2024 Inflammation and Immune Handout-1 PDF

Inflammation Dr Ruth Hannon [email protected] Natural Barriers Damjanov (2000) Figure 3.1 Inflammation  Lines of Defense  First line – Mechanical and chemical barriers   Second line – Inflammation    Non-specific Innate or natural immune system Third line – Adaptive (acquired) immunity  ...

Inflammation Dr Ruth Hannon [email protected] Natural Barriers Damjanov (2000) Figure 3.1 Inflammation  Lines of Defense  First line – Mechanical and chemical barriers   Second line – Inflammation    Non-specific Innate or natural immune system Third line – Adaptive (acquired) immunity   Natural barriers (A&P – HTH SCI 1CC6) Specific Humoral vs. Cellular Non-specific (Innate) Specific (Adaptive) Humoral Complement Cellular Granulocytes, Mast cells, B lymphocytes Macrophages T lymphocytes Antibodies Acute inflammation Healing Cells can re-grow Regeneration Restoration of normal structure and function Damage Persists Cells cannot re-grow Chronic inflammation *Overwhelming Healing by repair Damaging agent overcome *Sepsis / MODS Yes Scar formation; loss of specialized function No Persistence * Level 3 Patho Course Five Cardinal Signs!!      Heat Redness Swelling Pain Loss of function Acute Inflammation Power-Kean, Zettel & El-Hussein (2023) Figure 6.3 Inflammation    Goals (transport blood, deliver nutrients and cells, promote regeneration) Accomplished ( metabolic rate, dilation,  permeability) Causes Homeostasis Control (many options!!)  ENDOTHELIAL CELLS:  Vasoregulation Vasodilators Nitric oxide, PGs, prostacyclin, platelet activating factor, ATP  Vasoconstrictors Thromboxane A2, endothelin-1, ACE    Cell trafficking Coagulation ICAM, VCAM – adhesion molecules Antithrombotic tPA, heparans, tissue factor inhibitor  Prothrombotictissue factor (TF), plasminogen activator inhibitor-1 (PAI-1)   CYTOKINES:   Pro-inflammation TNFα, IL1, IL2, IL6, interferon Anti-inflammation IL4, IL10, IL11, IL13, TNF-solute, IL1ra Key Cells in Inflammation       Polymorphonuclear neutrophils (PMN) Basophils / Mast cells Eosinophils Monocytes / Macrophages Platelets Lymphocytes *These should be review! Macrophages – Locations           Bloodstream – circulating monocytes / macrophages Bone and bone marrow – Osteoclasts CNS – Microglia Connective tissue – Histiocytes Epidermis – Langerhans cells Liver – Kupffer cells Lung – Alveolar macrophages (dust cells) LN – lymphoid macrophages (fixed and free) Serous fluids – pleural macrophages, peritoneal macrophages Spleen – splenic macrophages Chemical Mediators  Any messenger that acts on blood vessels, inflammatory cells, or other cells to contribute to an inflammatory response  Wide range:  Cellular: Preformed granules  Newly synthesized   Humoral (Plasma) Factor XII (Coagulation system / Kinin system)  Complement  CELL Mediators in Inflammation  Cell derived, intracellular granules  Preformed granules Histamine / 5-hydroxytryptamine or 5-HT (Serotonin)  Lysosomal enzymes (eg, proteases, esterases, etc)   Newly synthesized Cytokines  Nitric oxide  Activated oxygen species (eg, ROS)  Interferon (IFNγ)  Arachidonic acid metabolites (eg, PGs, leukotrienes)  Mast Cell / Monocytes / Platelets / Vascular Endothelial cells / Leukocytes Inflammatory Stimuli Phospholipase A2 Arachidonic Acid Lipoxygenase pathway (5-LO) Cyclooxygenase pathway COX1 Leukotrienes Prostacyclin Thromboxane A2 5-HETE Lipoxin LTC4/LTD4/LTE4 Induces smooth muscle contraction, constricts pulmonary airways, increases microvascular permeability GI Protective Prostaglandins TxA2 – Vasoconstriction, bronchoconstriction, promotes platelet function COX2 Prostaglandins Induces vasodilation and bronchoconstriction, inhibits inflammatory cell function Power-Kean, Zettel & ElHussein (2023) Figure 6.6 PLASMA Mediators in Inflammation  Plasma derived, protein systems     Complement Bradykinin Clotting system All contain inactive enzymes (proenzymes)  Sequentially activated First proenzyme