HNI 310 - Inflammation and the Immune System SUMMER 2024 BS.pptx

Inflammation and the Immune System Pathophysiology HNI 310 Kenneth Faulkner, PhD, RN, ANP-BC, FHFSA  Objectives By the end of this lecture and after completing the required reading, the student should be a...

Inflammation and the Immune System Pathophysiology HNI 310 Kenneth Faulkner, PhD, RN, ANP-BC, FHFSA  Objectives By the end of this lecture and after completing the required reading, the student should be able to: 1.Describe the difference between the innate and adaptive immune system 2.Differentiate cell mediated and humoral immunity 3.Describe 2 physical barriers, 2 mechanical barriers and 2 biochemical barriers to infection 4.Describe how the normal flora protects against infection and what can happen if the normal flora is disrupted 5.Describe components of innate immunity in the urinary tract and the gastrointestinal tract 6.Describe the purpose of complement proteins, coagulation proteins, histamine, nitric oxide and arachidonic acid metabolites 7.Describe whether inflammation is a normal or abnormal process 8.Differentiate acute vs chronic inflammation 9.Name the 5 cardinal signs of inflammation and describe how they occur 10. Name and describe the cells involved in inflammation 11. Differentiate between the vascular and cellular changes seen in inflammation, including the cause of each 12. Describe the process of the cellular phase of inflammation (margination, adhesion, etc.) 13. Differentiate between the types of exudates and provide an example of each 14. Describe the process of chronic inflammation 15. Differentiate cellular proliferation from fibrous tissue repair  Objectives (cont.) 16. Describe how fibrous tissue replaces damaged tissue 17. Describe the 3 phases of wound healing 18. Differentiate between healing by primary intention and secondary intention 19. Describe the purpose of pattern recognition receptors and opsonins 20. Describe how an antigen presenting cell presents an antigen to a T lymphocyte 21. Differentiate CD4 cells from CD8 cells 22. Differentiate MHC I and MHC II 23. Describe the 3 things a T helper cell does when activated 24. Differentiate the 5 types of immunoglobulins/antibodies 25. Describe immunotherapy 26. Describe the difference between transplant rejection and graft vs host disease 27. Describe the criteria necessary for graft vs host disease and give an example of when a person is at risk for this condition 28. Differentiate the 4 types of hypersensitivity disorders 29. Differentiate central tolerance from peripheral tolerance 30. Describe the changes that occur often in autoimmune disorders 31. Differentiate active and passive immunity  Defenses against disease We are exposed to toxic substances and pathogens every day Our bodies have several mechanisms to protect ourselves against disease These include: 1. Innate immune system 2. Inflammation 3. Adaptive immune system 4. Chronic inflammation  Innate immunity FIRST LINE OF DEFENSE The natural defenses in place to provide protection against pathogens and stressors from the environment Include physical, mechanical and biochemical mechanisms designed to mitigate or prevent growth of pathogens and exposure to external stressors In place at birth FAST ACTING!  Innate immunity: physical barriers 1. Epithelial cells: – Tightly bound – Line the surfaces of the skin and the GI tract – Prevent deep penetration by pathogens 2. Low temperature of the skin: – Inhibits pathogen growth 3. Low pH of the skin and stomach: – Inhibits pathogen growth Innate immunity: mechanical barriers Mechanisms for clearing pathogens from the surfaces of epithelial cells 1. Vomiting: – Clears pathogens from the GI tract 2. Urination: – Clears pathogens from the GU tract 3. Goblet cells of upper respiratory tract: – Secrete mucous that traps pathogens – Ciliated cells then brush out the mucous and pathogens Innate immunity: biochemical barriers Substances synthesized by and secreted by epithelial cells designed to trap or destroy pathogens 1. Antimicrobial fatty acids and lactic acid – Secreted by sebaceous glands of skin 2. Antimicrobial peptides – Secreted by epithelial cells 3. Lysozyme – Component of perspiration, tears and saliva  Innate immunity: normal microbiome Bacteria and fungi colonize the surfaces of the body – Unique to a given area – Non-pathogenic under normal circumstances – Compete with other microorganisms for resources and