Department of Biology Welcome to Bio 3UU3 Animal Physiology – Regulatory Systems March 2022 Dr. Manar Angrini Immunity & Body Defenses Edward Jenner (1796) Objectives & Outlines § Explore lymphatic system § Define immunity § Classify immunity § Study types of the body defenses § Compare between T cells & B cells § Discuss resistance of the body to infection Lymphatic system § Organ system in vertebrates that is part of the circulatory and immune systems § it consists of a complex network of vessels, tissues, and organs. § The lymphatic system helps maintain fluid balance in the body by drainage excess fluid and particulate matter from tissues and depositing them in the bloodstream. https://www.google.com/url?sa=i&url=https%3A%2F%2Fmy.clevelandclinic.org%2Fhealth%2Farticles%2F21199-lymphaticsystem&psig=AOvVaw0ARZwOtTTnQrWXJ317dvAN&ust=1605281596322000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCPCAk5G q_ewCFQAAAAAdAAAAABAJ §It also helps defend the body against infection by supplying disease-fighting cells called lymphocytes. Lymphatic organs § Primary lymphoid organs = the sites of B and T cell maturation, § Secondary lymphoid organs = in which further differentiation of lymphocytes occurs. § Primary lymphoid organs include: § thymus, bone marrow, § fetal liver § in birds, the bursa of Fabricius. § In humans the thymus and bone marrow are the key players in immune function. https://www.fortislife.com/products/articles/-b-is-for-bursa/article055 Central and peripheral lymphoid organs Central: ØBone marrow ØThymus Peripheral: ØSpleen ØLymph nodes ØTonsils Lymphatic organs § All lymphocytes derive from stem cells in the bone marrow. § Stem cells destined to become B lymphocytes remain in the bone marrow as they mature, § while T cells migrate to the thymus to undergo further growth. § Mature B and T lymphocytes exit the primary lymphoid organs and are transported via the bloodstream to the secondary lymphoid organs, where they become activated by contact with foreign materials, such as particulate matter and infectious agents, called antigens. Lymphocytes § Initially immuno-incompetent § Mature (become immuno-competent) in either: Øthe bone marrow (B-cells or B-lymphocytes) Øor the thymus (T-cells or T-lymphocytes) Lymphocytes § Each lymphocyte possesses surface antibodies for a single pathogen (genetically determined) surface antibodies The lymphoid progenitor cells mature into the Bcells, T-cells, and innate lymphoid cells (ILCs), which include the natural killer cells (NK cells). https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.medicalnewstoday.com%2Farticles%2F285666&psig=AOvVaw0ARZwOtTT nQrWXJ317dvAN&ust=1605281596322000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCPCAk5Gq_ewCFQAAAAAdAAAAABAP Hematopoietic stem cells are (precursors) immature cells that develop ☞ into all types of blood cells. Myeloid progenitor cells are descendants of stem cells that further differentiate ☞ into specialized cell types § Natural killer cells recognize general signals of immune stress such as inflammation. § B and T cells recognize foreign antigens via hypervariable B cell and T cell receptors (BCRs and TCRs). § B cells recognize free, unprocessed antigens. § T cells recognize antigens within a complex of cell surface proteins on the surface of antigenpresenting cells. § Lymphoid progenitor T- cells B- cells Mature in Mature in thymus bone marrow https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.medicalnewstoday.com%2Farticles%2F285666&psig=AOvVa w0ARZwOtTTnQrWXJ317dvAN&ust=1605281596322000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCPCAk5Gq_ew CFQAAAAAdAAAAABAP Differentiate into Effector Tantibodycells secreting plasma cells T Cells & their receptors § T cell receptors (TCRs) are made up of two polypeptide chains (α &β) - compose one antigen binding cite § The T cell receptor structure is maintained by a disulfide bond linking the two chains together. https://irepertoire.com/t-cell-and-b-cell-overview/ T Cells & their receptors There are