Immune System and Disorders Lecture Introduction PDF

INTRODUCTION LECTURE Immune System and Disorders Ketut Suryana Divission of Allergy-Immunology, Department. of Internal Medicine Department of Pulomonology and Respiratory Tract Disease Medical Faculty of Udayana University – Prof IGNG N...

INTRODUCTION LECTURE Immune System and Disorders Ketut Suryana Divission of Allergy-Immunology, Department. of Internal Medicine Department of Pulomonology and Respiratory Tract Disease Medical Faculty of Udayana University – Prof IGNG Ngoerah General Hospital Merpati Clinic, Wangaya Type B Teaching Hospital Denpasar, 17 Oktober 2024 INTRODUCTION Innate / Natural Non specific immunity Type of Immune System Adaptive / Acquired / Specific immunity INTRODUCTION (con’t) Immunity (Levels of Defense against infection) Skin BARRIERS Mucous membranes If barriers penetrated Phagocytosis INNATE Natural Killer cells IMMUNITY (Internal Defenses) Inflammation Fever Cell-mediated ADAPTIVE Immunity If innate immunity insufficient IMMUNITY Humoral Immunity Phagocytes recognize microbes by several membrane receptors : Toll-like receptors (TLRs)  Epithelial barriers  Phagocytes ; Neutrophils and COMPONENTS monocytes / macrophages OF  Natural Killer Cells INNATE IMMUNITY  The complement system  Cytokines of innate immunity  Other Plasma proteins.  EPITHELIAL BARRIERS Physical barrier Killing of to infection microbes, by : The skin, mucous membranes Peptide antibiotics of gastrointestinal tract, intraepithelial lymphocytes respiratory tract (B lymphocytes / B-1 cells , (the common portals of entry of T lymphocytes) various microbes INNATE AND ADAPTIVE IMMUNITY Abbas AK , 2022 Function of epithelia in innate immunity Epithelia (physical barriers) : produce antimicrobial substance, and harbor lymphocytes  to kill microbes and infected cell. (Abbas AK, 2022) Recognition of Infected Cells by NK cells A.NK cells kill host cells infected by intracellular microbes, thus eliminating reservoirs of infection B.NK cell respond to IL-12 produced by macrophages and secrete IFN-, which activates the macrophages to kill phagocytosed microbes. (Abbas AK, 2022) The multi step process of leukocyte migration At sites of infection, macrophages that have encountered microbes produce cytokines (TNF, IL-1)→activate the endothelial cells of venules→produce selectins,ligands for integrins and chemokines. Selectins mediate rolling of leukocytes, integrins mediate adhesion. Chemokines activate leukocytes and stimulate their migration to sites of infections. CD31/PECAM-1 in transmigration. (Robbins & Cotran, 2010) ANTIGEN PRESENTING CELLS Antigen-presenting cells (APCs) are cell populations that are specialized to capture microbial and other antigens, display them to lymphocytes, and provide signals that stimulate the proliferation and differentiation of the lym- phocytes. Cytokines of innate immunity Microbes produce cytokines proinflammation (TNF, IL-1 ) and chemokines in inflammatory site  stimulate inflammation (leukocyte recruitment)  activate NK Cells to produce IFN (Abbas AK, 2022) The major cytokines of innate immunity TNF, IL-1, Chemokines, IL-12, IFN, IFN, IFNβ, IL-10, IL-6, IL-15, IL-18. (Abbas AK, 2012) Plasma proteins of innate immunity CRP (C-reactive protein)  acute phase proteins that increase rapidly after infection.  IL-6 stimulate the production of CRP by hepatocytes  CRP binds to phosphorylcholine on microbes and coats it for phagocytosis by macrophages which express a receptor for CRP. Toll-like Receptors ( TLRs )  TLRs / surface receptors are membrane proteins  Recognize a variety of microbe-derived molecules  Stimulate innate immune responses against the microbes.  