Module 1 Lecture Slides PDF

Module 1 Introduction to Pathophysiology: Tissue Responses to Injury and Infection 1  Outline Acute Inflammation Chronic Inflammation Special Patient Populations Hypersensitivity Reactions Immune Deficiency Cachexia E...

Module 1 Introduction to Pathophysiology: Tissue Responses to Injury and Infection 1  Outline Acute Inflammation Chronic Inflammation Special Patient Populations Hypersensitivity Reactions Immune Deficiency Cachexia Emerging Concepts in Pathophysiology 2 Acute Inflammation 3  Acute Inflammation ⬤ Inflammation is a protective physiological response to injury or infection Neutralization and elimination of micro-organisms Promotes tissue repair ⬤ Acute inflammation initiated seconds to minutes and resides within days of the original injury or microbial invasion ⬤ The inflammatory response primarily carried out by cells of the innate immune system Co-ordinated using signaling molecules known as cytokines and chemokines 4  Acute Inflammation 5 http://vet.uga.edu/ivcvm/courses/VPAT5200/03_inflammation/02_acute/inflamm02.htm  Acute Inflammation Sequence of Events 1.Foreign material or cellular damage is detected by local immune cells, including mast cells, macrophages, dendritic cells and lymphocytes Use non-specific receptors that detect conserved microbial sequences or signals of cell damage Immune Cell Bacterium A Activation Bacterium B Bacterium C Receptor 6  Acute Inflammation Sequence of Events 2.Local immune cells become activated and begin to secrete inflammatory mediators 7  Acute Inflammation Sequence of Events 3.Immune cells are recruited to site of inflammation and engulf foreign material and cellular debris 8  Acute Inflammation Sequence of Events Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 9 http://pathology4pas.blogspot.ca/2012/11/inflammation.html  Acute Inflammation Sequence of Events 2.Local immune cells become activated and begin to secrete inflammatory mediators Mast cells immediately secrete histamine Causes vasodilation and increased vascular permeability Mast cells and macrophages also release chemokines Recruit additional immune cells to site of inflammation Pro-inflammatory cytokines activate resident and newly recruited immune cells E.g. tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1, IL-6, IL-23 10  Acute Inflammation Sequence of Events 3a. Immune cells are recruited to site of inflammation and engulf foreign material and cellular debris Known as phagocytosis Neutrophils are first to respond, followed by monocytes/macrophages Neutrophils produce reactive oxygen species Causes collateral tissue damage Neutrophils and monocytes also release pro- inflammatory cytokines and chemokines to further enhance immune response 11  Acute Inflammation Sequence of Events Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 12 http://pathology4pas.blogspot.ca/2012/11/inflammation.html  Acute Inflammation Sequence of Events 3b. Neutrophils can produce Neutrophil Extracellular Traps (NETs) to capture micro-organisms Unravel DNA and extrude it into the extracellular space Micro-organisms will stick to this DNA Traps contain antimicrobial agents that kill or neutralize micro-organisms Exposed DNA serves as danger signal to other immune cells 13  Acute Inflammation 14 http://www.bloodjournal.org/content/120/6/1152?sso-checked=true  Acute Inflammation Sequence of Events 4.Professional antigen presenting cells present fragments of foreign material to T helper cells to induce adaptive immunity Provides specific immune response Memory cells are produced which allow adaptive immune response to occur faster upon secondary exposure 5.If the threat is successfully neutralized or eliminated, inflammation subsides, and immune cells help co-ordinate tissue repair 15  Acute Inflammation Local Manifestations ⬤ Acute inflammation is characterized by localized heat, swelling, pain and redness Vasodilation increases blood flow, causing heat and redness Increased vascular permeability promotes edema (swelling) Edema places pressure on pain fibres Prostaglandins and bradykinin activate pain fibres 16  Acute Inflammation Local Manifestations 17  Acute Inflammation Systemic Manifestations ⬤ Fever Caused by exogenous (lipopolysaccharide) and endogenous pyrogens (TNF-α and IL-1) Act on the hypothalamus to change the thermoregulatory set point ⬤ Leukocytosis Increased numbers of circulating leukocytes Increase in the proportion of immature cells ⬤ Increased plasma protein synthesis Acute-phase reactants C-reactive protein, fibrinogen 18 Chronic Inflammation 19  Chronic Inflammation ⬤ Defined as inflammation that lasts 2 weeks or longer ⬤ Characterized by excessive immune cell infiltration at the site of inflammation Lymphocytes and macrophages ⬤ Unlike acute inflammation, chronic inflammation is not a productive response Causes excessive tissue damage Promotes cancer development 20  Chronic Inflammation ⬤ Often caused by an unsuccessful acute inflammatory response ⬤ Other causes Micro-organisms possess mechanisms to evade host defense, thereby allowing them to persist Toxins continue to damage tissue even after micro- organisms have been eliminated Continuous exposure to chemicals, particulate matter, or physical irritants Idiopathic (no known cause) 21  Chronic Inflammation Granulomas ⬤ A granuloma is a tumor-like mass that is often found at the site of chronic inflammation Functions to wall off and isolate the infected area ⬤ Infectious agent is resistant to destruction by immune cells E.g. Mycobacterium tuberculosis ⬤ Macrophages fuse together to form multinucleated giant cells ⬤ Lymphocytes form a wall around the central core of macrophages, giant cells and debris ⬤ Collagen can be deposited to form fibrous capsule 22  Chronic Inflammation Granulomas http://www.humpath.com/spip.php?article275 23  Chronic Inflammation Granulomas 24 Chronic Inflammation and Cancer ⬤ Chronic inflammation is an important factor in the development of cancer Cytokines released from inflammatory cells Reactive oxygen species Promote mutations in DNA Decreased response to DNA damage Chronic infections can also promote cancer development E.g. Chronic Helicobacter pylori infection can cause gastric cancer 25 Special Patient Populations 26  Pediatrics ⬤ Neonates have transiently depressed immune function Immune system develops in sterile environment and typically has not been exposed to micro-organisms before birth Neutrophils are not capable of efficient recruitment to sites of injury or infection (chemotaxis) Exhibit complement deficiency More susceptible to serious bacterial infections, especially intracellular pathogens 27  Pediatrics ⬤ Maternal antibodies are delivered to fetus across placenta Exist in baby’s blood for first few months as it begins to produce its own antibodies Antibody levels are lower than that of adults for upwards of 1 year 28  Older Adults Older adults also exhibit impaired immune function Associated with chronic illness and certain medications Ø Diabetes, cardiovascular disease, etc. Healing response is diminished due to loss of the regenerative ability of the skin T lymphocyte function declines with age Thymus atrophies which changes proportions of T lymphocyte subsets in circulation There is a decrease in antibody production and a decrease in memory B cells as well Infections are therefore more common in older adults 29 HYPERSENSITIVITY REACTIONS 30  Hypersensitivity Reactions ⬤ Hypersensitivity: defined as an excessive immunologic reaction to an antigen that results in disease or damage to the host ⬤ Three major types of hypersensitivity reactions: Allergy –environmental antigens Autoimmunity –self-antigens Alloimmunity –tissues from another individual e.g. during transfusion, transplantation, and pregnancy ⬤ Four major mechanisms: Type I, Type II, Type III and Type IV Immediate/humoral – occurs within minutes – Types I-III Delayed/cell-mediated – occurs within days – Type IV 31  Hypersensitivity Reactions Sensitization ⬤ Initial exposure to antigen promotes: Excessive antibody production Generation of large numbers of memory T cells ⬤ Re-exposure to antigen therefore produces an exaggerated immune response ⬤ Can occur after a single exposure or may take multiple exposures ⬤ Required for the development of all hypersensitivity reactions 32  Immediate/Humoral Hypersensitivity Reactions Type I Hypersensitivity ⬤ Mediated by IgE antibodies ⬤ IgE antibodies bind to surface receptors on mast cells following initial sensitization ⬤ Re-exposure stimulates mast cell degranulation ⬤ Most type I hypersensitivity reactions occur against environmental antigens and are allergic Ø Examples include allergic rhinitis (hay fever) and peanut allergies ⬤ Severe allergic response can cause anaphylaxis 33  Immediate/Humoral Hypersensitivity Reactions Type I Hypersensitivity Sensitization Re- exposure Degranulation Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 34  Immediate/Humoral Hypersensitivity Reactions Type II Hypersensitivity ⬤ Characterized by an immune response directed at a specific cell type or tissue ⬤ Antibodies bind to tissue specific antigens or antigens that have attached to particular tissues ⬤ Cells/tissues are then destroyed by Complement activation Phagocytosis The release of cytotoxic substances from immune cells ⬤ Examples include Graves disease and Myasthenia Gravis 35  Immediate/Humoral Hypersensitivity Reactions Type II Hypersensitivity Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 36  Immediate/Humoral Hypersensitivity Reactions Type III Hypersensitivity ⬤ Characterized by the production of antigen-antibody complexes that get deposited in blood vessels or extravascular tissues ⬤ Cause tissue damage via complement activation and neutrophil-mediated cell death ⬤ Size of complex affects location of deposition and associated symptoms Intermediate sized complexes are most damaging Can cause inflammation of the kidneys, blood vessels or joints Examples include systemic lupus erythematosus and rheumatoid arthritis 37  Immediate/Humoral Hypersensitivity Reactions Type III 38  Delayed/Cell-Mediated Hypersensitivity Reactions Type IV Hypersensitivity ⬤ Characterized by T cell-mediated destruction of target cells ⬤ Inflammation takes 48-72 hours to develop Requires antigen presentation to memory T cells Examples include contact dermatitis and a TB Skin Test 39 Delayed/Cell-Mediated Hypersensitivity Reactions 40 Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 41 Immune Deficiency 42  Immune Deficiency ⬤ Defined as the failure of the immune mechanisms of self-defense to protect the body against infection ⬤ Characterized by an increased tendency to develop unusual or recurrent, severe infections Opportunistic infections ⬤ Primary Immune Deficiency Often caused by a sporadic genetic mutation ⬤ Secondary Immune Deficiency Caused by an additional illness More common than primary immune deficiency 43  Acquired Immunodeficiency Syndrome (AIDS) ⬤ An infectious disease caused by the human immunodeficiency virus (HIV) ⬤ In 2022, there were approximately 39 million individuals living with HIV globally (World Health Organization, 2023) 1.5 million of which were < 15 years old 1.3 million new HIV cases and 630,000 AIDS-related deaths (WHO, 2023 estimates) ⬤ In Canada alone, 62,790 individuals had HIV in 2020 (PHAC, 2022) Approximately 10% of these individuals were not aware that they were infected by HIV 44  Human Immunodeficiency Virus (HIV) ⬤ HIV is a retrovirus that primarily infects and destroys CD4+ T helper cells of the adaptive immune system Can also infect macrophages, dendritic cells, NK cells and cytotoxic T cells ⬤ Found in blood, vaginal fluid, semen and breast milk of infected individuals ⬤ Transmitted through blood or blood products, intravenous drug abuse, sexual intercourse and maternal-child transfer before or during birth 45  Human Immunodeficiency Virus (HIV) ⬤ HIV is enveloped by a membrane that contains the viral glycoprotein gp120 ⬤ gp120 binds to CD4, which is primarily expressed by T helper cells ⬤ Once the virus has attached to its target cell, it inserts its genetic information The HIV genome is encoded for by RNA HIV uses the virally encoded enzyme reverse transcriptase to convert this RNA into DNA (retrovirus) The enzyme integrase then incorporates this DNA into the host genome Allows HIV to remain dormant for many years 46 47  Human Immunodeficiency Virus (HIV) ⬤ HIV reproduces over the first several days after initial infection Plasma viral load is high and CD4+ T cell numbers decline ⬤ The body eventually mounts an immune response against the virus Patientsexhibit non-specific signs of infection The virus enters a dormant state and CD4+ T cell numbers improve ⬤ Once the virus is reactivated, viral load increases and CD4+ T cell numbers drastically decline 48 Human Immunodeficiency Virus (HIV) 49 Acquired Immunodeficiency Syndrome (AIDS) ⬤ Characterized by a drastic reduction in the number of CD4+ T helper cells Healthy patients have 600-1200 CD4+ T cells per µL of blood AIDS is often diagnosed when < 200 CD4+ T cells are present per µL of blood ⬤ CD4+ T helper cells are directly destroyed by: Viral replication CD8+ cytotoxic T cell destruction ⬤ CD4+ T helper cells are also indirectly killed Infected cells shed gp120 which can induce apoptosis in uninfected T cells 50 Acquired Immunodeficiency Syndrome (AIDS) ⬤ CD4+ T helper cells are crucial to adaptive immune system ⬤ AIDS patients therefore have an increased susceptibility to opportunistic infections Tuberculosis, Candidiasis infections, pneumonia, meningitis Most common cause of death ⬤ They are also more susceptible to cancers Kaposi sarcoma, non-Hodgkin lymphoma ⬤ Often experience cachexia 51 Cachexia 52  Cachexia ⬤ Cachexia is a complex