many types of T cells, each has a specialized function. § Cytotoxic T cells = Killer T cells-- target cancer, virally infected, or damaged cells. § Roles of killer cells: ØSecretes hole-forming proteins, called perforins, that punch round holes in the membrane causing fluid to rapidly flow into the cell ØAlso can release cytotoxic substance directly into attacked cell Guyton and Hall, 12th edition T Cells & their receptors § Helper T cells= ¾ of total T-cells § They help B cells by releasing cytokines. ØAIDS patients, inactivated or destroyed T helper cells which leaves the body unprotected against infectious disease Roles of helper cells: Ø Stimulate growth and proliferation of cytotoxic and suppressor T-cells Ø Stimulate growth and differentiation of B-cells to form plasma cells and antibodies Ø Activate macrophages Ø Feedback loop stimulating helper t-cells themselves T Cells & their receptors § Memory T cells have an extended lifetime and help to recognize antigens to which they were previously exposed. § Suppressor T cells block the actions of some other types of lymphocytes, to keep the immune system from becoming over-active. T-cells Plasma Cells B-cells § B cell receptors (BCR) are made up of four peptides – two light chains and two heavy chains –comprise two antigenbinding regions immunoglobulin (Ig). § Heavy chains can be IgG, IgA, IgM, IgD, or IgE isotypes. § B cells can be activated in two ways: Ø T cell-dependent activation Ø T cell-independent activation. B Cells & their receptors https://irepertoire.com/t-cell-and-b-cell-overview/ During T cell-dependent activation: B cells absorb the antigen and then present pieces of the antigen on their surface, and helper T cells can then recognize those antigens and activate the B cells. For T cell-independent activation to take place, the B cell must both encounter an antigen and receive a “danger signal,” T-cells Plasma Cells B-cells § Activated B cells can then B Cells & their receptors either become effector B cells or memory B cells. § Effector B cells, also called plasma cells→ produce antibodies. § Antibodies work as alarms to target invading agents for destruction by other immune agents like macrophages. https://irepertoire.com/t-cell-and-b-cell-overview/ § Memory B cells, like memory T cells, help the immune system respond more quickly to future invasions by the same agent. T Cells vs B Cells B Cells T Cells Origin Bone marrow Thymus Often called B lymphocytes T lymphocytes Position Outside lymph node Inside lymph node Surface antibodies Present Absent Connect They connect to the surface of invading bacteria and virus They connect only to the virus antigen on the outside Life Span Short Long Secrete Antibodies Only one active type Lymphokines Types Two types: Helper and Killer Body Defenses Nonspecific defenses Specific defenses ! First Line of Defense • Physical and chemical barriers (Skin, mucous membranes)• Nonspecific & Local ! Second Line of Defense • Phagocytes and natural killers • Inflammation • Nonspecific & Local ! Third Line of Defense • Immune response T and B cells (lymphocytes) •Specific & Systemic •Has memory Immunity § It is the ability to resist damage from foreign substances such as microorganisms and harmful chemicals. § The immune system has evolved to protect the host from a universe of pathogenic microbes that are themselves constantly evolving. § The immune system helps the host eliminate toxic or allergenic substances that enter through mucosal surfaces. § A central to the immune system’s ability to: Ø to distinguish self from non-self. Øto detect and eliminate pathogenic microbes. https://www.ncbi.nlm .nih.gov/pmc/articles/ PMC2923430/ First line of defense § Physical & chemical barriers, Include: ØSkin (physical = keratin) & (Chemical = acidity and sebum (oily secretion of the sebaceous glands) have bacteriostatic effect) ØMucous membranes (sweat, tears, stomach acid, saliva, urine flow, vaginal secretions, urine flow) First line of defense • Mucous membrane secretions Øgastric secretions