C2 Immunology PDF

MIC343 ~Immunology~ Innate immunity – non specific body defense system CHAPTER 2  Syllabus content Barrier Defences Molecules of innate immunity Cells involved in innate immunity Mechanisms of innate immunity  Inna...

MIC343 ~Immunology~ Innate immunity – non specific body defense system CHAPTER 2  Syllabus content Barrier Defences Molecules of innate immunity Cells involved in innate immunity Mechanisms of innate immunity  Innate immune response The response that is available to us when we are born and is immediately available. It is nonspecific – this response can react against any infection or pathogen. The first line of defense in the innate immune response consists of mechanical, chemical and microbial barriers. The second line of defense against infection involves specific cells and molecules.  Barrier defences (First line defense)  1) The barrier - Skin Semi-watertight barrier made up of epidermis and dermis. The epidermis is composed of many layers of tightly packed dead and dying cells that contain keratin – keratin is a tough protein that gives the strength, flexibility and semi-waterproof properties to the skin. The epidermis are continuously being sloughed off.  The barrier - Skin Epidermal layer have no access to blood or lymph – intrusion of pathogens will be localized and not systemic. Normal flora microbes blocks the growth or other microbes. The skin synthesize and arrange proteins with antimicrobial activity, e.g. psoriasin (posses antibacterial activity against E. coli).  The barrier - skin The salty and acidic pH of skin perspiration inhibits bacterial growth. Sebum, the oily secretions of sebaceous gland contains chemicals that are toxic to bacteria. The skin is dry and has a temperature lower than 37oC - these conditions are not favorable to bacterial growth. Hair follicles and sweat glands produce lysozyme and toxic lipids that can kill bacteria. Beneath the skin surface is skin-associated lymphoid tissue (SALT) that contains cells for killing microbes and sampling antigens on the skin to start adaptive immune responses against them.  2) The barrier – mucous membrane Mucous membranes are : composed of an epithelial layer that secretes mucus, and a connective tissue layer. line body cavities that open to the outside environment. constantly sloughing cells to remove microbes. Resident normal flora of the mucosa also inhibit potentially harmful microbes. The stomach mucosa secretes HCl and protein- digesting enzymes that could kill pathogens.  The barrier – mucous membrane Mucus helps defend against any intrusions through a mechanism called mucociliary escalator. the goblet cells of lower respiratory tract produce mucus which traps any microorganisms that have entered the tract the ciliated cells move the mucus up before it is swallowed or expectorated. coats the stomach wall to protect it against the acidic fluids needed for digestion.  3) The barrier – lacrimal apparatus Lacrimal apparatus is a group of organs concerned with the production and drainage of tears. Tears are produced in the lacrimal glands and constantly flush any foreign particles into the nasal cavity.  The barrier – lacrimal apparatus Tears contain: i) Lysozyme – enzyme that destroys peptidoglycan of the bacterial cell walls. ii) Lipocalin – inhibit the pathogens by binding the irons. iii) IgA – antibody that prevents microbial attachment and neutralizes toxin. Discuss the chemicals presence in tears with their roles in the innate immunity. (6 marks)  4) The barrier – saliva Saliva is produced by salivary glands. It functions to cleanse the teeth and mucous membranes of the mouth and prepare food for digestion. It washes microbes down the esophagus and into the stomach. Saliva also contains lysozyme, IgA and histatin; peptide that has antifungal activity and has a role in wound repair.  5) The barrier – epiglottis Epiglottis is a flap of tissue at the back of the throat. The epiglottis prevents liquids, foods and saliva from entering the lower respiratory tract.  6) The barrier – urine and vaginal secretions The acidity of urine inhibits most microbial growth in the urinary tract. The flushing action of this body fluid keeps microbes from attaching to tissues. Urine also contains lysozyme. Vaginal secretions and lactic acid produced by resident bacteria help make the vagina more acidic, thus help prevent colonization by potentially pathogenic bacteria. However, as low-pH conditions allow fungal organisms to grow, yeast infections are more common in women than in men.  7) The barrier – transferrins Transferrin is blood proteins that bind iron and prevent microbes from using it in their growth and metabolism. Molecules of innate immunity  1) Pattern recognition receptor (PRR) Recognition of non-self foreign substances are made by the immune system receptors called pattern recognition receptors (PRRs). PRRs identify molecules associated with foreign substances and enable immune cells to differentiate between self and non-self. They are mainly expressed by antigen presenting cells (APC) but they are also found in other immune and non-immune cells. Recognition is essential!  