BENG 0011_Introduction to Immunology 2024.pdf

Introduction to Immunology BENG0011 Learning Outcomes Classify and compare the various types of immunity Innate immunity Adaptive immunity How the immune system is applied to counteract foreign bodies (pathogens, microbes, etc) Analyse the va...

Introduction to Immunology BENG0011 Learning Outcomes Classify and compare the various types of immunity Innate immunity Adaptive immunity How the immune system is applied to counteract foreign bodies (pathogens, microbes, etc) Analyse the various types of acquired immunity that can be used to aid the immune system Passive immunisation Active immunisation Assess the malfunction and consequence of the immune system Content The Immune System Innate immunity Cells of the immune system Role of cytokines Complement cascade Adaptive immunity Role of antigen presenting cells T cells and helper cells Role of B cells Antibody-mediated immunity Passive & Active Immunisation Immunopathology and associated diseases Hypersensitivity reactions Autoimmunity Inflammation immunodeficiency Review Articles Chaplin, Allergy Clin Immunol. 2010 February ; 125(2 Suppl 2): S3–23 Hilligan & Ronchese, Cellular & Molecular Immunol (2020) 17:587–599 Kawai & Akira, International Immunol, 2009, 21, 4:317–337 Marshall et al., Allergy Asthma Clin Immunol 2018, 14(Suppl 2):6-14 Rouse & Sehrawat, Nat Rev Immunol. 2010; 10(7): 514–526 … and references therein! Background / General Introduction The Immune System A complex network of cells, tissues, organs, and the substances they make that helps the body fight infections and other diseases (NCI) A complex network of organs, cells and proteins that defends the body against infection, whilst protecting the body's own cells (Better Health, Australia) A collection of cells, chemicals and processes that function to protect the skin, respiratory passages, intestinal tract and other areas from foreign antigens, such as microbes, e.g.,: Bacteria Fungi Parasites Viruses Cancer cells Toxins In addition, the immune system keeps a record of every microbe it has ever defeated so it can recognise and destroy it quickly if it enters the body again The Immune System Recognition Activation Infection Inflammation of pathogens of cells Two lines of defence: Innate immunity Adaptive immunity The Immune System Innate immunity Recognition of Activation of Removal of Infection pathogens by cells and infectious sensors inflammation agent Innate immunity First line of defence Quick – immediate or within hrs of confronting an antigen Antigen-independent (nonspecific) mechanism used by the host No immunologic memory – therefore unable to recognise or memorise the same pathogen should the body be exposed to again The Immune System Adaptive immunity Expansion and Stimulation of T Migration training of Removal of Infection and B cells – to infection effector T and B infectious agent lymphoid organ site cells Adaptive immunity Specific – antigen-dependent and antigen-specific Therefore involves lag time between exposure to the antigen and maximal response Capacity for memory – enables the host to prepare a more rapid and efficient immune response next time (same antigen) Long-term The Immune System Innate and adaptive immunity are not mutually exclusive mechanisms of host defence, but are complementary, with defects in either system resulting in host vulnerability or inappropriate responses Innate Immunity Innate Immunity There are 4 types of defensive barriers in innate immunity: Anatomic (skin and mucous membrane) Physiological (temp, low pH and chemical mediators) Endocytic and phagocytic Inflammatory Innate Immunity: Non-specific Host Defence Mechanisms Barrier Mechanism Skin Mechanical barrier delays entry of microbes Acidic environment (pH 3–5) slows down growth of microbes Mucus membrane Normal flora compete with microbes for attachment sites Mucous entraps foreign microbes Cilia propel microbes out of body Physiological Temperature Body temperature/fever response inhibits growth of some pathogens Low pH Acidic pH of stomach kills most microbes Chemical mediators Lysozyme cleaves bacterial cell wall IFNs induces antiviral defences in uninfected cells Complement lyses microbes or facilitates phagocytosis Endocytosis & Phagocytosis Endocytosis – internalise and break down foreign macromolecules Phagocytosis – specialised cells (blood monocytes, neutrophils, tissue macrophages) internalize, kill and digest whole organisms Inflammatory Tissue damage and infection induce leakage of vascular fluid containing serum protein with antibacterial activity, leading to influx of phagocytic cells into the affected area Innate Immunity: PRRs & PAMPs Innate immunity to pathogens relies on pattern recognition receptors (PRRs) which allow a limited range of immune cells to detect and respond rapidly to a wide range of pathogens that share common structures, known as pathogen associated molecular patterns (PAMPs) Pattern recognition 1 Signal Sensor Cytokines & Pathogens Interferons 2 