is converted to an active enzyme  Substrate of activated enzyme becomes the next component in the series   Components short lived and rapidly deactivated Complement System Hannon & Porth (2017) Page 370 Marieb & Hoehn (2019) Figure 21.6 McCance & Huether (2019) Figure 7.8 McCance & Huether (2019) Figure 7.9 Events Marieb & Hoehn (2019) Figure 21.3 Wound Healing Hannon & Porth (2017) Figure 18.9 Power-Kean, Zettel & El-Hussein (2023) Figure 6.13 Wound Healing Summary  Acute inflammation     Proliferative phase    Myofibroblasts Angioblasts Fibrinoblasts Extracellular Matrix Remodeling phase Great article to review this information too  Gantwerker, E.A., & Hom, D.B. (2011). Skin: Histology and physiology of wound healing. Facial Plastic Surgery Clinics of North America, 19(3), 441-453. Chronic Inflammation     Lymphocyte, macrophage, plasma cell infiltration Tissue destruction Attempts to repair Otherwise: Persistent injury/infection  Autoimmune disease  Summary of Inflammation Marieb & Hoehn (2019) Figure 21.4 Pathogenesis of Fever    Complex Neurologic / Endocrine response Benefits Damjanov (2000) Figure 2.18 Fever McCance & Huether (2019) Figure 16.8 Sepsis-3 Definitions  No longer considered a continuum of disease, severe sepsis has been dropped     SIRS (Sepsis-1), 1992 Sepsis-2, 2001 Sepsis-3, 2016 Definition    Organ dysfunction (SOFA score) and infection Table 1 (JAMA article by Singer) qSOFA (RR, Mentation/GCS, SBP) Septic Shock   Subset of sepsis Profound circulatory, cellular, and metabolic abnormalities     Mitochondrial dysfunction Tissue damage Both pro- and anti-inflammatory responses Criteria:   BP Serum lactate Clinical Presentation  Hypermetabolic state   Vasodilation   SNS, fever, increased energy requirements Hypovolemia, decreased afterload, hypotension Capillary permeability increased  Hypovolemia, hypotension, edema, hypoproteinemia Types of Shock  Distributive:     Septic Neurogenic / Vasogenic Anaphylaxis Other types:    Cardiogenic Hypovolemic Obstructive You should also review Chapter 24 in the textbook for more information about shock Sepsis Algorithm Singer et al. (2016) Figure 1 Neurogenic Shock Power-Kean, Zettel & El-Hussein (2023) Figure 24.44 Anaphylactic Shock McCance & Huether (2019) Figure 49.5 *Similar to Figure 24.45 in textbook Cardiogenic Shock Power-Kean, Zettel & El-Hussein (2023) Figure 24.42 Hypovolemic Shock Power-Kean, Zettel & El-Hussein (2023) Figure 24.43 Final Common Pathway Power-Kean, Zettel & El-Hussein (2023) Figure 24.41 Current Treatment  Support ABC’s, CAB’s    Hypermetabolic state Capillary permeability Vasodilation  Elimination of Source Additional support  (Activated Protein C (Xigris) – no longer available)  Key Points for Inflammation       Complexity Generalized process Essential Localized versus systemic Impact of other co-morbidities Research McCance & Huether (2019) Figure 49.6 References Adams, M.P., Urban, C.Q., Sutter, R.E., El-Hussein, M., & Osuji, J. (2021). Pharmacology for nurses (3rd Canadian ed.). Pearson Canada Inc. Damjanov, I. (2000). Pathology (2nd ed.). W.B. Saunders Company. Earn, D., Andrews, P.W. & Bolker, B.M. (2014). Population-level effects of suppressing fever. Proceedings of the Royal Society B, 281, 20132570. Gantwerker, E.A., & Hom, D.B. (2011). Skin: Histology and physiology of wound healing. Facial Plastic Surgery Clinics of North America, 19(3), 441-453. Gomez, C.R., Nomellini, V., Faunce, D.E & Kovacs, E.J. (2008). Innate immunity and aging. Experimental Gerontology, 43, 718-728. Hannon, R & Porth, C. (2017). Porth Pathophysiology (2nd Canadian ed.). Lippincott Williams & Wilkins. Marieb, E. & Hoehn, K. (2019). Human Anatomy and Physiology (11th ed.). Pearson Education Inc. McCance, K., & Huether, S. (2019). Pathophysiology (8th ed.). Mosby, Inc. Power-Kean, K., Zettel, S., & El-Hussein, M.T. (2023). Huether and McCance’s understanding pathophysiology (2nd Canadian