Mechanisms of Defence2023 TranscriptBB - Tagged (1).pdf

Lecture: Mechanisms of Defence 2023 Today’s topic with look at mechanisms of defence of our bodies Slide 1: Mechanisms of Defence In the last lecture we looked at a range of organisms and how they can cause infection in the human body. Today we will begin to look at the defence mechanisms that our b...

Lecture: Mechanisms of Defence 2023 Today’s topic with look at mechanisms of defence of our bodies Slide 1: Mechanisms of Defence In the last lecture we looked at a range of organisms and how they can cause infection in the human body. Today we will begin to look at the defence mechanisms that our body uses to both prevent infectious agents (IF) gaining access to our body, but also if they do, how our body attempts to remove these & eradicate them. Slide 2: The Problem All organisms, including the human body, are susceptible to infections or parasitisation, which is a problem as they can cause harm to our bodies. Disease can be caused by many infectious agents/foreign invaders examples are: viruses, bacteria, fungi, worms, protozoa - All of which we mentioned in our previous lecture. these organisms need to gain access to our body to cause disease – how to they do that? There are a number of routes of entry into body that can offer access to infectious agents into our body: Dust/droplet particles containing infectious agents can be – inhaled/breathed in through the nose Infectious agents can be ingested through the mouth either accidently or inadvertently eg contaminated food or touch mouth with hands that have microbes/other IF on them, without thinking. IF can gain access to body either transplacentally or via the blood. However, many of us do not fall ill and even if we do, we do not die. Slide 3: Compromised Hosts The reason for this is that our bodies have a number of ways to prevent these IF agents getting into the body. And even if they do manage to get in, our bodies also have other defence mechanisms that are set in motion to attempt to localise, remove or eradicate them from our body. However, despite these protective and defence mechanisms, that prevent access to these Ifs, or if they do, immune system In some cases/circumstances our bodies are more susceptible to disease by infectious agents, this is when our bodies are weakened or compromised i.e. compromised hosts.  Age can affect susceptibility to disease Fetus: is susceptible during gestation to different infectious agents should they be exposed to these, at different times periods/at particular time periods. Eg rubella, toxoplasma & parvovirus and The damage to the fetus will be dependent on the infectious agent, gestation time & duration of exposure Consequence may be no effect, minimal, congenital abnormality or lead to miscarriage – talk more in Genetic disease lecture. Young children: under the age of 3yrs are more susceptible to the effects of viruses & bacteria – leading to excessive vomiting or diarhoea which can potentially lead to an imbalance of electrolytes. This together with massive fluid loss can lead to severe dehydration and if not corrected could be fatal. Ageing/the Elderly: are more susceptible to infection due to the decline in efficiency of the immune system as a function of age. They are also more susceptible to an increase in severity of illness. Eg young person flu symptoms may be mild, but in case of the elderly could be more severe: leading to pneumonia and even be fatal – hence flu vaccines are offered annually to people over age of 60 years.  Stress, Malnourishment/ill health – all increase our bodies susceptibility to infection due to the negative effects on the immune defence leading to it decline and its ability to defence  Physical trauma: eg cuts, burns – which we mentioned in the introduction to pathology. eg. if the skin that surrounds and protects our whole body by acting as a barrier to micro-organisms suffers an injury eg cut/burn that open the body to expose underlying tissues/internal environment, so that bacteria enter and cause a secondary infection. - Smoking can also compromise the body - impairs the ciliated mucosal epithelium in the respiratory system, blunting the cilia and affecting the cilia action which are essential in moving mucus with any trapped dust/bacteria in it away from the lungs. Mucus with bacteria within remains within the respiratory canal, increasing the risk of developing respiratory infection.  