space (block attachment to the epithelium) – Secrete chemicals (ammonia, etc.) that inhibit growth Immune system suppresses growth of normal flora – If immune system is suppressed, may lead to opportunistic infections  Innate immunity: normal microbiome Lactobacillus: – Common component of vaginal microbiome – Produces hydrogen peroxide and lactic acid to inhibit growth of pathogens Use of broad-spectrum antibiotics can kill the microbiome – Organisms that are resistant to the antibiotic have the opportunity to replicate – Candida albicans → thrush – Clostridium difficile → pseudomembranous colitis  Innate immunity: the genitourinary tract Genitourinary tract – Urinary tract is normally sterile – Urination flushes bacteria from system and disrupts adhesion – Increased risk of bacterial growth if there is: Short urethra Reflux/retrograde flow Obstruction Innate immunity: the respiratory tract Respiratory tract – Many bacteria, viruses, etc.. inhaled daily – Mucociliary blanket lining nose and upper respiratory tract trap microbes Smoking damages this – Goblet cells secrete mucous and trap microbes – Cilia in upper airway move encapsulated bacteria to back of throat where they are swallowed or expelled – Alveolar macrophages destroy small organisms that travel down airway  Innate immunity: the gastrointestinal tract Gastrointestinal tract – Most pathogens are transported via food contaminated with fecal material – Gastric acid destroys pathogens in stomach – Viscous mucous layer coats gut and entraps microbes – Pancreatic enzymes and bile detergents destroy organisms – IgA secreted by mucous membranes in gut – Normal bacterial flora compete with pathogens for nutrients  Inflammation SECOND LINE OF DEFENSE Programmed response to tissue injury Integrated system of humoral (dissolved in blood) and cellular responses designed to: 1. Limit tissue damage 2. Destroy pathogens 3. Initiate adaptive immune system 4. Begin healing Rapid response in vascularized tissue (begins in seconds) Vascular and cellular components  Cells of Inflammation Endothelial cells: layer of cells lining blood vessels – connected to underlying connective tissue 1. Release nitric oxide (NO) to promote vasodilation 2. Release inflammatory mediators (interleukens, prostaglandins, etc.) to regulate cellular changes during inflammation 3. Control movement of cells through endothelial layer 4. Release tissue factor in response to injury (activates extrinsic pathway of clotting cascade)  Cells of Inflammation Mast cells: cells that lie in connective tissue near blood vessels When activated, mast cells: 1. Degranulate (release inflammatory mediators stored in cellular granules) Immediate Primarily histamine 2. Synthesize new inflammatory mediators Delayed  Cells of Inflammation: Phagocytic cells Neutrophils – First phagocytic cells to arrive in inflammation – Main function: 1. Phagocytosis of pathogens Neutrophils are not able to survive the acidic environment of inflammation for long They become a component of purulent exudate Britannica, T. Editors of Encyclopaedia (2018, November 16). Neutrophil. Encyclopedia Britannica. https://www.britannica.com/science/neutrophil  Cells of Inflammation: Phagocytic cells Eosinophils – Two main functions: 1. Defense against parasites 2. Regulate changes associated with allergic reactions (mast cells, eosinophils, histamine, etc.) – Mildly phagocytic https://www.verywellhealth.com/guide-to-eosinophils-797211  Cells of Inflammation: Phagocytic cells Dendritic cells – Link between innate and adaptive immune system – Two main functions: 1. Function as antigen-presenting cells (APCs) to initiate adaptive immunity 2. Phagocytosis (mild) https://pixels.com/featured/9-human-dendritic-cell-dennis-kunkel-microscopyscience-photo-library.html  Cells of Inflammation: Phagocytic cells Monocytes/macrophages – Monocytes are precursors to macrophages – Capable of surviving in acidic environments Last longer than neutrophils – Main functions: 1. Function as antigen-presenting cells (APCs) to initiate adaptive immunity 2. Clear pathogens and debris from injured tissue/wounds https://www.pinterest.com/pin/267753140315494132/  Chemical mediators of inflammation Responsible for coordination of vascular and cellular aspects of inflammation Tightly regulated! – Lots of checks and balances Exceedingly numerous – so we will only cover the most important  Chemical mediators of inflammation 1. Histamine: – First inflammatory mediator released – Produced by mast cells – Responsible for: 1. Vasodilation 2. ↑ vascular permeability 3. Bronchoconstriction (contraction of bronchial smooth muscle) – Temporary – Leukotrienes will take over once synthesized https://www.dreamstime.com/stock-illustration-histamine-action-adverse-effects-mechanism-target-organs-immune-responses-image654  Chemical mediators of inflammation 2. Bradykinin: – Initiated by activation of Hageman factor (factor XII) – Responsible for: 1. Vasodilation 2. ↑ vascular permeability 3. Bronchoconstriction 4. Pain  Chemical mediators of inflammation 3. Clotting factors: produced by liver – Induces the clotting cascade – Chain of events that leads to production of fibrin clot  Chemical mediators of inflammation 4. Complement proteins: – Plasma proteins – Present in inactive form – As part of inflammation: 1. ↑ vascular permeability 2. Promote chemotaxis (movement of cells following concentration gradient) – As part of immune system 1. Act as opsonins and facilitate phagocytosis 2. Create holes in cell membrane of pathogens (membrane attack complex - MAC)  Chemical mediators of inflammation: Arachidonic acid metabolites 5. Arachidonic acid metabolites: – Arachidonic acid is a fatty acid present in the cell membrane – Metabolized by one of two pathways: 1. Cyclooxygenase (COX) pathway Produces prostaglandins and thromboxane Prostaglandins promote – Bronchoconstriction – Vasodilation Thromboxane promotes platelet aggregation Aspirin/NSAIDs block COX pathway 2. Lipoxygenase pathway Produces leukotrienes Promote – Bronchoconstriction – ↑ capillary permeability  Chemical mediators of inflammation 6. Interleukins (IL) and tumor necrosis factor (TNF): – Proteins produced mainly by lymphocytes and macrophages – Many kinds – Some are pro-inflammatory (IL-1β, IL-6) – Some are anti-inflammatory (IL-4, IL-10) – Many overlapping functions including: 1. Recruitment and activation of leukocytes (WBCs) 2. Induce acute-phase responses of  Chemical mediators of inflammation 7. Interferons – Produced by virus-infected cells and lymphocytes – Enhances defense against viruses – Interfere with viral replication by inhibiting DNA/RNA synthesis – Some activate macrophages to destroy viruses 8. Nitric oxide – Produced by endothelial cells – Promotes smooth muscle relaxation and vasodilation  Types of Inflammation Acute inflammation – Early, short-term and self-limiting – Occurs before adaptive immunity can exert its effect – Designed to remove injurious agent and limit extent of damage – Neutrophils predominate in first 24 hours Chronic inflammation – Late, long-term and self-perpetuating – Usually the result of recurrent inflammation/irritation or slow processes that fails to induce an acute response – Macrophages and lymphocytes are more common  Acute inflammation: Vascular response Following tissue injury: 1. Initial vasoconstriction – Controls loss of blood 2. Vasodilation – ↑ flow of blood to the area – Makes area warm and red 3. ↑ vascular permeability – Endothelial cells contract – Fluid leaks through gaps between cells Initially plasma with little protein (transudate) Quickly followed by movement of protein-rich fluid (exudate) – Outflow of protein draws water from vessels to surrounding tissue (edema)  Inflammatory exudates 1. Serous – early stages of inflammation – Watery/yellow with little protein or cellular component 2. Fibrinous – advanced inflammation – ↑ protein/fibrin content 3. Purulent/suppurative – – Large amounts of leukocytes and pus – Grey, malodorous – Lesions may be walled-off (cysts/abscess) 4. Hemorrhagic/sanguinous – – Exudate is filled with erythrocytes Acute inflammation: cellular response Several stages: 1. Endothelial activation: – Inflammatory mediators (histamine, interleukins, etc.) promote expression of integrins on surface of leukocytes (mostly neutrophils) – Also promotes expression of selectins and intercellular adhesion molecules (ICAM) on surface of endothelial cells 2. Margination: circulating leukocytes are swept against blood vessel wall 3. Tethering: integrins on leukocytes bind loosely to selectins on endothelium 4. Rolling: leukocytes move from selectin to selectin 5. Firm adhesion: integrins on leukocyte attach firmly to ICAM Acute inflammation: cellular response 6. Diapedesis/transmigration: leukocyte moves through gap between endothelial cells 7. Chemotaxis: leukocytes follow chemical gradient