TLRs contain of ; Leucine-rich repeat motifs by characteristic cysteine-rich motifs in their extracellular regions TIR (Toll / IL-1 receptor) domain in their cytoplasmic regions  Different TLRs are involved in responses to different microbial products. Different TLRs are involved in responses to different microbial products. (Robbin & Cotran, 2010) Signaling by a prototypic TLR to bacterial LPS. Signaling by a prototypic TLR, TLR4In response to bacterial LPS. An Adapter protein links the TLR to a kinase, which activates transcription factors such as NF-қB and AP-1, TIR, Toll / IL-1 receptor domain. (Robbin & Cotran, 2010) Role of Innate immunity in stimulating Adaptive Immune Responses A. Macrophage respond to phagocytosed microbes by expressing costimulators (e.g. B7 proteins, which are recognized by the CD28 receptor of T cells). Secreting cytokines (e.g. IL-12). Costimulators, IL-12, with antigen recognition  active the T cells. (Abbas AK, 2022) ADAPTIVE IMMUNITY Two types of adaptive immunity :  Humoral immunity  Cell - mediated immunity That are mediated by different cells and molecules. Are designed to provide defense against extra and Intracellular microbes. Humoral and cell - mediated immunity Adaptive immunity Cellular immunity which is responsible for defense against intracellular microbes. Humoral immunity which is responsible for defense against extracellular microbes and their toxins. (Robbin & Cotran, 2010) Properties of adaptive immune responses - Specificity for structurally distinct antigens - Memory of prior exposure to antigen. Specificty, memory & self-limitation in adaptive immunity Specificity ; Antigens X and Y Induce the production of different antibodies. Memory ; The secondary response to antigen X is more rapid and larger than the primary response. Self-limitation ; Antibody levels decline with time after each Immunization. (Abbas AK, 2022) Phase of Adaptive immune response Antigen recognition Activation of lymphocytes Effector phase (elimination of antigen) The response declines as Antigen-stimulated Lymphocytes die by apoptosis. Atigen-specific cells that survive are responsible for memory. (Abbas AK, 2022)  Antigen Is any substance that causes your immune system to prompts the generation of antibodies Antigens can be proteins, polysaccharides, conjugates of lipids with : proteins (lipoproteins) and polysaccharides (glycolipids) An antigen may be a foreign substance from the environment such as chemicals, bacteria, viruses, or pollen. An antigen may also be formed within the body, as with bacterial toxins or tissue cells. Origin of Antigens Antigens can be classified in order of their class - Exogenous antigens - Endogenous antigens - Autoantigens Exogenous antigens Exogenous antigens are antigens that have entered the body from the outside, for example by inhalation, ingestion, or injection. Exogenous antigens (inhaled, ingested, or injected) are taken up by antigen-presenting cells (APCs) The immune system's response to exogenous antigens is often subclinical by endocytosis or phagocytosis. Endogenous antigens Endogenous antigens are antigens that have been generated within cells as a result of normal cell metabolism, or because of viral or intracellular bacterial infection. Auto-antigens An auto-antigen is usually a normal protein or complex of proteins (and sometimes DNA or RNA) that is recognized by the immune system of patients suffering from a specific autoimmune disease. These antigens under normal conditions, not be targeted of the immune system, but due to mainly genetic and environmental factors, the normal immunological tolerance for such an antigen has been lost in these patients. Antibody Antibody Structure Antibodies are globular plasma proteins They have sugar chains added to some of their amino acid residues. In other words, antibodies are glycoprotein Produced by B-cell Are antigen-specific Bind and inactivate foreign particles The basic functional unit of each antibody is an immunoglobulin Y-shaped molecule Each antibody consists of four polypeptides - two heavy chains and two light chains connected by disulfide bonds, joined to form a "Y" shaped molecule.  