contain HCl and proteolytic enzymes Øacidic vaginal secretions are bacteriostatic Ømucus traps microorganisms • Exocrine secretions ØSaliva, tears, and perspiration contain lysozyme (bacteriostatic enzyme) Second line of defense § May take days to respond to a primary invasion § Includes: 1. Antimicrobial substances 2. Natural killer cells 3. Phagocytes 4. Inflammation 5. Fever 2nd Line – Phagocytes • Macrophages Copyright ã Jones and Bartlett Publishing, Alcamo 6th ed. 2003 • Lysosomes: contain lysozyme + low pH 2nd Line – Natural Killer (NK) Cells § NK cells always looking for foreign cells • Looks for MHC proteins (major histocompatibility complex) § If MHC proteins NOT present NK cells release deadly cocktail of enzymes and chemicals Inflammation (“set on fire”) non-specific response triggered when tissues are injured (or infected) Purposes of Inflammation § prevent spread of the noxious (toxic and harmful) agent (infection) § eliminate cell debris and noxious agent § prepare the tissue for repair Chemicals of Inflammation • Many chemicals such as: • Histamine: released by basophils and mast cells • promotes vasodilation, increased capillary permeability of the capillaries to WBC and protein • Kinins - plasma protein kininogen is activated by enzymes from lysosomes (e.g., in neutrophils) → kinin- induce pain • Lymphokines - released by lymphocytes- enhance inflammation, and immune response Stages of Inflammation 1. cell injury 2. vascular response 3. cellular response 1- Cell Injury § Common Causes: Ømechanical trauma Øthermal trauma (heat or cold) Øchemicals Ømicrobes Øhypoxia (deficiency of oxygen) Øautoimmunity 2- Vascular response Characterized by: vasodilation ® ­ blood flow Hyperemia & Erythemia ­ capillary permeability exudation of fluid (pus or clear fluid) & albumin out of the wound into interstitial space edema Edema (swelling) 3- Cellular response § diapedesis of leukocytes (passage of leukocytes through the intact walls of the capillaries) § chemotaxins attract them to the site of cell injury § phagocytes (neutrophils and macrophages) engulf pathogens and secrete cytotoxic chemicals Cardinal (First) signs of Inflammation § Redness (rubor or erythema)= capillary dilation ® hyperemia (­ blood flow to the area) § Heat (hyperemia) ® localized heat (more blood to surface) § Swelling (tumor)= hyperemia ® ­ tissue permeability exudation of albumin (and fibrinogen) • Pain = stimulation of nerve endings by edema • Inflammation chemicals such as (bradykinin) stimulate pain receptor by pressure exerted by edema § Impaired function = (if a joint is involved) § edema ® joint stiffness Third line of defense § highly specific § systemic § has memory § also called the immune response § dependent upon antigen-antibody reactions Antigen § “antibody generating” § any material that can stimulate an immune response (i.e., production of antibodies) e.g. of antigens • Proteins or carbs on the cell membrane of bacteria, viruses, parasites, transplanted tissues • represent the “non-self” Antibody (immunoglobulin) § Protein produced in response to an antigen § specific: § neutralizes only the antigen against which it was developed § also called immunoglobulin or gamma globulin An Antibody 2 antigen-binding sites Antibody § Antibody is Y-shaped protein molecule with two arms, the arms contain antigen-binding sites. § Antigen binds with the antibody at the antigenbinding site in a lock & key manner Types of Immunity • Cell-mediated immunity - T cells directly attack invading antigens - Driven by activated T lymphocytes • Antibody-mediated immunity (humoral immunity) - B cells transform into plasma cells (larger than B cells), circulate in the blood & lymph - secrete antibodies or immunoglobulin ØType of response depends on type of invader ØMany pathogens provoke both types Types of Immunity Guyton and Hall, 12th edition B-cells- Humoral immunity (antibody-mediated immunity)- involves b-cells Humoral immunity B-cells recognize pathogenic antigen B-cells become fully competent