ed.). Elsevier. Singer, M., Deutschman, C.S., Seymour, C.W., Shankar-Hari, M., Annane, D., Bauer, M., … Angus, D. (2016). The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA, 315(8), 80-810. Wood, S., Lavieri, M & Durkin, T. (2007). What you need to know about sepsis. Nursing 2007, 37 (3), 46-51. Immune System Dr Ruth Hannon [email protected] Inflammation vs. Immune Response Non-specific (Innate) Specific (Adaptive) Humoral Complement Antibodies Cellular Granulocytes Mast cells, Macrophages B lymphocytes T lymphocytes Innate Lymphoid Cells Lymph Organs  Primary / Central    Bone marrow Thymus Secondary / Peripheral Hannon & Porth (2017) Figure 17.11 Thymus Tortora & Derrickson (2021) Figure 22.5a Overview of Cells Innate Lymphoid Cells Silverthorn (2019) Figure 24.3 Adaptive Immunity  Goals  Detect wide variety of pathogens  Eradicate foreign molecules/pathogens  Remove dead/damaged tissues and cells  Distinguish from normal tissue Antigens – in subsequent slide     Specificity Memory Lymphocytes Adaptive Immunity Overview Power-Kean, Zettel, El-Hussein (2023) Figure 7.1 Antigens     Immunogenic Antigenic determinant (epitope) Self-antigen Allergens Hannon & Porth (2017) Figure 17.2 Antigen Presenting Cells (APCs)  Antigen recognition  Antigen is directly recognized by circulation antibody, antigen receptors on B cells (BCR), and T lymphocytes (TCR) Silverthorn (2019) Figure 24.9 and 24.10 Major Histocompatibility Complex (MHC) MHC I - CD8 MHC II - CD4  MHC I: present on all cells     presents endogenous antigen viral, intracellular bacteria, tumour antigen A, B, and C alleles MHC II: present on antigen presenting cells (dendritic cells, macrophages, B-cells)    presents exogenous antigen extracellular pathogen DR, DP, and DQ alleles Klein & Sato (2000) Figure 2 Characteristics of T cells   Overall TM cell    TC cell TReg cell    Dormant in tissue and with second presentation of antigen become activated Formally known as suppressor T cells Importance TH cell   Master regulator of immune system Subgroups (ie TH1, TH2, TH17, etc) T Cytotoxic Cell Marieb & Hoehn (2019) Figure 21.19 T cell subtypes Power-Kean, Zettel, El-Hussein (2023) Figure 7.13 B Cells … Power-Kean, Zettel, El-Hussein (2023) Figure 7.1 Antibodies / Immunoglobulins  Classes of antibody   IgG, IgA, IgM, IgD, IgE General Structure (FYI only)  Antigen-binding fragment (Fab)   Crystalline fragment (Fc)    Responsible for biological function Polypeptide chains (4)   Recognition sites (receptors for antigenic determinants) Light chains (2) and heavy chains (2) Hinge region Constant and variable regions   Complementary determining regions (CDRs) Framework regions (FRs) Immunoglobulins Hannon & Porth (2017) Table 17.4 B Cells  Functions    Antibody titres       Direct – Neutralization, Precipitation, Agglutination Indirect – Opsonization ANCA, ANA, RF, ACPA (or anti CCP), etc. Specific to organs i.e. thyroid, pancreas for DM Type I Seroconversion (Monoclonal antibodies) Primary response Secondary response Antibody Action Opsonization Marieb & Hoehn (2019) Figure 21.15 Functions of Antibodies Adams et al. (2021) Figure 39.2 Vaccines Offit, P.A., Quarles, J., Gerber, M.A. et al. (2002). Addressing parents’ concerns: Do multiple vaccines overwhelm or weaken the infant’s immune system? Pediatrics, 109, 124-129. www.Canada.ca / CPS: A parent’s guide to vaccination / Vaccine safety HealthyChildren.org (AAP): Vaccine safety: Examine the evidence page Power-Kean, Zettel, El-Hussein (2023) Figure 7.9 Acquired Immunity  Active immunity   Antibodies or T cells produced after either a natural exposure to an antigen or after immunization Passive immunity  Preformed antibodies or T lymphocytes are transferred from a donor to a recipient mRNA! Marieb & Hoehn (2019) Figure 21.13 Naturally Acquired - Passive Power-Kean, Zettel, El-Hussein (2023) Page 174 Natural Killer (NK) Cells as part of the Innate Lymphoid Cells (ILCs)   Class of lymphocytes Function     Viral infections