Although the general structure of all antibodies is very similar, a small region at the tip of the “Y” varies greatly among different antibodies This variable region, composed of 110-130 amino acids, allowing millions of antibodies with slightly different type structures, or antigen binding sites The variable region includes the ends of the light and heavy chains. Antibody Isotypes Name Types Description IgA 2 Found in mucosal areas, such as the gut, Antibodies can come in respiratory tract and urogenital tract, and prevents colonization by pathogens. Also different varieties known found in saliva, tears, and breast milk IgD 1 Functions mainly as an antigen receptor on B as isotypes or classes. cells that have not been exposed to antigens. Its function is less defined than other In placental mammals, isotopes. IgE 1 Binds to allergens and triggers histamine there are five antibody release from mast cells and basophile, and is involved in allergy. Also protects against isotypes known as IgA, parasitic worms IgG 4 In its four forms, provides the majority of IgD, IgE, IgG and IgM, antibody-based immunity against invading pathogens. The only antibody capable of based on their constant crossing the placenta to give passive immunity to fetus. region structure and IgM 1 Expressed on the surface of B cells and in a secreted form with very high avidity. immune function Eliminates pathogens in the early stages of B cell mediated (humoral) immunity before there is sufficient IgG Function Antibodies contribute to immunity in three ways: they prevent pathogens from entering or damaging cells by binding to them they stimulate removal of pathogens by macrophages and other cells by coating the pathogen they trigger destruction of pathogens by stimulating other immune responses such as the complement pathway The Complement system  A circulating and membrane associated proteins (important in defense against microbes).  The activation of the complement system  initiated by three distinct pathways ; Classical pathway Alternative pathway Mannose-binding Lectin pathway  Pathways of complement activation. Three distinct pathways of complement system lead to production of C3b (the early steps). C3b initiates the late steps of complement activation, culminating in the production of “membrane attack complex” (MAC)  creates holes in plasma membranes. (Abbas AK, 2022) Disorders of the Immune System / Diseases of immunity - Hypersensitivity reactions - Autoimmune diseases - Immunologic deficiency syndromes Hypersensitivity reactions A reflection of excessive or abberant immune responses. Mechanisms of Immunologically Mediated diseases Type Prototype Disorder Immune Mechanism Pathologic Lesions Immediate (type I) Anaphylaxis; bronchial Production of IgE antibody  Vascular dilation, edema, hypersensitivity asthma (atopic forms) immediate release of vasoactive smooth muscle amines and other mediators from contraction, mucus mast cells; recruitment of production. inflammatory cells (late-phase Inflammation reaction) Antibody- Autoimmune hemolytic Production of IgG, IgM  binds to Cell lysis, inflammation mediated (type II) anemia; Goodpasture antigen on target cell or tissue  hypersensitivity syndrome phagocytosis or lysis of target cell by activated complement of Fc receptors; recruitment of leukocytes Immune complex- Systemic lupus Deposition of antigen  antibody Necrotising vasculitis mediated (type III) erythematosus; some complexes  complement (fibrinoid necrosis); hypersensitivity forms of activation  recruitment of inflammation glomerulonephritis; leukocytes by complement serum sickness; products and Fc receptors  Arthus reaction release of enzyme and other toxic molecules Cell-mediated Contact dermatitis; Activated T lymphocytes  i) Perivascular cellular (type IV) multiple sclerosis; release of cytokines and infiltrates, edema; cell hypersensitivity type I, diabetes; macrophage activation; ii) T cell- destruction; granuloma transplant rejection; mediated cytotoxicity formation tuberculosis (Robbins and Cotran, 2005) Type of hypersensitivity diseases Type of hypersensitivity Pathologic immune Mechanisms oftissue mechanisms Injury & disease Immediate IgE antibody Mast cells & their mediators Hypersensitivity : (vasoactive amines, lipid mediators, Type I cytokines). Antibody mediated: Type II IgM, IgG antibodies against Opsonization & phagocytosis of cell surface or extracellular cells. Complement- & Fc receptor matrix antigens mediated recruitment & activation of leukocytes (neutrophils, macrophages). Abnormalities in cellular functions (eg; hormone receptor signaling). Immune complex Immune complexes of Complement- & Fc receptor mediated Mediated : Type III circulating antigens & IgM or recruitment & activation of IgG antibodies. leukocytes. T cell mediated : Type IV 1. CD4+ T cells (delayed 1. Macrophage activation, type hypersensitivity) cytokine-mediated inflammation. 