Pattern recognition receptor The PRR are divided into several groups: i) Toll-like receptors (TLR) ii) Nucleotide oligomerisation receptors (NLR) iii) C-type lectin receptors (CLR) iv) RIG-1 like receptors (RLR)  Pattern recognition receptor The receptors present: i) at the cell surface to recognize extracellular pathogens (e.g. bacteria & fungi). ii) in the endosomes where they sense intracellular invaders (e.g. viruses). iii) in the cytoplasm. PRR recognize particular overall molecular patterns of the pathogen that are generally absent from the host. 2) Pathogen associated molecular patterns Pathogen Host cell The pattern found on pathogens are called pathogen- associated molecular patterns (PAMPs).  Pathogen associated molecular patterns (PAMP) Characteristics of PAMP : Pathogens (especially bacteria) have unique microbial structural patterns of motifs that are not shared with their host. It include combinations of sugars, certain proteins, particular lipid-bearing molecules and some nucleic acid motifs. The molecules are shared by groups of related microbes. The structures are relatively invariant; that is, do not evolve rapidly. These molecules are essential for the survival of those organisms. In addition, unique molecules displayed on stressed, injured, infected, or transformed human cells also act as PAMPs.  Pathogen associated molecular patterns Some TLR and the non-self components they bind: TLR Ligand bound TLR-1 Lipoproteins TLR-2 Bacterial lipoproteins TLR-3 Double-stranded RNA TLR-4 Lipopolysaccharide, some viral proteins TLR-5 Flagellar protein TLR-6 Lipotechoic acid TLR-7 Single-stranded viral RNA TLR-8 Single-stranded viral RNA TLR-9 Bacterial DNA TLR-10 Unknown  3) Cytokines Cytokines are low-molecular-weight proteins secreted by cells of both innate and adaptive immune systems and can regulate diverse functions in the immune response. Cytokines have a fundamental role in communication within the immune system and in allowing the immune system and host tissue cells to exchange information. Cytokines act in an antigen-nonspecific manner – they affect whatever cells they encounter that bear appropriate receptors and are in a physiological state that allows them to respond.  Cytokines Two major families of cytokines : i) hematopoietin family; eg: growth hormones and interleukins (ILs) ii) tumor necrosis factor (TNF) family. Even though both families involved in innate and adaptive immune responses, when TLRs recognize a pathogen, a variety of cytokines are released, chiefly from the TNF family.  Cytokines Cytokines can affect the cells by several mode of action: i) Autocrine action: cytokines bind to receptors on the membrane of the same cell that secreted it (affect the cells that produce them). ii) Paracrine action: cytokines bind to receptors on a target cell in close proximity to the producer cell (cytokines affect the neighboring cells). iii) Endocrine action: cytokines bind to target cells in distant parts of the body (cytokines affect cells in other areas of the body).  Cytokines The action of a cytokine depends on the concentration of that cytokine. Cytokines act through specific receptors on their target cells and alter the activity of the cells with several characteristics: i) pleiotropy: cytokines has different biological effects on different target cells.  Cytokines ii) redundancy: two or more cytokines mediate similar functions (thus it is difficult to ascribe a particular activity to a single cytokine). iii) synergism: the combined effect of two cytokines on cellular activity is greater than the additive effects of the individual cytokines.  Cytokines iv) antagonism: the effect of one cytokine inhibit or offset the effects of another cytokine. v) cascade induction: the action of one cytokine on a target cell induces that cell to produce one or more other cytokines, which may induce other target cells to produce other cytokines.  Cytokines Functions of cytokines: i) Promote inflammation. ii) Endogenous pyrogen – occurs especially when the invading organisms have spread into the blood iii) Decrease iron concentration in plasma – iron is needed to support bacterial multiplication. iv) Stimulates the release of acute phase proteins – aid in inflammatory process, tissue repair, immune cell activities. v) Stimulate the release of histamine. vi) Enhance the proliferation and differentiation of B cells and T cells. vii) Stimulates the synthesis and release of neutrophils and monocyte by the bone marrow  Test yourself! Differentiate mast cells and dendritic cells (4m) Describe 3 examples of chemical barrier which helps to prevent the invasion of pathogen into human body (6m) Discuss the properties of antigen’s pattern detected by PRR (5m) Cells of the innate immunity  Cells of the immune system Leukocytes or white blood cells contain a nucleus, lack hemoglobin and colourless cytoplasm. The leukocytes fall into two main categories, depending on the → appearance of their nuclei → the presence or absence of granules in their cytoplasm when viewed microscopically  Cells of the immune system Neutrophils, eosinophils and basophils are categorized as polymorphonuclear granulocytes – nuclei are segmented into several lobes, and the cytoplasm contains abundance of granules. Monocytes and lymphocytes are known as mononuclear agranulocytes – both have a single, large, nonsegmented nucleus and few/less granules. Cells of the immune system  Neutrophil Neutrophils showed no dye preference - granulated cytoplasm is stained with both acid and basic dyes. The first defenders on bacterial invasion – increase number of neutrophils typically accompanies acute bacterial infections. They sense the site of the infection, migrating to it and destroying the infectious organisms by phagocytosis. They attach to the walls of the blood vessels thus blocking the passageway of antigens that try to gain access to the blood through a cut or infectious area. Produce toxic substances that are released into extracellular fluids and damage host cells.  