to the site of injury – Chemicals are released by immune and non- immune cells 8. Leukocyte activation: A chain of events that leads to attachment of a leukocyte to a pathogen and phagocytosis – Through a) Pattern recognition receptors (PRRs) b) Opsonization  Acute inflammation: leukocyte activation Phagocytic cells recognize pathogens through two methods: a) Pattern recognition receptors (PRRs) – Ex: Toll-like receptors – Molecules on the surface of phagocytic cells that recognize pathogen-associated molecular patterns (PAMPs) on surface of pathogens PAMPs are not present on mammalian cells – PRR attachment to PAMP stimulates activation of the phagocytic cell and phagocytosis Acute inflammation: leukocyte activation  Acute inflammation: leukocyte activation b) Opsonization – Ex: Complement proteins, cytokines, c-reactive protein – Soluble molecules that bind to particles on surface of pathogens – Phagocytic cells bind to opsonins on the surface of pathogen – Opsonin attachment stimulates activation of the phagocytic cell and phagocytosis Acute inflammation: cellular response 9. Phagocytosis: engulfment of pathogens by leukocytes – Engulfment: once activated, pseudopods extend around pathogen and enclose it in a phagocytic vacuole (phagosome) – Fusion: phagosome merges with lysosome – Killing of ingested pathogen: enzymes inside the lysosome degrade the pathogen  Local manifestations of inflammation All local manifestations occur as the result of vasodilation and increased vascular permeability 1. Heat – due to vasodilation 2. Redness – due to vasodilation 3. Swelling – due to ↑ capillary permeability 4. Pain – due to ↑ capillary permeability – Exudate compresses nerves in tissue – Presence of prostaglandins and bradykinin 5. Loss of function  Systemic manifestations of inflammation Fever: – Early response induced primarily by IL-1 acting on the hypothalamus Leukocytosis: – ↑ in leukocytes to fight infection – May be accompanied by “left shift” in severe infections Plasma protein synthesis: – Fibrinogen, prothrombin, clotting factors, plasminogen, complement proteins, etc. produced by liver  Chronic inflammation Persistent infections (>2 weeks) may result in chronic inflammation – Acute response may have been unable to control the infection or clear foreign objects (splinter, dirt, asbestos, etc.) Also may occur independently – Some microorganisms can survive and replicate inside phagocytic cells (Mycobacterium tuberculosis, Mycobacterium leprae, Salmonella typhi) – Activates chronic inflammation  Chronic inflammation Acute inflammation was characterized by high numbers of neutrophils Chronic inflammation is characterized by high numbers of macrophages and lymphocytes If macrophages cannot destroy the organism, the body attempts to contain the organism in a granuloma – Core of macrophages surrounded by lymphocytes – May contain fibroblasts that produce collagen – May become calcified – Center of granuloma can become necrotic Acute vs Chronic Inflammation Acute inflammation Chronic inflammation Fast, early Slow, late Characterized by: Characterized by: Infiltration by Infiltration by neutrophils macrophages and Protein rich exudates lymphocytes Presence of fibroblasts that secrete collagen Can become calcified Core can become necrotic  Adaptive immunity THIRD LINE OF DEFENSE Process designed to create a specialized immune response against a particular pathogen Augments protection already in place and Innate Adaptive prepares long term protection Fast Slow Two branches: Always similar Specialized 1. Cell-mediated: mediated by T- response response lymphocytes 2. Humoral: mediated immunoglobulins End products End products (antibodies) produced by plasma cells must be can remain in Major components removed or body to 3. Cells of adaptive immune system can cause provide 4. Antibodies damage to prolonged normal tissue protection  Cells of the adaptive immune system Antigen presenting cells (APCs): – Immune cells that initiate adaptive immunity Macrophages Dendritic cells Some B lymphocytes – Bind to an antigen, engulf them, break them down into protein fragments – Attach a protein fragment to a molecule of major histocompatibility complex (MHC) – Presents the MHC/protein fragment to T lymphocytes for activation  Major histocompatibility complex (MHC) aka human leukocyte antigen (HLA) Glycoproteins on the surface of cells responsible for antigen presentation and helping the immune