Created with BioRender.com e.g.,: Bacterial cell wall components such as lipopolysaccharides (LPS) Double-stranded ribonucleic acid (RNA) produced during viral infection Innate Immunity: PRRs & PAMPs Cellular locations of Pattern Recognition Receptors (PRRs) Extracellular Recognition Cytosolic Recognition Endosomal Recognition fungal polysaccharide nucleic acids of bacterial cell ingested microbes wall lipid viral RNA bacterial peptidoglycans TLR lectin NLR RLR TLR TLR – toll-like receptor NLR – nod-like receptor RLR – rig-like receptors Lectins – proteins that bind to carbohydrates Created with BioRender.com The Role of Cytokines Innate Immunity: The Role of Cytokines A major function of innate immunity is to rapidly recruit immune cells to sites of infection and inflammation This is achieved through the production of cytokines and chemokines – small proteins involved in cell-cell communication and recruitment Cytokine production mobilises many defence mechanisms throughout the body while also activating local cellular responses to infection or injury Key inflammatory cytokines released during the early response to bacterial infection are: Tumour Necrosis Factor (TNF) Interleukin 1 (IL-1) Interleukin 6 (IL-6) These cytokines are critical for initiating: Cell recruitment Local inflammation – essential for clearance of many pathogens Contribute to the development of fever Disruption/Unregulated cytokine production is associated with inflammatory or autoimmune disease – Important therapeutic targets The Complement System Innate Immunity: The Complement System The complement system part of the innate immune system that enhances the ability of antibodies and phagocytic cells to clear the invading microbes and damaged cells from the body The complement system is a biochemical cascade that functions to identify and coat bacteria and other pathogens It renders pathogens susceptible to phagocytosis – immune cells engulf microbes and remove cell debris. It can also kills some pathogens and infected cells directly The phagocytic action of the innate immune response promotes clearance of dead cells or antibody complexes – removes foreign substances present in organs, tissues, blood and lymph It can also activate the adaptive immune response through the mobilisation and activation of antigen-presenting cells (APCs) Cells of the Immune System Innate Immunity Many types of cells are involved in the innate immune Neutrophil Eosinophil Basophil Mast Cell Macrophage Monocyte NK Cell Lymphocyte Dendritic Cell Innate Immunity: Phagocytes Phagocytes are sub-divided into two main cell types: Neutrophils Macrophages Neutrophil Macrophage Both of these cells share a similar function – engulf (phagocytose) microbes and kill them through multiple bactericidal pathways In addition to their phagocytic properties, neutrophils contain granules and enzyme that assist in the elimination of pathogenic microbes Unlike neutrophils (which are short-lived cells), macrophages are long lived cells that not only play a role in phagocytosis, but are also involved in antigen presentation to T cells Innate Immunity: Dendritic Cells Dendritic cells also phagocytose and function as APCs, initiating the acquired immune response and acting as important messengers between innate and adaptive immunity Dendritic Cell Innate Immunity: Mast Cells & Basophils Mast cells and basophils share many noticeable features with each other. Both are instrumental in the initiation of acute inflammatory responses, e.g., as seen in allergy and asthma Basophil Mast Cell Mast cells also have important functions as immune sentinel (guard) cells and are early producers of cytokines in response to infection or injury Unlike mast cells, which generally reside in the connective tissue surrounding blood vessels and are particularly common at mucosal surfaces, basophils reside in the circulation Innate Immunity: Eosinophils Eosinophils are granulocytes that possess phagocytic properties and play an important role in the destruction of parasites that are often too large to be phagocytosed Eosinophil Innate Immunity: NK Cells Natural killer (NK) cells play a major role in the rejection of tumours and the destruction of cells infected by viruses NK Cell Destruction of infected cells is achieved through the release of perforins and granzymes (proteins that cause lysis of target cells) from NK-cell granules and induce apoptosis NK cells are an important source of cytokine – interferon-gamma (IFN-γ), which help to mobilize APCs and promote the development of effective antiviral immunity NK cells (like mast cells and basophils) also control mechanisms associated with allergy and asthma Innate Immunity: Innate Lymphoid Cells (ILCs) Innate lymphoid cells (ILCs) play a regulatory role in innate immunity Lymphocyte There are many types of ILCs: ILC-1 ILC-2 ILC-3 ILCs selectively produce cytokines such as IL-4 IFN-γ IL-17 Cytokines to direct the appropriate immune response to specific pathogens and contribute to immune regulation in