Some Genetic disorders e.g. EB: epidermolysis bullosa - by virtue of fact that skin blisters and blisters break, thereby opening up body’s internal environment to bacteria and so secondary infection  Immunocompromised patients: include those immunosuppressed therapeutically such as patients that have undergone organ transplantation or by those suffering from a disease that affects the immune system eg AIDS – autoimmune deficiency syndrome – are compromised hosts and have an increased susceptibility to infection. Slide 4: Host Defence Mechanisms So the reason we do not become ill, or if we do, we do not die, is because our bodies have a number defence mechanisms that it uses to prevent pathogens/IF agents getting into our body, These mechanisms are: Passive host defences  physical and chemical barriers – prevent access to organisms that cause harm  normal flora - ‘commensal’ bacteria – these bacteria that exist within our bodies living in a symbiotic relationship with our bodies – not causing harm to our bodies, but competing with pathogenic bacteria for nutrition & receptor sites for binding/attaching to our body Active host defences – include innate immunity & adaptive immunity that we have mentioned. - kick in to try to eradicate any organisms that have managed to get past the passive defence mechanisms and access our bodies. Slide 5: Passive Mechanisms of Defence – may be  Physical Barriers: anatomic & specialised  Secretions (also a physical barrier as preventing micro-organisms from to attaching to our body) often used in combination with:  Washing mechanisms – Movement/ Reflexes – attachment prevented – these then forcefully remove/displace the non-attached micro-organisms out of body. Reflexes, if you remember when we looked at spinal reflexes we said they were protective. Here we are talking about protective mechanisms such as blinking to prevent eg a fly from going into our eye. So here they are protecting against various micro-organisms/irritants getting into various organs within our body to prevent them harming us.   Chemical: also within body, sometimes in secretions to protect our body e.g. anti-microbial agents in tears  Resident microbes: commensal bacteria  that live in or on our bodies to essentially compete for attachment sites or nutrients to prevent those pathogenic bacteria from colonising our bodies Slide 6: Physical barriers If we start with physical barriers, these will overall protect our bodies by preventing access of pathogens to our bodies or by preventing them from attaching to our bodies so they cannot gain access - Some physical barriers such as bone = physical barrier, offers protection against injury, rather than infection. Includes: 1. eg Bone: skull surrounds brain, ribcage that surrounds lungs and internal organs from being damaged by physical injury 2. Epithelium: specialised cell surface throughout our body that protects the internal environment of our body as well as the external surface (i.e. skin). Important to remember that in the case of skin, it is important in maintaining the health status of our bodies as well as the epithelium forming a surface barrier, surrounding our body to prevent organisms trying to gain access to it. e.g. skin, intestine, lungs, cornea, conjunctiva Epithelium of skin is a stratified multi-layered epithelium that is similar to that of cornea & conjunctiva in that they are both multi-layered. Note that in the case of the lungs and the intestine, the specialised epithelium is a monolayer of epithelial cells. Note that multi-layered epithelium are present in external structures such as skin, conjunctiva and cornea, whilst the monolayer epithelium of the lungs and intestine line the inner surfaces within eg lungs or intestine. All these epithelia is that they have continuous cell layers and are bound by tight junctions, and the cells in these tissues are being turned over so you have shedding from outer surface thus any adhering bacteria/virus can be shed before gaining access to the cells. In case of multi-layered epithelia – any infectious agent has to first attach to its surface cell layer, and then find a way to get through a number of cell layers before it can access body and cause disease. The epithelium forms as continuous cell layer(s) in whatever tissue they are part of, and cells have tight junctions between them to prevent infectious agents entering body. All are present to deter entry of micro-organisms e.g. bacteria into cell/body. The cells undergo continual cell turnover – for instance remember when we looked at the skin and corneal epithelium – we discussed that they continually underwent cell turnover – with cells shed from the surface being replaced as a result of cell division in the stem cells in limbus (epidermal proliferative unit in skin) & TACS in basal epithelium. If any micro-organisms/infectious agents attach to the outer surface cells – these will be shed too – preventing them from gaining access to other epithelial cell layers. So the epithelium is a specialised surface that can be present externally, such as on skin, or internally lining the body cavities, e.g ciliary mucosal epithelium Physical barriers are internal and external External:  Cornified skin: dead external surface – no nucleus and therefore no genetic material (important as prevents viruses from being able to hijack cell machinery for own purpose of viral replication) – has a dead external surface – also shed before any micro-organisms can gain access to live cells. Also it's important to note that the skin, conjunctiva and cornea produce lipids onto their cell surface, on the outer surface, which is very important because it makes it slippery.  Therefore lipids prevent attachment - skin, conjunctiva, cornea – slimy & slippery – therefore prevent attachment of infect agents. Eg ceramide, fatty acids & cholesterol Internal environment of the body the specialised cell surfaces e.g. ciliated mucosal epithelium: lines internal cavities of the body – nose, gut and produces mucus such that any organisms trying to gain entry into the which can trap any bacteria or dust or infectious agents that get in.  