Tumour cells Intracellular microbes Secrete antiviral cytokines  Gamma interferons Imbalances to Homeostasis    Autoimmune diseases Hypersensitivities Immunosuppression Autoimmune Diseases    Pathophysiology Diagnosis of an Autoimmune Disorder Examples       Immune thrombocytopenia (ITP) Goodpasture’s syndrome Systemic Lupus Erythematosus (SLE) Scleroderma Sjogren’s syndrome Rheumatoid Arthritis Hypersensitivities – Type I – Immediate Marieb & Hoehn (2019) Figure 21.20 Newman, J. (2006). Misery for all seasons: Allergies, a modern epidemic. National Geographic, 209 (5), page 128. Hypersensitivities – Type II, III and IV  Type II – Antibody-mediated      Type III – Immune complex-mediated   Hemolytic anemias Goodpasture’s syndrome Graves’ disease Myasthenia gravis Insoluble complex usually deposited in blood vessels or kidneys Type IV – Cell-mediated (delayed)     Granulomatous disease Contact dermatitis TB / Mantoux test Organ rejection Hypersensitivities I. Allergic Anaphylaxis and Atopy II. antiBody III. immune Complex IV. Delayed Crowley (2004) Table 5.1 Immunosuppression  Immunosuppression (immunodeficiency, immunocompromised) involves any mechanism where the function of the immune system is impaired.    Inherited immunodeficiency diseases Due to disease state – direct effect of disease process (ie HIV) or treatment (ie chemotherapy) Induced – modulation of immune response to prevent autoimmune disease (ie lupus), allergic response, or transplant rejection Classification of Immunosuppression  Congenital (primary):  T-cell, B-cell    B-cell    SCID DiGeorge syndrome Wiskott-Aldrich syndrome Common variable immunodeficiency Innate immune response    Chronic granulomatous disease Chediak-Higachi Complement deficiency Acquired immunodeficiency (secondary) Example: Dialysis Patient Clinical manifestations of immune deficiency     High incidence of TB reactivation Attenuation of autoimmune disorders Development of skin anergy with delayed hypersensitivity testing Suppressed response to vaccines Consequences of Immunosuppression  The adverse effect of immunosuppression is infection and depends on particular aspect of the immune response that is suppressed     Neutrophil function: soft tissue bacterial infection, bacterial respiratory tract, urinary tract infection CD8 T-cell: viral infection, parasitic, intracellular organisms Complement deficiency: Neisseria species Splenectomy: encapsulated organisms Immunosuppression: Summary   Congenital (Primary) Acquired (Secondary)   Induced or iatrogenic    Age, malnutrition, diabetes, kidney disease Immunosuppression for autoimmune disease, allergy, transplantation, chemotherapy Main side effect: infection Type of infection depends on nature of immunosuppression   Innate immune response (diabetes, steroids, ESRD) Adaptive immune response (HIV, transplant meds) References Adams, M.P., Urban, C.Q., Sutter, R.E., El-Hussein, M., & Osuji, J. (2021). Pharmacology for nurses, (3rd Canadian ed.). Pearson Canada Inc. Crowley, L. (2004). Introduction to human disease (6th ed.). Jones and Bartlett Publishers, Inc. Hannon, R. & Porth, C. (2017). Porth Pathophysiology, (2nd Canadian ed.).Lippincott Williams & Wilkins. Klein, J. & Sato, A. (2000). The HLA system. NEJM, 343(10), 702-709. Marieb, E. & Hoehn, K. (2019). Human Anatomy and Physiology (11th ed.). Pearson Education Inc. McCance, K., & Huether, S. (2019). Pathophysiology (8th ed.). Mosby, Inc. Newman, J. (2006). Misery for all seasons: Allergies, a modern epidemic. National Geographic, 209 (5), 124-130. Power-Kean, K., Zettel, S., & El-Hussein, M.T. (2023). Huether and McCance’s understanding pathophysiology (2nd Canadian ed.). Elsevier. Silverthorn, D. (2019). Human physiology (8th ed.) Pearson Education Inc. Tato, C. & O’Shea, J. (2006). Immunology: What does it mean to be just 17. Nature, 441, 116-168. Tortora, G. & Derrickson (2021). Principles of Anatomy and Physiology (16th ed.). John Wiley & Sons, Inc.