MODULE 5 OBJECTIVES.docx

MODULE 5 OBJECTIVES ""Robbins Basic Pathology", 10th Edition, 2017. Chapter 5: Diseases of the Immune System. In particular: The Normal Immune Response: Innate Immunity and Adaptive Immunity - pp. 121-124 Cells and Tissues of the Immune System: Lymphocytes, T Lymphocytes, MHC Molecules, B Lymphocyt...

MODULE 5 OBJECTIVES ""Robbins Basic Pathology", 10th Edition, 2017. Chapter 5: Diseases of the Immune System. In particular: The Normal Immune Response: Innate Immunity and Adaptive Immunity - pp. 121-124 Cells and Tissues of the Immune System: Lymphocytes, T Lymphocytes, MHC Molecules, B Lymphocytes, Natural Killer Cells, Antigen-Presenting Cells, Dendritic Cells - pp. 124-129 Overview of Lymphocyte Activation and Adaptive Immune Response; Cell-Mediated Immunity, Humoral Immunity – pp. 130-134. Summary: The Normal Immune Response: Overview of Cells, Tissues, Receptors, and Mediators - p. 134 Hypersensitivity: Immunologically Mediated Tissue Injury (Type 1 – Type 4 hypersensitivity reactions) – pp 134-135; See Table 5-2, p. 135 “Mechanisms of Hypersensitivity Reactions” Autoimmune Disorders – pp. 145-146 (also p. 150 on Tolerance), scan section on SLE see Summary – p. 158; Primary – pp. 168-170, Summary, p.173; Secondary – p. 173 (quite a detailed description of pathological and clinical features of AIDS – see Summary p. 177; Clinical Features, pp.180-181. By the completion of the module students should be able to: Top of Form Outline the features and function of the innate and adaptive immune system What is Innate Immunity? Bruise Splinter Abscess A physical protective barrier comprised of skin and mucosal surfaces An automated response to physical or infectious injury Players of innate immunity Physical players: Skin, hair, etc Chemical players: saliva, tears, mucus, pH Cellular players: – Phagocytes: monocytes, macrophages, neutrophils, basophiles, eosinophiles, platelets immature dendritic cells – NK cells PROCESSES: PHAGOCYTOSIS INFLAMMATION COMPLEMENT ACTIVATION COAGULATION The Skin and Mucosal Surfaces as Protective Barriers Stratum corneum: physical impermeable barrier comprised of corneocytes embedded in a lipid matrix Eccrine Glands: secrete sweat (acidic pH) and antimicrobial peptide Sebaceous gland: secrete sebum; coats the skin in antimicrobial lipid Physical barrier, acidic pH, antimicrobial lipids and antimicrobial peptides • Disrupt bacterial membranes Nasal, oral, respiratory, gastrointestinal, urinary and reproductive surfaces Cells of innate immunity: Granulocytes, also known as Polymorphonuclear leukocytes, have a multi-lobed nucleus and their cytoplasm is packed with granules that are loaded with antimicrobial enzymes and other proteins/peptides that contribute to innate immunity Cells of Innate Immunity: The Neutrophil Polymorphonuclear cell (PMN), recognized by multi-lobed nucleus 55-60% of bone marrow dedicated towards production of PMNs ~ 10^11 PMNs enter and leave circulation daily; 10 h lifespan Neutrophil granules contain antimicrobial peptides, proteases, phospholipase, myeloperoxidase, lysozyme, bactericidal permeability increasing factor (BPI), lactoferrin Kills bacteria by iron restriction, destruction of cell wall and membrane, oxidation (toxic free radicals) After phagocytosis, neutrophil granules (azurophiles) fuse with the phagosome to release antimicrobial peptides, proteases (cathepsins) and enzymes required for ROS production The NADPH Oxidase/Myeloperoxidase System Defect in Innate Immunity: Chronic Granulomatous Disease Descripton: Inherited X-linked and autosomal recessive disorder affecting 1:250,000 to 1:500,000 patients CGD patients suffer from recurrent infections, and in response to inflammation, develop severe chronic inflammation, leading to granuloma formation. S.aureus: most common cause of infection in CGD patients Cause: Failure to produce cytochrome b558 due to defect in gp91phox (60% of patients) and p47phox (30%) components of NADPH oxidase; therefore cannot generate superoxide anion Susceptible to infection due to inability to generate reactive oxygen species, including H2O2, HOCI, free radicals etc. Cells of innate immunity: Baso- and Eosin Basophils: Fight parasitic infection and contribute to allergic reactions: Produce heparin which is an anticoagulant