Eosinophil Granulated cytoplasm is stained with acid dye eosin red. Increase number of eosinophils are associated with allergic conditions (e.g. asthma and hay fever) and with internal parasitic infestations (e.g. worms). Eosinophils are less active in terms of their phagocytic function. Eosinophils attach to the worms and secrete substance to kill it. Modulate the inflammatory response.  Basophil Granulated cytoplasm is stained with basic dye methylene blue. Least numerous and most poorly understood of the leukocytes. Basophils differ from eosinophils and neutrophils in that they are not phagocytes They synthesize and store histamine; involved in allergic reactions and inflammations, as well as, increase and magnify innate immune response.  Monocyte/macrophage The largest leukocyte. Professional phagocytes. Normally the number of monocytes circulating in the blood is quite small; it increases during an infection. Monocytes are called to the site by chemotactic factors released from damaged tissue and neutrophils. Once it reach the site, they migrate out into the tissues and differentiate into macrophages (produce granules within themselves).  Monocyte/macrophage They can recognize, engulf, and destroy bacteria, fungi, protozoa, as well as, removing tumor cells, virus-infected cells, and normal cells that have undergone apoptosis. They also function in wound healing, tissue repair and bone remodeling They process the antigens to be recognized by T cell. They secrete cytokines for various roles in immune system.  Dendritic cells Participate in both innate (by phagocytosis) and the adaptive (by Antigen Presenting Cell) immune response. They have long membranous extensions that resemble the dendrites of nerve fibers. Located in the skin and mucosal tissues associated with routes of pathogens entry such as the oral, respiratory and genital mucosae. They help to trigger the adaptive immune response. Migrates to lymph node upon activation.  Mast cells Contains a lot of granules – synthesize and store histamine and heparin. Responsible for allergic reactions and response to parasitic infections. Found throughout the body but most commonly in tissues that are exposed to the external environment, such as mucous membranes. They can rapidly and selectively produce mediators that work in host defense. They can enhance the recruitment of effector cells that respond to infection. They can influence the adaptive immune response. The mechanism of innate immunity  The mechanism of innate immunity Detection of PAMPs brings multiple components of immunity into play. It includes: NK cells action  1. Inflammation Definition: The initial, rapid and localized response of the tissue due to damage/injury, infection, antigen challenge and physical/chemical damage or other trauma. Acute inflammation plays role in innate immunity by: i) Destroying the infectious agent and remove it and its by products and any cell debris. ii) Localize the infectious agents by building a ‘wall’ around them so that they do not spread to neighbouring sites. iii) Heal, repair, and replaced the damaged tissue. During inflammation process, damaged mast cells and leukocytes release chemicals, e.g. histamines and kinin.  1. Inflammation Sequence of event that occur: i) Vasodilation of the blood vessels around the site of infection, which increase blood flow to that area, as well as bring loads of immune system cells that will move to the site of infection and removes toxic products released by invading microbes. ii) Increase permeability of the blood vessels, thus some leukocytes, plasma and antibodies leak out into the infected tissue. The leukocytes will phagocytose invading pathogens and release molecular mediators that may contribute to the inflammatory response and the recruitment and activation of effector cells.  1. Inflammation iii)Chemokines (mediators of inflammation) are induced in response to infection. It will act as chemoattractants – to attract more leukocytes, which cause extravasation process (leukocytes adhere to endothelial cells in the inflamed region and pass through the walls of capillary and into the tissue spaces). iv) Systemic response may occur, e.g. fever, which will help to accelerate the proliferation of leukocytes. 1. Inflammation  1. Inflammation The common cardinal signs of acute inflammation: - redness: due to increased blood flow. - hotness: due to increased metabolic activity. - swelling: due to leakage of fluid from capillaries. - painful : the inflammatory process may also stimulate nerves and cause pain. - loss of function. https://www.youtube.com/watch?v=9bvMv5dQ7RU 1. Inflammation  2. Phagocytosis Definition: The process of ingestion of solid substances (e.g. cells, bacteria, parts of necrosed tissue) by phagocytes and transported to a site within the phagocytes where it is broken down by lysosomal enzymes. When an infection begins, the traumatized tissue produces chemokines. The presence of chemokines signals phagocytes to move to the damaged site Neutrophil (yellow) engulfing by chemotaxis. Bacillus anthracis (orange).  