multiply rapidly (cloning) some become plasma cells (large cells that secretes 2,000 antibodies/second) others become memory cells antigen exposure B-cell plasma cell humoral immunity § 4 - 5 days later the plasma cells die § Antibodies circulate and bind to pathogenic antigens Primary immune response § Occurs following initial exposure to a particular antigen § Response begins 3-6 days following exposure § Antibody level in blood falls usually within 28 days § Memory cells remain Secondary Immune Response § Occurs following re-exposure to an antigen § Faster, more antibodies, and more prolonged than primary response because memory cells remain from previous exposure § Onset occurs within hours of re-exposure to antigen, increases for about 2 days § Blood antibody level in the blood remains elevated for weeks to months Immunological memory With secondary response: Ø Shorter lag phase (Following the first exposure to a foreign antigen, a lag phase occurs in which no antibody is produced, but activated B cells are differentiating into plasma cells.) Ø Higher levels of antibody Ø Higher affinity for the antigen https://pediaa.com/difference-betweenprimary-and-secondary-immune-response/ Clonal selection theory of immunity § Also called "Burnet’s clonal selection theory” § Clonal selection: is a process proposed to explain how a single B or T cell that recognizes an antigen that enters the body is selected from the pre-existing cell If the antigen is part of the surface pool of differing antigen of a virus or bacterium, then the specificities and then antibody labels that organism as reproduced to generate a foreign ("not-self"). The organism is clonal cell population that then ingested by phagocytic cells eliminates the antigen. and degraded. Co-Receptors APC § The activation of specialised immune cells from the adaptive immune response (i.e. B cells and T cells) is controlled: Ø by their specific antigen receptor Ø by co-receptors Janeway et al., 6th edition Garland Science T cell co-receptors Naïve T cells need to be activated by two signals. 1- signal from the T-cell receptor (TCR)= TCR recognises a small part of the antigen (called peptide), this ensures the specificity of the response; only T cells that recognise this antigen will be activated. Co-Receptors 2- signal 2 (co-stimulatory signal) is provided by a costimulatory molecules, which are induced by antigen presenting cells, APC- cutting antigen into small peptides for presentation in a complex with MHC (Major Histocompatibility Complex) protein T-cells recognize only antigens bound to MHC APC Janeway et al., 6th edition Garland Science Guyton and Hall, 12th edition Co-Receptors • There is also another set of coreceptors which inhibit T-cell activation. They are called coinhibitory receptors, include CTLA-4 and PD-1. https://www.immunology.org/public-information/bitesizedimmunology/systems-and-processes/co-receptors-function § These molecules are only expressed on T cells that have already been activated. § Stimulation of these induced co-inhibitory receptors contribute to a balanced immune response. § Defects in these co-inhibitory receptors lead to unusual immune responses, such as lymphoproliferation and autoimmunity. Co-Receptors B cell co-receptors The specific B-cell receptor (BCR, an immunoglubulin molecule attached to the membrane of the B cell) recognises the antigen in native form Co-stimulation of B cells is notably achieved by the molecule CD40. CD40 ligand is expressed on T cells. dialogue between T- and B cells ☞ allows continuous B-cell proliferation and activation ☞ leading to their differentiation into plasmocytes (mature B cells) ☞ producing high affinity antibodies against the antigen. Janeway et al., 6th edition Garland Science https://www.frontiersin.org/articles/10.3389/fcell.2020.597627/fu ll Methods of Acquiring Immunity Two branches of our immune system Adaptive immune response • Antibodies • Life long protection Innate immune response • Phagocytic cells (macrophages) • Engulfed and digested