that tissue Characteristics & Function of Cells in Innate Immunity Functions Lifespan Pathogenic Target Macrophage Phagocytosis Months – yrs Various Antigen presentation to T cells Neutrophil Phagocytosis Hrs – days Bacteria Degranulation Fungi Eosinophil Degranulation 8 – 12 days Parasites Release of enzymes, growth factors, (circulation 4-5 Various allergic tissues cytokines hrs) Basophil Degranulation 1 – 2 days Various allergic tissues Release of histamine, enzymes, Cytokines Mast cell Degranulation Months – yrs Parasites Release of histamine, enzymes, cytokines Various allergic tissues Lymphocytes Th cells (CD4+) – immune response Weeks – yrs Th cells: intracellular bacteria (T cells) mediators Cytotoxic T cells/NK cells: Cytotoxic T cells (CD8+) – cell destruction virus-infected and tumour cells Monocytes Differentiate into macrophages and Hrs – days Various dendritic cells to elicit an immune response Natural killer Tumour rejection 7 – 10 days Various and tumour cells (NK) cell Destruction of infected cells Release of perforin and granzymes which induce apoptosis Adaptive Immunity Adaptive Immunity Expansion and Stimulation of T Migration training of Removal of Infection and B cells – to infection effector T and B infectious agent lymphoid organ site cells Adaptive immunity is aided by the actions of the innate immune system It is critical when innate immunity is ineffective in eliminating infectious agents The primary functions of the adaptive immune response are: Recognition of specific non-self (exogenous) antigens – from self antigens Generation of pathogen-specific effector pathways that eliminate specific pathogens or pathogen-infected cells Development of an immunological memory – rapidly eliminate a specific pathogen if same infections occur again Adaptive immune responses are the basis for effective immunisation against infectious diseases Stages of Adaptive Immunity Stages of Adaptive Immunity Infection Induction Response Memory Level of microorganism Threshold level for antigen activation Time Entry Clearance Created with BioRender.com Classes of Adaptive Immunity Two main classes of adaptive immunity * * * * * * * * * Pathogen-infected cell Pathogen + Innate Immune 1 Response 2 Antibody Response: Cell-mediated Response: B cells differentiate into plasma Antigen-specific T cells activated to cells to produce antibody proliferate thru the action of APCs Adaptive Immunity & APCs Types of Antigen Presenting Cells (APCs) Dendritic cell Macrophage B Cells microbial toxin virus antigen bacterium virus uptake infection infection receptor binding Neutralise or Death…?! Created with BioRender.com Adaptive Immunity APC recruit 1 2 Cytotoxic T cells recognise infected B cells release neutralising antibodies cell… leading to cell death B cell Cytotoxic T cell Viral antigen Immune attack Blocks binding Infected cell killed Cells not affected by virus Created with BioRender.com Adaptive Immunity For instance… 1 2 3 4 Virus infects and replicates Dendritic cell T and B cell readying in within the epithelium activation the lymph nodes Adaptive immunity Lymph node Antibodies and T cells attack virus-infected cells Activated B cell Plasma cell dendritic cell Dendritic cell Infected dendritic cell T cell activation travels to lymph node Adaptive Immunity Antigen Presenting in Cancer Antigen shedding by tumour T cell mediated tumour cell kill Activated T cell Antigen presenting by migrates to tumour dendritic cell (APC) APC activated T cell Created with BioRender.com T Cells & APCs Adaptive Immunity: T Cells & APCs T cells derive from hematopoietic stem cells in bone marrow and, following migration, mature in the thymus These cells express a series of unique antigen-binding receptors on their membrane, known as the T-cell receptor (TCR) Each T cell expresses a single type of TCR and has the capacity to rapidly proliferate and differentiate if it receives the appropriate signals T cells require the action of APCs (usually dendritic cells, but also macrophages, B cells, fibroblasts and epithelial cells) to recognise a specific antigen Adaptive Immunity: T Cells & APCs The surfaces of APCs express a group of proteins known as the major histocompatibility complex (MHC) MHC are classified as either: Class I (also termed human leukocyte antigen [HLA] A, B and C) which are found on all nucleated cells Molecules present endogenous (intracellular) peptides Class II (also termed HLA DP, DQ and DR) which are found only on certain cells of the immune system, including macrophages, dendritic cells and B cells Molecules on APCs present exogenous (extracellular) peptides to T cells MHC Class I MHC Class II Adaptive Immunity: T Cells & APCs The surfaces of APCs express a group of proteins known as the major histocompatibility complex (MHC) MHC are classified as either: Class I (also termed human leukocyte antigen [HLA] A, B and C) which are found on all nucleated cells Molecules present endogenous (intracellular) peptides Class II (also termed HLA DP, DQ and DR) which