Mucus secretion e.g. respiratory system; - traps any bacteria within it, then  Cilia (nasal passages, trachea) – beating upwards & outwards to move mucus away from entering lower respiratory canal, including dust particles & any bacteria trapped within, to be spat & sneezed out of body to prevent damage to lungs. Even nasal passages are lined with cilia to prevent dust particles additionally, entering upper respiratory canal. Other protective mechanisms of skin: role in  Temperature regulation: sweat glands & blood vessels at skin surface (vasoconstriction in cold, withdraw heat from our extremities & skin surface, to prevent heat loss and maintain core body temperature of body organs. Conversely, vasodilation occurs when the environment is hot to promote heat loss.  Additionally, we have sebaceous glands which are important for hydration of skin, to waterproof it by secreting oily sebum - note both sweat & sebum also contain chemicals which are toxic to bacteria in an attempt again to get rid of noxious agents or bacteria and prevent them from gaining access to our bodies. Sweat, like the tear film, has lysozyme that can break down bacteria, as well as other anti-microbial substances Slide 7: Secretions: physical & chemical defence Secretion ssuch as e.g. tear film, stomach fluid, saliva, mucus = physical barriers also, but also have substances within them that can aid in defence against various bacteria. As a physical barrier, secretions such as mucus (as mentioned) can prevent micro-organisms from attaching to surface. Mucus is mainly glycoprotein in nature, forming a slimy surface and they can repel Ifs before they are able to attach. If they do attach they can incapacitate them within the mucus to prevent them from gaining access to the body. Chemicals – within secretions may be bactericidal enzymes or chemicals that can inactivate or actively destroy the target bacteria causing them to lyse. Secretions creating a chemical environment that is toxic to bacteria include: secretions in the gut which has a pH of 2, skin : pH 4-6 & saliva: pH 6.7 which are pHs detrimental to some bacteria, preventing them from thriving, thus offering protection to our bodies. The oxygen tension in various tissues can also be detrimental to bacteria, for example the high oxygen tension in the lungs: can lead to generation of oxygen free radicals that can in turn lead to lysing of these bacteria and killing them, thus preventing them from gaining access to our body. Slide 8: Secretions offer internal chemical protection Chemicals within secretions can again protect the body from IFs. Examples include those within the urinary system (flushes the system), Respiratory system (see above) and Digestive system. Here: Saliva has enzymes in mouth that are bactericidal -> lysis, preventing bacteria from entering the body Tongue: friendly bacteria that convert food nitrates into nitrites that pass into stomach, where the acidity of the environment can kill the bacteria, or convert those nitrites to NO; which itself is toxic to bacteria. In intestine: resident bacteria (commensal bacteria) that are friendly to our bodies preventing other pathogenic bacteria from colonising our gut or intestine. These commensal bacteria essentially compete with pathogenic bacteria for attachments sites in the gut and also nutrients, so that the pathogenic bacteria cannot thrive, so die. Slide 9: Movement/Washing: Removal of pathogens Often go hand in hand with secretions & will actively and physically remove the pathogens from their attachment sites. Examples: Urinary tract flushing Gut motility Respiratory tract Respiratory system in more detail: Has ciliated mucosal epithelium lining the airways, both in the upper or lower respitratory tract, and there are millions of tiny hair-like projections i.e. cilia, which beat upwards and outwards to remove anything that is trapped within the mucus that lines the respiratory tract. Note: mucus is glycoprotein; = thick, sticky lining traps dust, bacteria. Cilia moves the bacteria/dust up and outwards to be expelled i.e. spat or sneezed out of body. Reflexes: offer protection to vital body parts. Good e.g. of body’s adaptation to prevent injury from noxious substances gaining entrance to the body and damaging vital organs. Reflexes = important as they forcefully remove/expel any irritants, toxins or pathogens. In the eye, eyelid blinking protects against anything trying to enter the eye. In case of lungs, have sneeze and cough. In case of the stomach, vomiting of noxious chemicals prevents them from gaining access further into our bodies or being absorbed. Slide 10: Resident microbes = commensal bacteria present in/on human body, generally harmless to our bodies, living in a symbiotic relationship i.e. bacteria live in body with both body & bacteria benefitting. They have attachment sites and nutrients, and successfully compete against pathogenic bacteria to prevent them from gaining access to our body.  