Chapter+4+Inflammation%2C+Allergic+Diseases%2C+and+Autoimmune+Response+in+progress.docx

Chapter 4: Inflammation and Healing First line of defense Nonspecific-will attack any foreign object Mechanical barrier Unbroken skin and mucous membranes Chemical barriers include Secretions such as tears (lysozyme enzyme damages cell wall of bacteria) and gastric juices Second line of defense Also...

Chapter 4: Inflammation and Healing First line of defense Nonspecific-will attack any foreign object Mechanical barrier Unbroken skin and mucous membranes Chemical barriers include Secretions such as tears (lysozyme enzyme damages cell wall of bacteria) and gastric juices Second line of defense Also nonspecific Phagocytosis –neutrophils and macrophages engulf and destroy bacteria, damaged cells, other foreign matter Inflammation-series of events that attempt to limit effects of injury or dangerous agents in body Interferons are specific agents made by cells to protect uninfected cells Third line of defense Specific immunity B cells and T cells must be ‘trained’ to respond to certain invaders Like Star Wars Clone Wars movies B cells oversee Humoral immunity and produce antibody T cells oversee Cell Mediated Immunity and destroy invaders once they are activated. Memory cells keep a close watch for the same invaders in the future and launch a response quickly Inflammation Normal defense mechanism (nonspecific) One cause of inflammation is infection Must be treated Conditions are named with suffix ‘itis’ –inflammation of Another cause is allergy, burns, or insect bites When tissue injury occurs, the damaged mast cells and platelets release chemical mediators including bradykinin, serotonin prostaglandins, and leukotrienes into blood and interstitial fluid Cytokines communicate within the tissue fluid and send messages to lymphocytes, macrophages, immune system, and hypothalamus to induce fever Steps of inflammation: Release of bradykinin from injured cells Activation of pain receptors by bradykinin Mast cells and basophils release histamine. Capillary dilation (bradykinin and histamine) Increased blood flow and capillary permeability (vasodilation) Bacteria may enter the tissue. Neutrophil and monocytes come to injury site. Neutrophils phagocytize bacteria. Macrophages leave bloodstream for phagocytosis of microbes Local Effects of Inflammation (cardinal signs) Redness and warmth Caused by increased blood flow to damaged area Swelling (edema) Shift of protein and fluid into the interstitial space Pain Increased pressure of fluid on nerves; release of chemical mediators (e.g., bradykinins) Loss of function May develop if cells lack nutrients; edema may interfere with movement. Exudate Serous Watery, consists primarily of fluid, some proteins, and white blood cells Fibrinous Thick, sticky, high cell and fibrin content Purulent Thick, yellow-green, contains more leukocytes, cell debris, and microorganisms Abscess Localized pocket of purulent exudate in solid tissue Hemorrhagic exudate Present when blood vessels are damaged Systemic effects: Mild fever (pyrexia) Common if inflammation is extensive Release of pyrogens like Interleukin-1 Malaise Feeling unwell Fatigue Headache Anorexia –loss of appetite Diagnostic Tests Leukocytosis-increased white blood cells Elevated serum C-reactive protein (CRP) Erythrocyte sedimentation rate (ESR) Elevated plasma proteins and cell enzymes are nonspecific and do not indicate the reason for the inflammation (see table 5.3). Differential count-observe the numbers of blood cells (allergic reaction and parasites increase eosinophil count for example) Helpful to distinguish between bacterial and viral infection Circulating plasma proteins-fibrinogen, prothrombin, alpha-antitrypsin increase when protein synthesis increases in hepatocytes Cell enzymes but are not necessarily tissue specific AST (aspartate aminotransferase) is elevated in liver disease and in acute stage of heart attack Isoenzymes may be elevated Isoenzyme of creatine kinase with myocardial component (CK-MB) is specific for MI The enzyme alanine aminotransferase (ALT) is specific for the liver Elevated levels indicate liver damage and often appears before jaundice Necrosis Extensive necrosis leads to ulcers and erosion of tissue Potential Complications depend of site of inflammation Infection Microorganisms can more easily penetrate edematous tissues. Some microbes resist phagocytosis. The inflammatory exudate also provides an excellent medium for microorganisms. Skeletal muscle spasm after injuries like sprains or fractures and may force joints out of normal alignment Causing increased pain Chronic Inflammation: Follows acute episode of inflammation Less swelling and exudate Presence of more lymphocytes, macrophages, and fibroblasts Continued tissue destruction More collagen produced in the area leading to fibrous scar tissue Granuloma may develop around foreign object like a splinter but also a step of infection when a person has TB. Potential Complications of chronic inflammation May cause deep ulcers because