2. CD8+ CTLs (T cell- 2. Direct target cell killing, mediated cytolysis) cytokine-mediated inflammation (Abbas AK, 2005) 1. Immediate Hypersensitivity (Type I) Anaphylactic reaction (IgE mediated reaction) Anaphylactic reaction / IgE mediated reaction Anaphylactoid reaction (Non IgE mediated) - Complement activation - Physical factors - Substance for Histamine released - Idiopathic - Arachidonic acid modulation (Roitt I, 1997)  Sensitization against allergens and type - I hypersensitivity B cell TH2 Histamine, tryptase, kininegenase, ECFA Leukotriene-B4, C4, D4, Newly prostaglandin D, PAF synthesized mediators 2. Antibody mediated (Type II) Hypersensitivity (Abbas AK, 2004) 3. Immune Complex-Mediated (Type III) Hypersensitivity (Robins & Cotran, 2005) 4. Cell-Mediated (Type IV) Hypersensitivity Mechanism of T cell-mediated (type IV) hypersensitivity reactions. A. In delayed type hypersensitivity reactions, CD4+ T cells (and sometimes CD8+ cells) respond to tissue antigens by secreting cytokines that stimulate inflammation and activates phagocytes, leading to tissue injury. B. In some disease, CD8+ cytolytic T lymphocytes (CTLs) directly kill tissue cells. APC, antigen-presenting cell. (Abbas AK, 2004) Classification of Hypersensitivity Reaction Reaction Type of Immune Patophysiological Clinical symptoms Typical reaction Type Respon mechanisms Chronology I IgE Degranulation of mast cell, Anaphylactic shock, Within 6 h after last basophil angioedema, urtica, medical intake bronchospasm II IgG IgG and complement – Cytopenia Days 5-15 after starting dependent cytotoxicity the medication III IgM or IgG and Deposition of immune Serum sickness, urticaria, Days 7-8 for serum complement complex vasculitis disease and urtica, Days 7-21 for vasculitis after drug exposure IV a Th1 (IFNα, IFNϒ) Imflammation induced by Eczema Days 1-21 after starting monocytes the medication IV b Th2 (IL4, IL5, IL13) Eosinophilic inflammation Maculopapular exanthema From 1 – several days IV c Cytotoxic cells (perforin, Keratinocyte apoptosis Maculopapular exanthema, Days 1-2 after starting granzim B) mediated by CD4 0r CD8 fixed dermatitis, SJS, pustular the medication for fixed exanthema dermatitis Days 4-28 after starting the medication for SJS IV d T cells Neutrophilic inflammation Acute Days 1-2 after drug (IL8 / IL 17) generalizedexanthematous exposure (more delayed pustulosis terms are possible) CTM, 2016 Autoimmune diseases Diseases caused by failure of self – tolerance and subsquent immune responses against self or autologous antigens Mechanisms of autoimmune diseases Role of susceptibility genes Susceptibility genes that may interfere with self- tolerance & environmental triggers (inflammation, other inflammatory stimuli) that promote lymphocyte entry into tissues, activation of lymphocytes & tissue injury. ( Robbins & Cotran, 2005 ) Mechanisms of Autoimmunization Molecular mimicry-Cross reacting foreign Antigens Polyclonal B cell activation Breakdown of immunological homeostasis (Tolerance) Sequestered Antigens Immunodeficiency disease (IDD) Results from a genetic or developmental defect or acquired factors in the immune system, and is a syndrome mostly characterized by infection in clinic Primary immunodeficiency diseases Inducement: heredity, developmental defect Age: infancy and childhood Pathogenesis: the differentiation and development of hemopoietic stem cells Secondary immunodeficiency diseases (SIDD) - Succeed some diseases SIDD - Iatrogenic SIDD - Acquired immunodeficiency syndrome (AIDS) Acquired Immuno Deficiency Syndrome (AIDS)  Mechanisms of CD4 cells loss in HIV infection Viral replication in infected cells is the major mechanism by which HIV causes lysis of CD4+ T cells (death of infected cells / cytopathic effect of the virus). Apoptosis of uninfected CD4+ T cells by binding of soluble gp120 to the CD4 molecule, followed by activation through the T-cell receptor by antigens, cross-linking of CD4 molecules & T-cell activation leads to abberant signaling & activation of death pathways. CD8+ cytotoxic T lymphocytes may kill uninfected CD4+ T cells that are coated with gp120 released from infected cells. ( Robbins & Cotran, 2005 )