system differentiate native cells from foreign cells MHC has a groove that accommodates the protein fragment derived from an invading pathogen When the MHC/protein fragment complex of an APC is presented to T- cells, the T-cells become activated Two main MHC glycoproteins: – MHC II: on APCs: Activate CD4+ cells to become T-helper cells – MHC I: on all nucleated cells: Activate CD8+ cells to become cytotoxic T cells Cells of the adaptive immune system Lymphocytes: – B lymphocytes: when activated, differentiate into plasma cells and make antibodies – T lymphocytes: several types differentiated by “cluster of differentiation” (CD) protein on the surface (CD4+ vs CD8+): CD4+ T lymphocytes: convert into T-helper cells when presented with antigen peptide/MHC II complex by APCs – Function: Regulate adaptive immune system and create memory CD8+ T lymphocytes: convert into cytotoxic T-cells when presented with antigen peptide/MHC I complex by virus infected cells or cancer cells – Function: Release reactive oxygen species and enzymes to destroy infected cells  Pathogen recognition by T helper cells: Cell-mediated immunity 1. APCs engulf pathogen, break it down, bind an protein fragment to MHC II – Antigens can be microbial (virus, bacteria, fungi) or non- microbial (plant pollen, poison ivy resin) 2. APCs present MHC II/antigen complex to CD4+ T lymphocyte 3. CD4+ cell becomes an active “T helper” cell 4. T helper cell then does 3 things: 1. Cytokines are released by CD4+ cells that activate B cells to become plasma cells, which will produce antibodies 2. Memory T cells are made 3. Cytokines are released by CD4+ cells to recruit “cytotoxic” CD8+ T cells Pathogen recognition by T helper cells: 1 – Secrete cytokines that convert 2 - Create a B cells into memory T- plasma cells cell 3 – Secrete cytokines that recruit cytotoxic T- cells More memory!!  Cytotoxic T cell response: Cell-mediated immunity 1. Recruited CD8+ cells bind to MHC I/antigen complex of infected cell 2. CD8+ cell becomes an active “cytotoxic T cell” 3. Cytotoxic T cell releases enzymes/cytokines that destroy the infected cell  Humoral immunity The immune response mediated by antibodies Antibodies form complexes with antigens Complexes may result in precipitation of antigen-antibody complexes, agglutination of pathogens, phagocytosis or lysis of infected cells Primary immune response: – First exposure to an antigen – Slow to develop – Results in memory B cells Secondary immune response: – Subsequent exposure to the antigen – Much quicker response  Immunoglobulins (aka antibodies) Proteins produced by plasma cells in response to an antigen The “Y” ends are the “antigen-binding fragments” (Fab) – The parts of the antibody that bind to the antigens The tail end determines the function and class (Fc) of the antibody  Immunoglobulins (aka antibodies) IgG – Most abundant (75%) – Only one that crosses placenta – Arrives late – Binds to infected and immune cells (macrophages, NK cells) and promotes lysis of infected cells IgA: – Common in mucous membranes and secretions – Provides local immunity IgM: First to appear in response to antigen – Promote agglutination of organisms for lysis or phagocytosis IgD: – On B cells – Required for B cell maturation IgE: – Binds to Fc receptors on mast cells releasing histamine – Inflammation, allergic responses, and parasites  Active Immunity Immunity developed by vaccination or having the disease Body exposed to antigen and develops IT’S OWN immunity – Pathogen may be weakened or killed Immune system of the host responds by creating antibodies to the antigen (may be a vaccine) Long term  Passive immunity Immunity from another Fetus is protected by IgG of mother Hyperimmune serum (IVIg) Short term  Disorders of immune response Hypersensitivity Disorders Transplant rejection Autoimmune disease HIV (already discussed)  Hypersensitivity disorders Excessive or inappropriate activation of immune system 4 types: – Type I IgE-mediated – Type II antibody-mediated – Type III immune complex-mediated – Type IV T cell-mediated  Hypersensitivity disorders (cont.) Type I “IgE mediated” or “immediate” or “atopic” or “anaphylactic” – Rapid allergic reactions (minutes) – Localized (atopic) – localized edema and vasodilation (rhinitis, food allergies) – Systemic (anaphylaxis) – widespread edema, vasodilation 1. Initial exposure (sensitization): – IgE produced by plasma cells in response to antigen – IgE binds