activated by the SARS coronaviruses, including SARS-CoV-2. The viral capsid protein activates the lectin pathway, whereas the S (spike) protein activates the alternative pathway. This may contribute to the risk of cytokine storm and ARDS associated with COVID-19. Evading the Complement System Some bacteria evade the complement system by means of their capsules. For example, some capsules contain large amounts of a monosaccharide called sialic acid, which discourages opsonization and MAC formation. Other capsules inhibit the formation of C3b and C4b and cover the C3b to prevent it from making contact with the receptor on phagocytes. Some gram-negative bacteria have lipid-carbohydrate complexes on their surface that help them evade the complement system.  For example, Salmonella can lengthen the O polysaccharide of the LPS in their cell wall, a structural alteration that prevents MAC formation. Other gram-negative bacteria, such as N. gonorrhoeae, Bordetella pertussis, and Haemophilus influenzae type b, attach their sialic acid to the sugars in the outer membrane, ultimately inhibiting MAC formation. In addition, some bacteria produce destructive enzymes. Gram-positive cocci, for example, release an enzyme that breaks down C5a, the fragment that serves as a chemotactic factor that attracts phagocytes. With respect to viruses, some not only evade the complement system, but take advantage of it. Lymphocryptovirus (HHV-4), for example, attaches to complement receptors on body cells to initiate its life cycle. Interferons- Because viruses hijack host cells to carry out viral multiplication, it is difficult for the immune system to inhibit viral infections without affecting body cells too. One way an infected host cell counters viral infections is with a family of cytokines called interferons (IFNs) ◦ These are a class of proteins produced by certain animal cells, such as lymphocytes and macrophages. We make interferons from our own cells when we get a particular virus inside the cell, the cell that has the virus secretes interferons and theres different types, A and B are specifically made when a virus enters a cell. M Interferon gamma helps with macrophages and neutrophils to do there job and to properly digest organism. Cytokines produced by cells; have antiviral activity There are three main types of human interferons ◦IFN-α and IFN-β: produced by cells in response to viral infections and in small quantities that diffuse to uninfected neiboring cells ; Both types are host-cell–specific but not virus-specific. They react with plasma or nuclear membrane receptors, inducing the uninfected neighboring cells to manufacture mRNA for the synthesis of antiviral proteins (AVPs) that inhibit viral replication which are enzymes that disrupt various stages of viral multiplication. ‣ They also stimulate NK cells to produce IFN-γ, which induces neutrophils and macrophages to kill bacteria ◦IFN-γ: causes neutrophils and macrophages to kill bacteria ‣ causes macrophages to produce nitric oxide, which appears to kill bacteria by inhibiting their ATP production ‣ IFN-γ also increases the expression of MHC molecules and antigen presentation Figure 16.14 Antiviral Action of Alpha and Beta Interferons (IFNs) What happens is the original cell gets the virus and once the virus comes in, the cell that has the virus is dead but it can start making a protein called interferon, and interferon gets secreted from the cell and goes to into next door neighbor and once its interferon is in the cell all of a sudden start having the cell make antiviral proteins. So it triggers the cell to start make antiviral proteins so if the virus attempts to get into that cell it can’t replicate Interferons are useful for treating all of the viral diseases and they have been used and cloned and cells that make interferons are used to treat people with chronic hepatitis. Used in certain treatments in cancer caused by viruses Interferons would seem to be ideal antiviral substances, but certain problems do exist. They are stable for short periods of time in the body, so their effect is limited. When injected, interferons have side effects such as nausea, fatigue, headache, vomiting, weight loss, and fever. High concentrations of interferons are toxic to the heart, liver, kidneys, and red bone marrow. Another problem is that interferons have no effect on viral multiplication in cells already infected, and some viruses (such as adenoviruses) have resistance mechanisms that inhibit antiviral proteins. Iron-Binding Proteins Bacteria want iron for their vegetative growth and reproduction. So we want to protect it as much as we can. An infection creates a situation in which pathogens and humans compete for available iron. Most pathogenic bacteria require iron for growth and reproduction. Pathogens may compete with host for available iron The concentration of free iron in the human body is low bc host proteins bind iron tightly with iron-binding proteins: we make all of these iron binding proteins that hide the iron from bacteria ◦Transferrin: found in blood and tissue fluids ◦Lactoferrin: found in milk, saliva, and mucus ◦Ferritin: found in the liver, spleen, and red bone marrow ◦Hemoglobin: located in red blood cells ◦The iron-binding proteins not only transport and store iron but also, by doing so, deprive most pathogens of the available iron. Some bacteria produce siderophores to compete with iron-binding proteins by binding it more tightly. They try to get any iron hat is free. ◦Once the iron–siderophore complex is formed, it is taken up by siderophore receptors on the bacterial surface and brought into the bacterium; then the iron is split from the siderophore and utilized Antimicrobial Peptides-Small by made proteins the tohelp body infections fight Are short peptides (consist of a chain of about 25-50 amino acids made on ribosomes) produced in response to protein and sugar molecules on microbes AMPs have a broad spectrum of antimicrobial activities, including activity against bacteria, viruses, fungi, and eukaryotic parasites Synthesis of AMPs is triggered by protein and sugar molecules on the surface of microbes. Cells produce AMPs when chemicals in microbes attach to Toll-like receptors. Over 600 different peptides have been discovered in plants and animals. Have different functions ◦Some Inhibit cell wall synthesis ◦Form pores in the plasma membrane causing lysis ◦Destroying D N A and R N A The idea is they protect us from pathogens that might enter us.  Examples made by humans: ◦Dermcidin- produced by sweat glands (skin), defensins- produced by neutrophils, macrophages and epithelium, cathelicidins- produced by neutrophils, macrophages and epithelium (neutrophils, macrophages), thrombocidin- produced by platelets AMPs have shown synergy (working together) with other antimicrobial agents, so that the effect of them working together is greater than that of either working separately. AMPs are also very stable over a wide range of pH. What is particularly significant is that microbes do not appear to develop resistance even though the microbes are exposed to them for long periods of time. In addition to their killing effect, AMPs can sequester the LPS shed from gram-negative bacteria, thereby preventing endotoxic shock. AMPs have been found to vigorously attract dendritic cells, which destroy microbes by phagocytosis and initiate an adaptive immune response. AMPs have also been shown to recruit mast cells, which increase blood vessel permeability and vasodilation. This brings about inflammation, which destroys microbes, limits the extent of damage, and initiates tissue repair. Other Factors In addition to the aforementioned factors that provide resistance to infection, several others also play a role. Genetic resistance is an inherited trait in a person’s genome that provides resistance to a disease. It confers a selective survival advantage. ◦One example is the relationship between sickle cell trait and Plasmodium falciparum; individuals who have sickle cell trait are relatively protected against P. falciparum malaria. ◦Another example is the relationship between prions and spongiform encephalopathy; a naturally occurring variant of a human prion has been found that completely protects against the disease. ◦Age also influences resistance: young children (whose immune systems are still developing) and older adults (whose immune systems are less responsive) are more susceptible to disease. ◦Finally, observing healthy protocols such as proper handwashing, controlling sneezing, employing standard precautions, avoiding cross-contamination and fecal-oral transmission, and safer sex practices also provide resistance to infection.