metabolic disorder characterized by muscle wasting and atrophy, with or without a loss of white adipose tissue Results in muscle weakness and fatigue ⬤ Affects 40-80% of cancer patients Incidence varies with tumor type Indirectly responsible for the death of approximately 20% of cancer patients Degree of cachexia inversely correlated with survival time of patient ⬤ Cachexia symptoms are also apparent during active acute or chronic inflammation 53  Cachexia ⬤ Patients with cachexia exhibit an abnormal energy balance Energy input is not sufficient to meet energy requirements of body Can result from a decrease in energy input and/or an increase in energy output ⬤ Patients consume fewer calories ⬤ Energy production in skeletal muscle and adipose tissue also becomes less efficient ATP production in mitochondria is impaired through uncoupling of proton motive force 54  Cachexia ⬤ Muscle wasting and impaired function is due to: Increased myofibril protein degradation Increased amount of apoptosis Impaired regenerative capacity of cells ⬤ In some patients there is a loss of body fat due to: Increased lipid breakdown Impaired lipid synthesis 55  Cachexia ⬤ Inflammation facilitates cancer cachexia Energy imbalance is promoted by pro-inflammatory cytokines, including TNF-α and IL-1 ⬤ Other possible contributors include: Factors directly released from tumour cells Chemotherapeutic agents Abnormal metabolic requirements of growing tumors Alterations in hormones involved in the regulation of appetite Increase in appetite supressing hormones and decrease in appetite stimulating hormones 56 EMERGING CONCEPTS IN PATHOPHYSIOLOGY Microbiota and Epigenetics 57 MICROBIOTA 58  Microbiota ⬤ The term microbiota refers to the complete collection of micro-organisms associated with the human body ⬤ Also known as the microflora or normal flora ⬤ Primarily consists of bacteria ⬤ The human body contains 10 times more bacteria than it does human cells ⬤ Reside on essentially every surface that is exposed to the external environment ⬤ Gastrointestinal tract contains the greatest amount of bacteria ⬤ Colon alone contains 70% of our microbiota 59 Gastrointestinal Microbiota Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 60 Integumentary Microbiota Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 61 Nature Reviews Microbiology (2011). 9: 244-253  Microbiome ⬤ Refers to the complete collection of genes expressed by the micro-organisms making up our microbiota ⬤ Microbiome is much greater than the collection of genes coded for by human DNA ⬤ 22,000 genes in human genome ⬤ 3.3 million non-redundant genes in microbiome of gastrointestinal tract alone ⬤ Much higher diversity across population ⬤ 99.9% of human DNA is identical ⬤ Only 10-20% of microbiome is conserved across the population 62  Microbiota ⬤ Performs several important functions ⬤ Prevents colonization of pathogenic bacteria ⬤ Regulates the development of the immune, cardiovascular and nervous systems ⬤ Increases nutrient acquisition from food ⬤ Many of these functions have been identified through studies using gnotobiotic mice that are raised in a sterile environment ⬤ Mice are exposed to specific bacterial species and changes in physiology are assessed 63  Microbiota ⬤ Alterations in the microbiota have been associated with several diseases ⬤ Irritable bowel syndrome ⬤ Inflammatory bowel disease ⬤ Obesity ⬤ Malnutrition ⬤ Type II Diabetes mellitus ⬤ Certain cancers ⬤ Cardiovascular disease ⬤ Antibiotic treatment transiently reduces diversity of microbiota ⬤ Returns to pre-treatment composition within several weeks 64 EPIGENETICS 65  Epigenetics ⬤ Defined as the modification of gene expression without alterations to the genetic sequence ⬤ Modifications include methylation, acetylation, phosphorylation, ubiquitination and SUMOylation ⬤ These modifications alter DNA packaging, which regulates accessibility to RNA polymerase ⬤ Modifications that make DNA more compact will decrease gene expression → heterochromatin ⬤ Modifications that make DNA packaging looser will increase gene expression → euchromatin 66 Epigenetics 67  Epigenetics ⬤ Epigenetic changes occur naturally and are required for the normal functioning of many genes ⬤ Allow different cells to express different sets of genes ⬤ Modifications are largely reversible, but can be passed on to daughter cells ⬤ Some of these changes can even be passed on to progeny! ⬤ Environmental factors cause epigenetic modification of genes ⬤ Epigenetic modifications have been linked to several diseases, especially cancers 68 See you in Virtual Class 1 69