For example, these commensal bacteria are in/on: skin, oral cavity, respiratory tract, gut/intestinal tract and genitourinary tract E. coli and lactobacillus are examples in the intestine. It is also thought that that they have a role in absorption of various nutrients and even have a role in production of certain vitamins, as well as successfully competing with other pathogenic bacteria. Thought that there are 300- 500 species just within the intestinal tract. Slide 11: The Human Microbiome Project: The Human Microbiome is the collection of all the microorganisms living in association with the human body. These microbes (as we have mentioned before) are generally not harmful to us, but are essential for maintaining health. They colonize the surface and insides of our bodies helping us to:  produce certain vitamins and regulate our immune system.  digest our food  and keep us healthy by protecting us against disease-causing (pathogenic) bacteria. - In 2008, The Human Microbiome Project was launched by the National Institute of Health (NIH), with the aim to build resources to enable the characterization of the human microbiome and analysis of its role in human health and disease. It’s aim was to identify and characterize flora and fauna in the human microbiome, with the ultimate goal: to test how changes in the human microbiome are associated with human health or disease. Before this project, the microbiome was poorly understood. So the HMP is revolutionary project, in that it mapped out the human microbiome in all its complexity. Slide 12: Introduction to Immunology: basic terms IMMUNOLOGY: is the study of physiological mechanisms that our body uses to defend itself from invasion by other organisms Infection with an organism (if not fatal) provides IMMUNITY to that organism in the future THE IMMUNE SYSTEM is the systems and cells that the body invests in, in order to prevent organisms gaining entrance to our body’s or if they do, eradicating them. Role of Immune System? First needs to recognise that a foreign organism is invading it [PATHOGENS: organism causing harm to body) Role in preventing the spread of the infectious agent that attempted to access the body, and finally it will clear away or eradicate the pathogens from the body. Slide 13: Host Active Defence System: Immune System = immune system and its purpose is to recognise invading foreign organisms (PATHOGENS), to prevent spread of the pathogens if they do gain access, and to clear pathogens, fully remove them, from the body Innate immune system: able to detect pathogens by recognition of general molecular mechanisms –of a wide range of bacteria /viruses (= non-specific), does not lead to long term immunity. If pathogen enters body, it the keeps enemy at bay and localises the site of infection, until more selective weapons of adaptive immune system are developed. Adaptive immune system: focuses on a specific target i.e. the particular species pathogen at hand in order to develop antibodies and cytotoxic cells against that specific target. It offers long-lived protection to that if that specific pathogen enters body again it is ready to kick in again, and launch an attack on it. Together the host active innate and adaptive immune system, together with the host passive defence mechanism forms => an effective defence system So despite all those infectious agents and pathogens around us, we can see why our bodies very rarely fall victim of those IF agents. Slide 14: So it’s important to note that the white blood cell ie leukocytes are the cells that are responsible for the immune systems All leukocytes, if you remember from our stem cell practical, are derived from stem cells in the bone marrow. This haemopoetic stem cell, in a process called haemopoiesis, will generate lymphoid and myeloid progenitor. The lymphoid progenitor cells will produce B and T lymphocytes and the myeloid progenitor cells will produce erythrocytes, macrophages, basophils, eosinophils and neutrophils. Most white blood cells, including the B lymphocytes, will mature in the bone marrow but the exception to this is the T lymphocyte which matures in the thymus. When the T cells leave the thymus they are mature T cells that are ‘tolerant’ to self proteins. During the thymus they have developed this property of self- tolerance which enables them to identify the cells that belong to our body and those that don’t. This helps the T cell understand which cells need to be removed from the body. We will talk more about this in the adaptive immune system lecture. Slide 15: Leukocytes can be grouped into 2 types: polymorphonuclear granulocytes, so- called because they have many-shaped nucleus, and granules in their cytoplasm. Neutrophils are mobile phagocytic specialists i.e. major role in phagocytosis. They are first on the scene in bacterial infections, as well as having a role in scavenging to clean up debris from tissue injury. Include bits of dead cell remnants, as well as matrix components that have been degraded. Eosinophils = upregulated in number in allergic conditions, especially in presence of parasitic infections. You can see that they have this many-shaped nucleus, with pink granules, hence name ‘eosinophil’ as they take up the dye eosin. Basophils take up a basic