Janeway et al., 6th edition Garland Sciences Innate immune cells https://www.google.com/url?sa=i&url=https%3A%2F%2Fneurohacker.com%2Fhow-does-the-immune-systemwork%3Futm_content%3Dbuffercca93%26utm_medium%3Dsocial%26utm_source%3Dfacebook.com%26utm_campaign%3Dbuffer&psig=AOvVaw2VOL7zK96F42N1vEDUW2d0&ust=1605287297249000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCNCPwK2 __ewCFQAAAAAdAAAAABAJ Infection triggers an inflammatory response Macropha ges Cytokines (increase permeability of blood vessels allowing for fluid and proteins to pass into tissues Chemokines (direct neutrophils to site of infection) Dendritic cells are essential for the interplay between the innate and adaptive immune responses Immature dendritic cells reside in peripheral tissue and have receptors for many pathogens ØE.g. peptidoglycans common in bacteria cell walls Although able to engulf foreign pathogens, main role is to carry antigens to peripheral lymphoid organs to present them to T lymphocytes https://www.google.com/url?sa=i&url=https%3A%2F%2Fscience.sciencemag.org%2Fcontent%2F346%2F 6209%2F597.1&psig=AOvVaw0xc5upXtqRay66oAfSQ2M3&ust=1605289413113000&source=images& cd=vfe&ved=0CAIQjRxqFwoTCMjY1p3H_ewCFQAAAAAdAAAAABAD Secrete cytokines that influence both innate and adaptive immune responses Types of Immunity Natural versus Artificial Active versus Passive Natural contract Active disease placental Passive transmission breast milk Artificial vaccination antiserum Leukemias Lymphocytic leukemias Caused by cancerous production of lymphocytes usually beginning in the lymph node Myelogenous leukemias Begins by cancerous production of young myelogenous cells in the bone marrow Causes WBC to be produced in many extramedullary tissues Rheumatic fever is an inflammatory disease that can develop when strep throat or scarlet fever isn't properly treated. caused by an infection with streptococcus bacteria. https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.thehindu.com%2Fnews%2Fnational%2Fkerala%2Frheumatic-fever-on-its-wayout%2Farticle17746214.ece&psig=AOvVaw203YQPrL2udaIUF6GftLQD&ust=1606562119982000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCPi1ibjMou0CFQAAAAAdAAAAABAb Glomerulonephritis is inflammation and damage to the filtering part of the kidneys (glomerulus) Symptoms may include: Ø Pink or cola-colored urine from red blood cells in your urine (hematuria) Ø Proteinuria Ø High blood pressure (hypertension) Myasthenia gravis= an autoimmunological inflammatory disorder of the neuromuscular junction Symptoms Weakness and rapid fatigue of any of the muscles under your voluntary control☞ caused by a breakdown in the normal communication between nerves and muscles. https://www.google.com/url?sa=i&url=https%3A%2F%2Fstudypages.com%2Fs%2Fbeatmg-phase-ii-trial-of-rituximab-in-myasthenia-gravis543091%2F&psig=AOvVaw13rrObkeAstCX8Kl6O1C1c&ust=1606562762103000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCIio0-nOou0CFQAAAAAdAAAAABA3 Poison ivy rash = allergy caused by activated T-cells § Repeated exposure cause formation of helper T-cells and cytotoxic T-cells § Upon next exposure, there’s a delayed reaction in which the T-cells from the blood diffuse into the skin to respond to the poison ivy toxin § T-cells elicit a cell-mediated type of immune response through the release of cytokines that activate more Tcells and macrophages Poison Ivy Allergic reaction to an oily resin in the leaves, stems and roots of poison ivy, poison oak Allergies in people with excess IgE antibodies Release of mast cell and basophil content causes: ØDilation of local blood vessels ØAttraction of eosinophils and neutrophils to reactive site ØIncreased permeability of capillaries Leads to anaphylaxis or hives or hayfever etc. https://franklincardiovascular.com/do-i-have-mastcell-activation-syndrome-mcas/ Hay fever, called allergic rhinitis, causes cold-like signs and symptoms, such as a runny nose, itchy eyes, congestion, sneezing and sinus pressure. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847274/