to mast cells 2. Subsequent exposure: – Allergen binds to IgE bound to mast cells and stimulates release of histamine and other mediators (prostaglandins, leukotrienes, etc.) from mast cells – Histamine → bronchoconstriction, vasodilation, ↑ capillary permeability  Hypersensitivity disorders (cont.) – Typically 2 phases: 1. Primary/initial phase – within 5-30 minutes Vasodilation, vascular leakage, and smooth muscle contraction 2. Secondary/late phase – onset 2- 8 hours after resolution of initial phase Continued vasodilation More intense infiltration with eosinophils and other immune cells Chemicals released by eosinophils promote tissue damage – Severity of reaction depends on degree of sensitization Type I Hypersensitivity  Hypersensitivity disorders (cont.) Type II “Antibody-mediated” – Mediated by IgG or IgM directed against target antigens (no IgE) – Antigens may be endogenous or exogenous – Location of the target antigen defines the response – Examples: 1. Antibody binding to cell-surface antigen or complement causes cell destruction (ABO/Rh incompatibility) IgM/IgG binding activates complement cascade → lysis of RBC 2. Antibody binding to cell receptors activates cell (Graves disease) 3. Antibody binding to cell receptor prevents cell activation (myasthenia gravis) Hypersensitivity disorders (cont.)  Hypersensitivity disorders (cont.) Type III “immune complex-mediated” – Antigen/antibody complexes formed in bloodstream – Complexes are eventually deposited in vascular endothelium or extravascular tissue Activates complement and initiates inflammation – The location of the deposited antigen-antibody complex defines the response – Examples: 1. Systemic lupus erythematosus (SLE) 2. Glomerulonephritis Type III Hypersensitivity  Hypersensitivity disorders (cont.) Type IV “T-cell-mediated” or “delayed” (no antibodies involved) – Sensitized T lymphocytes – Take time to develop, which is why it is “delayed” 1. Initial exposure (sensitization): – APCs that have processed antigen activate T-cells – T-helper cells produce memory T-cells 2. Subsequent exposure: – Rapid recruitment and activation of memory T-cells – Cytotoxic T-cells secrete enzymes that destroy tissue directly – Other types of T-cells secrete cytokines that recruit phagocytic cells Phagocytic cells destroy tissue Contact dermatitis – poison ivy, nickel, organ rejection, etc. Type IV Hypersensitivity  Transplant rejection Process involving cell-mediated and humoral immunity Most common is T-cell mediated and is known as cellular rejection – Donor antigens are presented to recipient T lymphocytes by APCs – APCs may come from recipient or from the donor 1. Direct pathway: antigen is pre-processed – APCs come from the DONOR – T cells (CD4 and CD8) of the RECIPIENT recognize foreign MHC molecules on the APCs of the DONOR TISSUE – Cytotoxic CD8+ T cells release enzymes and kill foreign tissue – CD4+ helper T cells secrete cytokines that are responsible for 3 things…  Transplant rejection (cont.) 2. Indirect pathway: antigen needs to be processed first! – APCs come from the RECIPIENT (host) – HOST APCs process the antigen from DONOR tissue – T cells (CD4 and CD8) of the RECIPIENT recognize foreign MHC molecules on the APCs and are activated – Cytotoxic CD8+ T cells release enzymes and kill foreign tissue – When the CD4+ cells are presented with the antigen, they do three things… Antibodies will be created that target the donor tissue – May be expedited if previously sensitized (ABO mismatch or prior organ rejection)  Transplant rejection (cont.) Hyperacute: very rare – Immediate – Occurs if someone was pre-sensitized (ABO non-compatibility) – Antibodies in the recipient react with antigens on the graft and create a type II hypersensitivity Acute: – Within 7-10 days of transplant – T lymphocytes of recipient interact with APCs (dendritic cells) in grafted tissue (direct pathway) – T helper lymphocytes of host do three things… Chronic: – Delayed (months/years) – Often a type IV hypersensitivity – Gradual proliferation and fibrosis of vascular smooth muscle → vascular occlusion and organ dysfunction  Graft vs. Host Disease Cells with functional immune capacity are transplanted into someone who is immunocompromised The grafted tissue (the graft) rejects the recipient (the host) 3 requirements: 1. Tissue must have functional immune component 2. Recipient must have antigens foreign to donated tissue 3. Recipient must be