and histamine which is a vasodilator Initiate chronic allergy and IgG-mediated anaphylaxis Eosinophil: Fight parasitic infection and contribute to the pathology of asthma Produce reactive oxygen species Cells of innate immunity: The macrophage Comparison of macrophages and neutrophils: Neutrophil life span is 10-12h but macrophage can live for several months Macrophages have additional capabilities for killing microbes including: Acidification of phagosome (vacuolar ATPase) Efflux of iron and manganese (nutrient restriction_ Influx of copper and zinc (reactive metals to support oxidative killing; free radical production) Reactive nitrogen intermediates; Nitric oxide synthase Pattern Recognition Receptors (How innate immunity cells recognize pathogens): TLR 1,2,6: Peptidoglycan Lipoproteins TLR4: Bacterial LPS (Gram Neg) Fungal mannans Viral envelope proteins TLR5: Bacterial flagellin TLR 3, 7,8, 9: Microbial and viral nucleic acids Comparison of Innate and Adaptive immunity: Cytokines and complement: How macrophages and neutrophils sense and respond to their environment Cytokines, chemokines and complement modify the functionality of immune cells and vascular endothelium When TLR’s are engaged, immune cells produce cytokines and chemokines Cytokines engage receptors on other immune cells and vascular endothelium to propagate the inflammatory response Summary of cytokine and chemokine functions relevant to innate immunity: Cytokines at work in innate immunity: Upon phagocytosis of microbes or viruses, a macrophage or dendritic cell produces interlukin IL-12, TNF and IL-1 IL12 instructs NK-cells to produce IFN-Y, which activates the macrophage to produce more inflammatory mediators TNF and IL-1 are major pro-inflammatory mediators that act on the other immune cells and the vascular endothelium to promote inflammation For example, TNF and IL-1 both promote expression of adhesion molecules on the vascular endothelium. This promotes adhesion and extravasation (diapedesis) of neutrophils The complement cascade: The complement cascade consists of several plasma proteins that act in sequential fashion to form Membrane Attack Complex (MAC), which pokes holes in bacterial membranes. Along the way: Bacteria are opsonized for phagocytosis by deposition of C3b C3a and C5a function as pro-inflammatory chemo-attractants, similar to the chemokines IL-8 The ALTERNATIVE complement pathway starts with deposition of C3b on the bacterial surface and doesn’t require specific antibody Clinical correlates of inflammation: Lymphocytes and Adaptive immunity: Lymphocytes recognize pathogens through antigen-specific receptors; these function like antibodies on the lymphocyte surface B-cells produce antibodies and develop in the bone marrow T cells develop in the Thymus and have both regulatory and immune effector functions Antibody Producing B-cells: B cells are responsible for producing antibodies. The antibodies produced by B cells circulate in the blood and bind to specific viruses or bacteria to neutralize them and help get them killed by other cells of the immune system (opsonization and complement activation) Maturation and clonal expansion of antibody producing B cells is aided by T-helper (Th) cells, which produce cytokines that promote B cell development CD4 T-helper cells (Th): Cell type Cytokines produced Primary function Th1 IFN-y, IL-2 Facilitate macrophages and cytotoxic cell responses Th2 IL-4, IL-6, IL-10 Stimulate antibody production by B-cells Th17 IL-17 Promote inflammation Treg TGF-B, IL-10 Suppress inflammation CD8 T-cells: The T-cell receptor on the CD8 cytotoxic T-cell recognizes a viral antigen that is presented by a virus infected cell Once the T-cell receptors and CD8 engage the MHC class I-viral antigen immune complex, the T-cell is triggered to release Perforin and Granzyme proteins that damage the membrane and nucleus of the target cell Major Histocompatibility Complex MHC: Here an antigen presenting dendric cell is presenting a “self” antigen in complex with Type I MHC. The CD8 T-cell does not have a receptor for the “self” antigen, so it’s not activated. With a few exceptions, cells in our body present self-antigens on MHC-I, which protects us from own immune system Here you can imagine that the dendric cell is presenting a