blue dye, hence the name, also present in allergic reactions. Only seen as a minor component in a healthy person who has not got allergic reactions. Cells will release heparin and histamine. Histamine is important in initiation of the inflammatory process, and heparin prevents blood from clotting in blood vessels. Slide 16: The second group of leukocytes are called agranulocytes, as they do not have granules in their cytoplasm. The first is the large monocyte which will transform as it leaves the blood and enters the tissue to become a mature macrophage. Monocytes circulate in the blood for 1-2 days, then when they enter the tissue they become resident macrophages, where they can remain for months to several years. They have a major role in phagocytosis, amongst other roles such as in acute and chronic inflammation as part of the innate immune system, and in antigen presentation in the adaptive immune system. Lymphocytes include the B and T lymphocytes or B and T cells and they play a role antibody mediated and cell-mediated immunity which we will talk more about these lymphocytes in the adaptive immune lecture. Slide 17: The innate immune system launches a non-specific immune response that kicks in immediately (very rapid onset) when the body has been invaded by an infectious agent. It initiates a non-selective immune defence, which means that the response is the same whatever the virus is, or whatever the bacteria is. Called the innate immune system as they are innate or built in within our body, ready to act immediately and very rapidly. Mechanisms are said to the first line of defence against a wide variety of enemy targets. Mechanisms used within the innate immune system are inflammation, leukocytes in processes of phagocytosis and exocytosis, natural killer cells, interferon and complement system. Slide 18: Adaptive Immune System When the adaptive immune system kicks in, it develops selective weapons that are selectively programmed to act against a specific target, eg a particular species of virus, whereas the innate immune system kicks in regardless of the virus/ type of bacteria. The adaptive immune system is mediated by lymphocytes which during the process of adaptive immunity will develop lifelong immunity. We will look how that is developed in the adaptive immune topic. Adaptive immune system is comprised of antibody-mediated and cell-mediated immunity. In terms of antibody-mediated immunity the B cells will perform a role. When activated, they transform into a plasma cell and produce antibodies. Antibodies themselves cannot destroy a target, but they can mark a target for destruction. In cell-mediated immunity, it is so-called because the T cells will directly interact with the cell that they are having an effect on. In case of cytotoxic T cell, it will directly interact with the target cell, which may be a virus-invaded cell or a cancer cell in orderto initiate its destruction. Slide 19: B & T lymphocytes develop from that haemopoietic stem cell and that B cell matures in bone marrow, but that T cell develops in thymus so that it develops that property of self-tolerance enabling it to determine between self and and non-self proteins so that the body can distinguish between those cells that belong in the body and those that don’t. B & T cells after being produced become deposited in the peripheral lymphoid tissues; called lymphatic tissues and 2 trillion lymphocytes can be deposited in these. There are both primary (bone marrow and thymus) and secondary ones can be grouped together in terms of respiratory-associated lymphoid tissues such as the adenoid and tonsil; and the gut -associated Peyer’s patch and small intestines. Additionally, there are the appendix, lymph nodes and spleen. These tissues are distributed strategically around the body and will contain deposits of lymphocytes ready to act should an invader attempt to enter the body. When the foreign invader does gain access, B and t cells are activated to form their antibody- and cell-mediated immune response. Slide 20: If we do, our body is able to combat these IF agents Looked at passive difference mechanisms which essentially try to prevent those IF agents from gaining access to the body, but if they do gain access, we have all the host active defence mechanisms of the innate and adaptive immune system which can combat a wide variety of IF against, which should they get past those passive defence mechanisms, will work together to contain & localise the site of infection to prevent the infection from spreading to other parts of the body, as well as developing selective weapons against particular viruses or bacteria to prevent harm in our bodies. In the previous lecture, we looked at how various organisms attempt to cause harm to us and disease. Today we have begun to look at the mechanisms our bodies use to prevent their entry into the body, and also if IF agents gain access, the mechanisms it uses to remove them from our body to prevent infection. In the next 2 lectures we will look further at the active host defence mechanisms, namely the Innate & Adaptive Immune systems, in their role in immune defence to prevent and eradicate infectious agents from our bodies.