2. Phagocytosis Once some phagocytes reach the damaged site, they also release chemokines, thus amplifying the effectiveness of the defensive response. Two most active phagocytes : i) Neutrophils: engulf between 5 to 20 bacteria - become inactive and die. ii) Macrophages: engulf up to 100 bacteria, debris from damaged cells and foreign matter.  2. Phagocytosis How they work: 1) Chemotaxis: phagocytes are attracted to site of infection. 2) Microbe binds to receptors on phagocyte. Pseudopodia surround microbe and engulf it.  2. Phagocytosis 3) The pathogen is now contained in phagosome @ phagocytic vesicle. Phagosome moves deeper into cell. 4) A lysosome fuses with the phagosome – it forms phagolysosome.  2. Phagocytosis 5) Contents from lysosome digests the microbe within the phagolysosome. 6) Content of lysosome further digest the microbe, forming the residual body containing indigestible material. 7) Contents of phagolysosome is eliminated by exocytosis. Using a flow chart, illustrate the process of phagocytosis (6 m)  2. Phagocytosis After a few days, the area is full of dead cells, which form pus. The contents of pus are dead neutrophils, tissue debris and some remaining pathogens. The pus may break through the surface of the skin or broken down and absorbed into the surrounding tissue.  3. Fever Some cytokines may function as endogenous pyrogen (e.g. interleukin 1), which induces the development of fever - it occurs especially when the invading organisms have spread into the blood. Exogenous pyrogens → produced by the invading pathogens e.g. bacterial toxins. Both pyrogens cause release of prostaglandin within hypothalamus – resets the hypothalamus temperature control thus resulting in elevation in body temperature.  3. Fever Fever is a beneficial response because: i) it inactivates many bacterial toxins by changing their 3D shape. ii) it lowers plasma iron concentration – without iron, pathogens do not grow well. iii) it increases the speed of host defenses process – augment phagocytosis, increase the rate of many enzyme-dependent inflammatory activities & promotes production of immune cells. iv) fever makes a person feel ill, thus forces a person to rest - allowing all available energy to be used for fighting off infection.  3. Fever However, if the body temperature is too high: i) vasoconstriction occur – inhibits the movement of phagocytes. ii) rate of metabolism increased – making the heart work harder. iii) denaturation of proteins occur. iv) nerve impulses is inhibited. v) electrolyte imbalance occur due to loss of water. These can lead to hallucinations, convulsions, coma and death. If fever goes beyond 40OC, antipyretic medications are given to the patient.  4. Complement system The complement system comprises a group of soluble proteins and glycoproteins, many of which exist in inactive forms. The complement system can be activated in two ways: i) Alternate complement pathway: binding directly to a foreign invader nonspecifically activates the complement cascade (innate immune response). ii) Classical complement pathway: binding to antibodies produced against and attached to a particular foreign invader specifically activates the complement cascade (adaptive immune response).  4. Complement system When complement becomes attached, or fixed, to foreign substances, it is activated and becomes a major factor in the fight against foreign substances. The complement fixation mediates opsonization, activation of inflammation and formation of membrane attack complexes that causes cell lysis. https://www.google.com/search?q=activation+of+complement&sca_esv=578040869&tbm=vid&source=lnms&sa=X&ved=2ahUKEwjiwY uGvJ-CAxVMe2wGHWhACFwQ_AUoAnoECAIQBA&biw=1422&bih=612&dpr=1.35#fpstate=ive&vld=cid:12f2adef,vid:E4dZ5w3D9ZM,st:0 Explain the complement system and its role in innate immune response. (6 marks) (Dis 2018)  5. Interferon Viruses enter the host cell as part of the infectious process. When cells are infected with viruses, they produce interferons. Interferon is a protein produced by virus-infected host cells and released from those cells. Interferon then diffuses to the surrounding uninfected cells and prompts them to make antiviral proteins. Antiviral proteins degrade viral mRNA, stop viral replication and also inhibit protein synthesis. Interferons are not virus-specific – are produced in response to any viral infection. 5. Interferon  5. Interferon Besides facilitating inhibition of viral replication, interferon: i) enhances phagocytic activity of macrophages. ii) stimulates production of antibodies iii) boosts the power of killer cells. iv) slows cell division and suppresses tumor growth.  6. Natural killer cells NK cells are involved in the innate immune response in two ways, through target-cell killing and through the production of cytokines. NK cells destroy cells infected by virus and tumor cells. NK cells release: i) perforin (and other molecules) which form pores in the cell membrane of the target cell. ii) granzymes which induce apoptosis or cell lysis.  Test yourself! 1. Distinguish the response of NK cells and interferon towards invasion of pathogens. (6 m) 2. Predict why the finger became warm, red, painful and swollen after a man had accidentally cut it. (4 m) 3. Discuss the principal changes that occur in the tissue during an acute inflammatory response. (4 m)