foreign viral antigen on MHC-I. the CD8 and T-cell receptors engage this complex and the T-cell is instructed to undergo “clonal expansion” MHC-I and MHC-II ( aka Human Leukocyte Antigen System, HLA: MHC-I: Expressed by all nucleated cells MHC-I can present a “Self” antigen Since all nucleated cells express MHC-I, any infected cell can also present an antigen to CD8 T-cells MHC-II: MHC-II is usually only present on professional antigen presenting cells (B-cells, macrophages, dendritic calls, Langerhans cells, activated T-cell) MHC-II will present antigens from “extracellular” pathogens (ie; tp CD4 helper T-cells), while MHC-I presents antigens from virus infected cells Immune disorders linked to variant HLA (MHC) alleles: Psoriasis Ankylosing spondylitis Type I diabetes mellites Multiple sclerosis Rheumatoid arthritis Reactive arthritis Natural Killer (NK) cells and MHC-I The NK cell recognizes activating ligands that are universally expressed on nucleated cells If an inhibitory receptor on the NK cell is not engaged by a “self” antigen presented on MHC-I, the NK cell will degranulate, releasing perforin and granzyme that will kill the target cell (similar to cytotoxic T-cells) SUPPLEMENT: Immune Warrior Super-Hero Cards: Examine the role of the immune system in infectious disease List causes of immune hypofunction and hyperfunction: Hypofunction: Primary (genetic or congenital) deficiency vs. secondary causes Hyperfunction: Hypersensitivity reactions Immune Disorders Disorders of the immune system may be broadly divided into: Hypofunction Hyperfunction Immunodeficiency Diseases - Immune Hypofunction   Hypofunction or immunodeficiency results in two main forms of disease: Disorders in Defense results in increased susceptibility to infections type of infection seen depends on whether cell-mediated, humoral or both forms of immunity are affected   Disorders of Surveillance lead to increased frequency of malignant disease patients with immunodeficiency syndromes and those on immunosuppressive medications have a much higher incidence of cancer Can occur as a result of: Primary (genetic or congenital) deficiency Secondary (acquired) causes   Clinical Features Associated With Immunodeficiency Chronic infection Recurrent infection (greater frequency than expected) Unusual infecting agents (low pathogenic potential) Poor resolution or poor response to antibiotic treatment Primary Immunodeficiency Disorders Pure B cell dysfunction (with normal T cell function) Pure B cell dysfunction is not detected until the infant is 5-6 months old, because of protection by maternal IgG antibodies e.g. Bruton's syndrome - congenital X-linked infantile hypogammaglobulinemia Cell-mediated immune deficiencies (T-cell dysfunction) May present very early in the neonatal period e.g. DiGeorge syndrome - congenital absence of thymus and parathyroid glands   Both T and B cell deficiency can occur in the same patient e.g. Severe Combined Immunodeficiency Disease Recurrent infections may also occur in the presence of intact T and B cell function. These are due to defects in specific complement components: e.g. Chronic granulomatous disease results from phagocytic dysfunction (absence of lysosomal enzymes in monocytes and granulocytes) Secondary Immunodeficiency Diseases These may occur due to: 1. Infections: Rubella, Measles, and Mycoplasma results in temporary immunodeficiency Human Immunodeficiency Virus (HIV) ---> Acquired Immunodeficiency Syndrome (AIDS). HIV infects CD4 helper T cells which leads to depletion of these cells and consequent suppression of cell-mediated and humoral immunity 2. Immunosuppressive therapy: Cytotoxic drugs, cortisone, (e.g., chemotherapy for cancer) Irradiation Anti-lymphocyte serum globulin (ALG) 3. Malignancy (especially lymphoma) 4. Chronic illness 5. Malnutrition 6. Aging Hyperfunction (hypersensitivity)  results in damage of normal tissue   Autoimmune Disease (Hyperfunction) Autoimmune diseases occur due to a breakdown of the normal processes which maintain a state of immunological tolerance to self-antigens. The current concepts of immunological tolerance involve two main factors: Discrimination of self and non-self antigens by antigen reactive T cells (recognition) Suppression of immune responses to self antigens by suppressor