are found only on certain cells of the immune system, including macrophages, dendritic cells and B cells Molecules on APCs present exogenous (extracellular) peptides to T cells The MHC protein displays fragments of antigens (peptides) when a cell is infected with an intracellular pathogen, such as a virus, or has phagocytosed foreign proteins or organisms Adaptive Immunity: T Cells & APCs T cells have a wide range of unique TCRs which can bind to specific foreign peptides During the development of the immune system, T cells that would react to antigens normally found in our body are largely eliminated T cells are activated when they encounter an APC that has digested an antigen and is displaying the correct antigen fragments (peptides) bound to its MHC molecules The opportunities for the right T cells to be in contact with an APC carrying the appropriate peptide MHC complex are increased by the circulation of T cells throughout the body (via the lymphatic system and blood stream) and their accumulation (together with APCs) in lymph nodes The MHC-antigen complex activates the TCR and the T cell secretes cytokines which further control the immune response This antigen presentation process stimulates T cells to differentiate primarily into either cytotoxic T cells (CD8+ cells) or T-helper (Th) cells (CD4+ cells) Adaptive Immunity: T Cells & APCs CD8+ cytotoxic T cells are primarily involved in the destruction of cells infected by foreign agents, such as viruses, and the killing of tumour cells expressing appropriate antigens They are activated by the interaction of their TCR with peptide bound to MHC class I molecules Clonal expansion of cytotoxic T cells produces effector cells which release substances that induce apoptosis of target cells Upon resolution of the infection, most effector cells die and are cleared by phagocytes However, a few of these cells are retained as memory cells that can quickly differentiate into effector cells upon subsequent encounters with the same antigen Adaptive Immunity: T Cells & APCs CD8 cells Kills virally infected cells Cytotoxic T cells kills infected cells CD8 TCR Cytotoxic T cells MHC class I Apoptotic cell Created with BioRender.com Helper T (Th) Cells Adaptive Immunity: Th cells CD4+ Th cells play an important role in establishing and maximising the immune response These cells have no cytotoxic or phagocytic activity, and cannot directly kill infected cells or clear pathogens However, they mediate the immune response by directing other cells to perform these tasks and regulate the type of immune response that develops Th cells are activated through TCR recognition of antigen bound to class II MHC molecules Once activated, Th cells release cytokines that influence the activity of many cell types, including the APCs that activate them Adaptive Immunity Dendritic cell MHC II CD40 IFN-g TCR CD40L INF-a/b IL-12 CD4 Antiviral CD4 T cell Created with BioRender.com Adaptive Immunity: Th Cells Several types of Th cell responses can be induced by an APC, with Th1, Th2 and Th17 being the most frequent The Th1 response is characterized by the production of IFN-γ which activates the bactericidal activities of macrophages and enhances anti-viral immunity as well as immunity to other intracellular pathogens Th1-derived cytokines also contribute to the differentiation of B cells to make opsonizing antibodies that enhance the efficiency of phagocytes An inappropriate Th1 response is associated with certain autoimmune diseases Like cytotoxic T cells, most Th cells will die upon resolution of infection, with a few remaining as Th memory cells Adaptive Immunity: Th Cells Th2 response is characterised by the release of cytokines (IL-4, 5 and 13) which are involved in the development of immunoglobulin E (IgE) antibody producing B cells, as well as the development and recruitment of mast cells and eosinophils that are essential for effective responses against many parasites Th2 also enhance the production of certain forms of IgG that aid in combatting bacterial infection Mast cells and eosinophils are instrumental in the initiation of acute inflammatory responses (e.g., allergy and asthma). IgE antibodies are also associated with allergic reactions An imbalance of Th2 cytokine production is associated with the development of atopic (allergic) conditions Adaptive Immunity: Th Cells Th17 cells have been more recently described They are characterised by the production of cytokines of the IL-17 family Associated with ongoing inflammatory responses, particularly in chronic infection and disease Adaptive Immunity: Th Cells A subset of the CD4+ T cell, known as the regulatory T cell (T reg), also plays a role in the immune response T reg cells limit and suppress immune responses and, thereby, may function to control aberrant responses to self-antigens and the development of autoimmune disease T reg cells may also help in the resolution of normal immune responses, as pathogens or antigens are eliminated These cells also play a critical