prolonged inflammation can cause necrosis and lack of regeneration can cause erosion of tissue. Can result in perforations or development of extensive scar tissue Treatment of Inflammation: Acetylsalicylic acid (ASA) Aspirin-not for children with viral infections (Reye Syndrome) Reduces prostaglandin synthesis at site of inflammation, reducing inflammatory response. Acetaminophen-Tylenol (careful with your dosage!) Nonsteroidal anti-inflammatory drugs (NSAIDs) Reduce production of prostaglandins Ibuprofen (Advil or Motrin) used for menstrual pain and headache, RA, etc. Newer NSAIDS are celecoxib (Celebrix) which has less unwanted effects on stomach (COX-2 inhibitor) COX-2 inhibitors (Vioxx-pulled by Merck after reports of increased heart attacks) Glucocorticoids (naturally occurring) Benefits include: Decreased capillary permeability Enhanced effectiveness of epinephrine and norepinephrine Reduced number of leukocytes and mast cells decreasing release of histamine and prostaglandins Reduces immune response (a common cause of inflammation) Corticosteroids –steroidal anti-inflammatory drugs that are synthetic and related to glucocorticoids Adverse effects of Glucocorticoids (long term use) Atrophy of lymphoid tissue; reduced hemopoiesis Increased risk of infection Catabolic effects Increased tissue breakdown; decreased protein synthesis Delayed healing Delayed growth in children Retention of sodium and water (leads to high blood pressure and edema) Increased gluconeogenesis (rise in blood sugar) Long term use will lead to reduction of normal secretion of natural hormones and atrophy of adrenal gland Suddenly stopping medicine will cause adrenal crisis (shock), so must be weaned off. First Aid Measures for injury related inflammation Rest Ice-cold causes local vasoconstriction and reduces pain and edema Compression-elastic stockings or brace Elevation-keep limb elevated to improve flow away from damaged area May use heat during long term therapy depending on situation. Acute RA treatment of heat and moderate activity may help remove excess fluid, painful chemical mediators and waste metabolites, and help with healing. Many things promote healing or delay the process Youth, nutrition, good circulation, clean wound promote healing Advanced age, poor nutrition, anemia, poor circulation, chemotherapy, prolonged use of glucocorticoids delay healing Allergic Diseases The eye is probably the most common site for development of allergic inflammatory disorders because it has no mechanical barrier to prevent impart of allergens such as pollen on its surface. There is a two-step process that causes someone to become ‘allergic’ to a substance. Sensitization is the first step The person develops a significant amount of IgE antibodies against an inhaled, ingested, or injected substance. Memory B cells appear and can produce more of this specific IgE antibody when stimulated. A person is not aware of this until they have been exposed again to the allergen. The second step of becoming allergic involves re-exposure to the allergen Symptoms can range from rhinitis to sudden death and anywhere in between. Scenario: 6-year-old boy is stung by yellow jackets while playing outside Yellow jacket antigen encounters T and B cells and is recognized as foreign Venom is cleared and only a mild reaction occurs at the site of the sting. Years later the young child receives another sting at a picnic. Within minutes he is wheezing and has difficulty breathing. He is gasping for air and becoming cyanotic as paramedics arrive Prompt treatment allowed him to survive the encounter. What caused this? The sensitization that occurred the first time he was stung. Allergy testing Skin testing is most sensitive and cost-effective way to screen Biological extracts of aeroallergens are available for testing with a small drop of antigen and scratching or pricking skin with a sharp plastic or lancet Reactions are usually fast and are measured by on the size of the wheal and flare Negative (saline) and positive (histamine) are controls Diagnostic studies IgE levels over 1.0 IU in umbilical cord blood of a newborn are indicative that the child will develop allergic disease Serum IgE in infants over 20 IU/ml can also predict allergic disease This doesn’t not work in young children or adults Weird examples: Exercise Induced Anaphylaxis About 2/3 of individuals with exercise induced anaphylaxis have a family history of atopy (heightened response to allergens) Symptoms include hives (urticaria), swelling, pruritus (itchy skin), flushing, wheezing, and GI involvement, including nausea, abdominal cramping, and diarrhea. Food dependent exercise induced anaphylaxis (reaction occurs a couple hours after eating) Insulin allergy Less common now that insulin is genetically engineered Reactions could be local or systemic Local are the most common and usually disappear after the first 4 weeks of therapy Systemic reactions include urticaria, angioedema, bronchospasm, and hypotension Latex allergy (now a significant cause of anaphylaxis) Due to