T cells Factors that lead to a failure of self-tolerance and the development of autoimmunity are: Genetic  inheritance of susceptibility genes that disrupt different tolerance pathways autoimmunity runs in families many patients have more than one autoimmune disease particular HLA alleles are linked to autoimmune diseases genetic polymorphisms are linked to autoimmune diseases Environmental factors infections and tissue injury can expose self-antigens and activate antigen presenting cells and lymphocytes in the tissues microbes including viruses and bacteria may trigger autoimmune diseases Other factors causing tissue damage include: UV radiation, smoking The clinical presentation of different autoimmune diseases depends on:   a) the target (antigen)   b) type of immune reaction (cell-mediated, humoral or both)   c) changes secondary to the destruction of the target organ or type of immune reaction   Examples: Systemic lupus erythematosus (SLE): Target: DNA Immune reaction: Type III - circulating DNA-anti-DNA complexes. Female predominance (90% of cases in women between 12 and 40 years old). Dermatitis, nephritis, arthritis: Due to trapping of complexes in the skin, kidneys and joint synovium.   Hashimoto's thyroiditis: Target: thyroid follicular cells Immune reaction: Type II - cytotoxic antibody; complement activation Type IV - cell-mediated Hypothyroidism due to destruction of thyroid cells. Outline the pathogenesis and give examples of hypersensitivity reactions Pathogenesis of Hypersensitivity reactions: 4 types of hypersensitivity: Type 1: IgE-mediated allergic reaction Cross linking: 2 IgE molecules Immediate hypersensitivity – occurs within minutes Two phases: Sensitization - allergens are detected by dendritic cells, which mature and condition CD4+ T cells to develop into Th2 cells. Cytokines produced by Th2 cells (e.g. IL-4), mediate production of IgE antibodies. IgE binds to receptors (FcεRI) found on the surface of tissue mast cells and blood basophils, sensitizing them Re-exposure - allergen binds IgE on the surface of sensitized mast cells and basophils. Two IgE receptors are “cross-linked” by allergen, leading to signal transduction through the γ chains of the receptor, influx of calcium, degranulation and release of mediators such as histamines, leukotriene, and prostaglandin Mechanism of Allergic Sensitization 4 Stages – Classic Model Mast cell degranulation: Type II: IgG and IgM mediated - – antibodies directed against the antigen (self or non-self) on cells of particular tissues Mechanisms Antibodies activate normal function of cells Antibodies activate the complement cascade causing target cell destruction. Antibody-dependent cellular cytotoxicity (ADCC) may be exhibited by both non-phagocytic natural killer (NK) cells or by phagocytic cells, such as neutrophils and monocytes. Some examples: Myastenia gravis and Graves’ disease; autoimmune hemolytic anemia; Rheumatic fever Graves Disease: Rheumatic fever may occur following an infection of the throat by the bacterium Streptococcus pyogenes. The underlying mechanism is believed to involve the production of antibodies against tissues. Type III: IgG binds to free antigens forming immune complexes Complexes circulate in the free state Under circumstances of increased vascular permeability, complexes deposit within tissues: Blood vessel walls (vasculitis) Synovial joints (arthritis) Glomerular basement membrane (glomerulonephritis) Deposition of immune complexes leads to: Activation of the complement system Chemotaxis of neutrophils to sites of immune complex deposition Local tissue damage and inflammation Type IV: Reaction occurs in 24 -48 hours and so is also known as delayed- type hypersensitivity. Mediated by T-cells and is antibody independent Two phases: Sensitization phase: Primary exposure sensitizes CD4+ T cells to develop into Th1 cells. Sensitizing agents for humans include metal ions, like nickel and chromium, various industrial chemicals and natural products present in dyes, drugs, fragrances, and plants such as poison ivy Effector phase: Re-exposure leads to activation of Th1 cells and cytotoxic T cells and their release of pro-inflammatory cytokines and chemokines that attract and activate macrophages and cytotoxic T-cells, leading to inflammation and