role in the development of “immune tolerance” to certain foreign antigens, such as those found in food Adaptive Immunity: Th Cells T Cell Activation & Differentiation CD4 MHC II TCR CD80/ CD28 CD86 cytokines APC native CD4 cell IL6 Polarising cytokines INF-g IL2 IL10 IL23 IL12 IL4 TGF-b TGF-b Th subsets INF-a IL4, IL5 IL17 IL10 Produced cytokines TNF-g IL9, IL13 IL22 TGF-b Created with BioRender.com The role of B Cells Adaptive Immunity: B Cells B cells arise from hematopoietic stem cells in the bone marrow and, following maturation, leave the marrow expressing a unique antigen-binding receptor on their membrane Unlike T cells, B cells can recognise antigens directly, without the need for APCs, through unique antibodies expressed on their cell surface The principal function of B cells is the production of antibodies against foreign antigens which requires their further differentiation Under certain circumstances, B cells can also act as APCs Adaptive Immunity: B Cell Differentiation Steps in B Cell Differentiation Antigen recognition induces Differentiation to antibody expression of effector molecules B cell proliferation secreting plasma cells and by T cell, which activates the B memory cells cell IL4, IL6 IL24 Plasma cell CD40L CD40 CD4 TCR MHC II Helper T Cell Activated B cell Memory B cell Adaptive Immunity: B Cells When activated by foreign antigens to which they have an appropriate antigen specific receptor, B cells undergo proliferation and differentiate into antibody-secreting plasma cells or memory B cells Memory B cells are long-lived survivors of past infection and continue to express antigen-binding receptors These cells can be called upon to respond quickly by producing antibodies and eliminating an antigen upon re-exposure Plasma cells, on the other hand, are relatively short-lived cells that often undergo apoptosis when the inciting agent that induced the immune response is eliminated However, these cells produce large amounts of antibody that enter the circulation and tissues providing effective protection against pathogens Adaptive Immunity: Types of B Cells Given their function in antibody production, B cells play a major role in the humoral or antibody-mediated immune response (as opposed to the cell-mediated immune response, which is governed primarily by T cells) Two types of B Cells Innate-like (no memory) Adaptive (memory) IgG natural IgM Adaptive IgM IgA IgE B-1 B cell B-2 B cell Antibody-mediated Immunity Adaptive Immunity: Antibody-mediated Immunity Antibody-mediated immunity is the branch of the acquired immune system that is mediated by B-cell antibody production The antibody-production pathway begins when the B cell’s antigen-binding receptor recognises and binds to antigen in its native form Local Th cells secrete cytokines that help the B cell multiply and direct the type of antibody that will be subsequently produced Some cytokines, such as IL-6, help B cells to mature into antibody-secreting plasma cells The secreted antibodies bind to antigens on the surface of pathogens, flagging them for destruction through complement activation, opsonin promotion of phagocytosis and pathogen elimination by immune effector cells Upon elimination of the pathogen, the antigen–antibody complexes are cleared by the complement cascade Adaptive Immunity: Antibody-mediated Immunity Five major types of antibodies are produced by B cells: IgA IgD IgE IgG IgM IgG antibodies can be further subdivided into structurally distinct subclasses with differing abilities to fix complement, act as opsonins, etc. The major classes of antibodies have substantially different biological functions and recognise and neutralise specific pathogens Adaptive Immunity: Antibody-mediated Immunity Ig Antibody Function IgM First immunoglobulin (Ig) expressed during B cell development (primary response; early antibody) Opsonizing (coating) antigen for destruction Complement fixation IgG Main Ig during secondary immune response Only antibody capable of crossing the placental barrier Neutralisation of toxins and viruses Opsonizing (coating) antigen for destruction Complement fixation IgD Function unclear; appears to be involved in homeostasis IgA Mucosal response; protects mucosal surfaces from toxins, viruses and bacteria through either direct neutralization or prevention of binding to mucosal surface IgE Associated with hypersensitivity and allergic reactions Plays a role in immune response to parasites Marshall et al., Allergy Asthma Clin Immunol 2018, 14, :49 Adaptive Immunity: Antibody-mediated Immunity Isotype IgM IgD IgG1 IgG2 IgG3 IgG4 IgA IgE Neutralisation + - +++ +++ +++ +++ +++ - Opsonisation - - +++ +/- ++ + + - Function Sensitisation for NK cells - - ++ - ++ - - - Sensitisation of mast cells - - + - + - - +++ Activation of complement +++ - ++ + +++ - + - Adaptive Immunity: Antibody-mediated Immunity Class switching Process whereby an activated B cell changes its antibody production from IgM to either IgA, IgG, or IgE depending on the functional requirements