increased use of gloves following AIDS precautions. Usually health care workers, patients with spina bifida, and people with a history of latex allergy are most likely to develop anaphylaxis Patients with latex allergies often have allergies to certain foods like avocados and bananas. Mastocytosis Rare disorder of abnormal mast cell proliferation with clinical features that include flushing, pruritus, abdominal pain, diarrhea, hypotension, syncope and musculoskeletal pain. These features are the result of mast cell mediator release and infiltration into target organs. Two main types: Systemic which affects adults can affect skin, organs, Cutaneous which affects children (mainly skin rash) Type I allergies (IgE mediated reactions) Most type I reactions are against environmental antigens (allergens) Exposure to allergen causes IgE proliferation by certain B cells Repeated exposure to fairly large doses of allergen is required to sensitize the patient IgE binds to the Fc receptors on the plasma membrane of mast cells After sensitization and after exposure to the antigen the patients mast cells degranulate and release histamine, neutrophil chemotactic factor and eosinophil chemotactic factor of anaphylaxis. Clinical manifestations of type I are attributed to the effects of histamine (that’s why antihistamines help) Atopic individuals have a higher concentration of IgE and more Fc receptors on their mast cells (inherited from parents) Examples of Type I allergies: Ingestants can cause gastrointestinal allergy to foods, drugs Inhalants can cause allergic rhinitis, bronchial asthma Injectants can cause anaphylaxis Type II allergies (tissue specific reactions) These hypersensitivities can destroy or alter cells by 4 mechanisms: Complement-mediated lysis of cells Phagocytosis by macrophages Cell destruction of Tc cells Antibody binding alone (doesn’t destroy the target cell) Examples include transfusion reactions and hemolytic disease of the newborn (Rh factor) Type III allergies (immune-complex-mediated reactions) Caused by antigen-antibody complexes formed in the circulation and deposited in vessel walls or extravascular tissue Are not organ specific Harmful effects are caused by complement activation Neutrophils attempt to infest the immune complexes but can’t because the complexes are bound to tissues Large quantities of lysosomal enzymes are released during neutrophils attempts to phagocytose the complexes These are released into the inflammatory site instead of inside the phagolysosome and cause most of the tissue damage. Examples are Arthus reaction and serum sickness Type IV (cell mediated tissue reactions) This is mediated by specifically sensitized T lymphocytes and do not involve antibody Typically involve either cytotoxic T cells or delayed hypersensitivity T cells Examples include Graft Rejection, tumor rejection, tuberculin reaction (diagnostic test for TB), and allergic reactions to poison ivy and metals (contact dermatitis) Classification of grafts: autograft (self), isograft (twin), allograft (same species), xenograft (animal to human) Autoimmune Disease: Systemic autoimmunities: Systemic Lupus Erythematosus (SLE) Butterfly rash across nose Autoantibodies produced against a variety of targets including organs and tissues, intracellular materials such as mitochondria Rheumatoid arthritis Progressive, debilitating damage to joints and may cause damage to lungs, eyes, skin, and nervous system Autoantibodies form immune complexes that bind to synovial membrane of joints, which activate cytokines Chronic inflammation develops and leads to scar tissue and joint destruction Autoimmunity of endocrine glands Graves disease Attachment of autoantibodies to receptors on thyroxin-secreting follicle cells of thyroid. Abnormal stimulation of these cells cause overproduction of this hormone and symptoms of hyperthyroidism Type I diabetes (possible autoimmunity) Beta cells of pancreas secrete insulin and cytotoxic T cells become sensitized which leads to destruction of beta cells Neuromuscular autoimmunities Myasthenia gravis (MG) is a syndrome caused by autoantibodies binding to receptors for acetylcholine First effects are muscles of eyes and throat, progresses to complete loss of skeletal muscle function and death Treatment is immunosuppressive drugs and therapy to remove autoantibodies from circulation Multiple Sclerosis (MS) is a paralyzing neuromuscular disease associated with lesions in the myelin sheath that surrounds white matter in CNS Most people have relapsing-remitting disease Women are more likely than men to have this disease (twice as likely) T cell and autoantibody-induced damage severely reduces the ability of neurons to send impulses resulting in muscle weakness, tremors, difficulty with speech and vision, and eventually paralysis Possible link between herpes virus VI and herpes IV (Epstein Barr) and onset of disease Disease modifying treatments (DMT) include immunosuppressant like cortisone and interferon beta are used to treat symptoms Monoclonal antibody treatment is also used