tissue damage  5. Apply the basic concepts of immunity to explain how vaccination works Bottom of Form Module 5: Immunocellular Alterations - Case Study In this case study, you'll apply what you've learned about Immunocellular Alterations, as you follow two young sisters, Giana and Isabella, through their experience getting their COVID-19 immunizations. SESSION OBJECTIVES Outline the features and function of the innate and adaptive immune system Examine the role of the immune system in infectious disease Apply the basic concepts of immunity to explain how vaccination works List causes of immune hypofunction and hyperfunction Outline the pathogenesis and give examples of hypersensitivity reactions Giana (she/her) is a 18-year old female, who is finishing her last year of high school, and working part-time as a grocery store clerk. Because of her essential worker designation, she qualifies for priority vaccination for COVID-19, and she is attending the vaccination center you’re working at for her first dose.  Giana has been healthy, with no history of allergies, and no previous reactions to other vaccinations (which she is also up to date on), beyond typical fatigue and a tender arm. She has no other relevant past medical history.  Following this dose of the COVID-19 vaccine, she again felt extra tired and a little feverish the day after, along with a sore shoulder, but was otherwise fine. Briefly, what is the adaptive immune system? How is it different from the innate immune system? In the context of the adaptive immune system, how does a vaccine prepare the immune system to protect against infectious disease, such as COVID-19? Be specific about cell types. Why might people feel unwell after a vaccination, with side effects like fatigue, fever/chills, body aches etc.? What can you recommend to people like Giana to help them manage any post-vaccination side effects? Why does it take a few weeks before someone is “protected” after a vaccination? (1-2 sentences) Explain the body's immunological response when it encounters a pathogen, like SARS-CoV-2, a few weeks after it's been vaccinated against the pathogen.  While Giana was eager to get her vaccination, there are people you may encounter as a nurse who are more hesitant about vaccines. How might you counsel or educate a patient or the guardians of a child who may be hesitant about vaccination (in general)? What strategies and resources could you use? A few weeks later, Giana’s 13-year old sister, Isabella (she/her), attends the same vaccination center you’re working at for her appointment for her first dose of the COVID-19 vaccine, accompanied by her father.  While Isabella has not had a serious reaction or anaphylaxis post-vaccination previously, you do see that she has a history of anaphylaxis due to a peanut allergy. Because of this, after you administer her vaccination, you must monitor her for 30-minutes, instead of the typical 15-minute waiting period after vaccination.  Around the 15-minute mark, Isabella begins to feel her chest tighten, and notices it’s harder to breathe. She also begins to feel clammy and dizzy. You suspect that Isabella is having an anaphylactic reaction, so you administer a dose of epinephrine, contact EMS, and prepare to transfer Isabella to Children's Hospital for further assessment and treatment. What are key signs and symptoms that indicate that someone is (or is likely) experiencing anaphylaxis? Why is it so important to recognize and treat anaphylaxis quickly? What type of hypersensitivity reaction does anaphylaxis fall under? Please describe briefly the pathophysiology of an anaphylactic reaction, but be specific about the cell types and cell mediators involved. While we’ve used vaccination as an example for a potential trigger for anaphylaxis, vaccine-related anaphylaxis is very rare. What are other common causes or triggers for anaphylaxis, (besides peanut allergy)? Compare and contrast the other 3 major types of hypersensitivity reactions using a table like the following:  Type Brief Description / Example   Key Cells / Components / Mediators (List)  Type __     Type __     Type __     5. Hypersensitivity reactions, like anaphylaxis, are examples of immune hyperfunction. List two main categories of immune hypofunction and give an example of each.