immuno-compromised T cell mediated  Autoimmune disorders Tissue specific (Graves disease) or may affect several systems (SLE) Tolerance – the ability of the immune system to differentiate self from non-self – Central tolerance: apoptosis of autoreactive cells prior to release into circulation T cells removed in the thymus B cells removed in the bone marrow – Peripheral tolerance: Mechanisms in place to eliminate autoreactive cells that escape the thymus or bone marrow  Autoimmune disorders (cont.) If tolerance mechanisms fail, autoantibodies will be released and autoimmune disorders will occur – Auto-antibodies will be produced that react with native tissue – Anti-nuclear antibodies (ANA) Attack DNA, histone proteins, and the nucleolus – Anti-phospholipid antibodies (APA) Phospholipid is necessary for clotting – Antibodies against blood cells (all types)  Autoimmune disorders (cont.) Many factors linked to autoimmune diseases 1. Heredity 2. Gender 3. Environment  Systemic Lupus Erythmatosus (SLE) Epidemiology: – Prevalence from 19-150 per 100,000 depending on definition – More prevalent in people assigned female at birth Triggers: – Common triggers include UV light and certain medications Pathophysiology: – Believed to be due to hyper-reactivity of B cells or underactivity by regulatory T cells – Body produces: – Antinuclear antibodies, antiphospholipid antibodies and antiplatelet antibodies – Antibodies form immune complexes with self-antigen in circulation – Immune complexes cause tissue damage (Type III hypersensitivity)  Systemic Lupus Erythmatosus (SLE) Clinical manifestations: systemic disease – Slow progression – Frequent exacerbations and remissions – Fatigue – Joint pain (90% of patients) – Rash (70-80%) – Renal disease (40-50%) – Hematologic issues/anemia (50% - most common cause of mortality) – CV disease (30-50%) Management: – No cure – Suppress immune response (steroids, immunosuppressants) – Supportive care (pain management - NSAIDS)  Tissue Repair Two main processes: 1. Tissue regeneration – Replacement of damaged tissue with cells of the same type – Complete return to normal structure and function – May take up to 2 years – Little evidence of the injury  Tissue Repair 2. Fibrous tissue repair – Normal tissue replaced with connective tissue – Scar often forms – Occurs if: 1. There is extensive damage 2. Tissue is not capable of regeneration 3. Abscess or granuloma develops 4. Fibrin persists in the area  Phases of wound healing 1. Inflammatory – Prepares wound for healing – Vasoconstriction followed by vasodilation – Fibrin mesh forms – Influx of macrophages and neutrophils – Macrophages and neutrophils clean the wound of debris (debridement) 2. Proliferative – Within 2-3 days of injury – Clot is replaced by normal tissue or scar tissue – Macrophages release growth factor that stimulates angiogenesis – Fibroblasts create granulation tissue, collagen, and ECM – Epithelial cells are produced at wound edges – Wound contraction occurs at the end of this phase  Phases of wound healing 3. Remodeling – 3 weeks after injury and can take up to 2 years to complete – Structure of scar changes Vascularity decreases Generation of collagen by fibroblasts Lysis of collagen by enzymes Wound contraction continues  Wound healing Keloid: – Raised scars due to excessive collagen production – Genetic predisposition – More prevalent among persons of African-American ancestry  Wound healing Healing: – Primary intention: Sutured wound , paper cut Less tissue damage and less shrinkage needed Faster – Secondary intention: Pressure ulcer, burn Greater tissue damage More shrinkage required Slower  Some helpful links Immune system: https://www.youtube.com/watch?v=wHCJUMBKgyo&list=PLYPwwTUmUyZVsK3zKg_m9t sa30DesE_iB&index=1 Inflammation: https://www.youtube.com/watch?v=LaG3nKGotZs PRR and PAMP: https://www.youtube.com/watch?v=4rEgaOW7Exk Type I hypersensitivity: https://www.youtube.com/watch?v=2tmw9x2Ot_Q Type II hypersensitivity: https://www.youtube.com/watch?v=kLaUz58CBMc&list=PLYPwwTUmUyZVsK3zKg_m9ts a30DesE_iB&index=15 Type III hypersensitivity: https://www.youtube.com/watch?v=0T_SAXyMs_c&list=PLYPwwTUmUyZVsK3zKg_m9ts a30DesE_iB&index=11 Type IV hypersensitivity: https://www.youtube.com/watch?v=6wOiDrObk_A&list=PLYPwwTUmUyZVsK3zKg_m9ts a30DesE_iB&index=7 Systemic lupus erythematosus: https://www.youtube.com/watch?v=0junqD4BLH4&list=PLYPwwTUmUyZVsK3zKg_m9ts  Thank you! Next week: Exam 1!!!