Influence of Cytokines on Antibody Isotype Switching cytokine IgA IgE IgG1 IgG2a IgG2b IgG3 IgM IL-4 Induces Induces Inhibits Inhibits Inhibits IL-5 Induces INF-γ Inhibits Inhibits Induces Induces Inhibits TGF-β Induces Induces Inhibits Inhibits IL-10 Induces Induces Adaptive Immunity: Antibody-mediated Immunity Antibodies play an important role in containing virus proliferation during the acute phase of infection However, they are not generally capable of eliminating a virus once infection has occurred Once an infection is established, cell-mediated immune mechanisms are most important in host defence against most intracellular pathogens Adaptive Immunity: Antibody-mediated Immunity 2o immune response Conc. Antibody Secondary Initial exposure exposure 1o immune response Time Adaptive Immunity: Antibody-mediated Immunity Cell-mediated immunity does not involve antibodies, but rather protects an organism through: The activation of antigen-specific cytotoxic T cells that induce apoptosis of cells displaying foreign antigens or derived peptides on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumour antigens The activation of macrophages and NK cells, enabling them to destroy intracellular pathogens The stimulation of cytokine (such as IFNγ) production that further mediates the effective immune response Cell-mediated Immunity Cell-mediated immunity is directed primarily at microbes that survive in phagocytes as well as those that infect non-phagocytic cells This type of immunity is most effective in eliminating virus-infected cells and cancer cells, but can also participate in defending against fungi, protozoa, cancers, and intracellular bacteria Cell-mediated immunity also plays a major role in transplant rejection Passive vs Active Immunity Immunity Acquired immunity is attained through either passive or active immunisation Passive immunisation refers to the transfer of active humoral immunity, in the form of ready-made antibodies, from one individual to another It can occur naturally by trans-placental transfer of maternal antibodies to the developing foetus, or it can be induced artificially by injecting a recipient with exogenous antibodies that are usually manufactured for this purpose and that are targeted to a specific pathogen or toxin The latter is used when there is a high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of chronic or immunosuppressive diseases Immunity Active immunization refers to the production of antibodies against a specific antigen or pathogen after exposure to the antigen It can be acquired through either natural infection with a microbe or through administration of a vaccine that can consist of attenuated (weakened) pathogens, inactivated organisms or specific proteins or carbohydrates known to induce immunity Effective active immunisation often requires the use of adjuvants which improve the ability of the immune system to respond to antigen injection Immunopathology Immunopathology Defects or malfunctions in either the innate or adaptive immune response can provoke illness or disease Such disorders are generally caused by: Hypersensitivity reactions – an overactive immune response Autoimmunity – an inappropriate immunity reaction to its own healthy cells Immunodeficiency – an ineffective immune responses Hypersensitivity Reactions Hypersensitivity reactions refer to undesirable responses produced by the normal immune system There are four types of hypersensitivity reactions: Type I: immediate hypersensitivity Type II: cytotoxic or antibody-dependent hypersensitivity Type III: immune complex disease Type IV: delayed-type hypersensitivity Type I Hypersensitivity Reactions Type I hypersensitivity is the most common type of hypersensitivity reaction It is an allergic reaction provoked by re-exposure to a specific type of antigen, referred to as an allergen Unlike the normal immune response, the type I hypersensitivity response is characterized by the secretion of IgE by plasma cells IgE antibodies bind to receptors on the surface of tissue mast cells and blood basophils, causing them to be “sensitised” Later exposure to the same allergen cross-links the bound IgE on sensitised cells resulting in degranulation and the secretion of active mediators such as histamine, leukotrienes, and prostaglandins that cause vasodilation and smooth-muscle contraction of the surrounding tissue Common environmental allergens inducing IgE-mediated allergies include pet (e.g., cat, dog, horse) epithelium, pollen, house dust mites, and molds Food allergens are also a common cause of type I hypersensitivity reactions, however, these types of reactions are more frequently seen in children than adults Type I Hypersensitivity Reactions Treatment of type I reactions generally involves trigger avoidance, and in the case of inhaled allergens, pharmacological intervention with bronchodilators, antihistamines and anti inflammatory agents Some types of allergic disease can be treated with immunotherapy Severe cases of type 1 hypersensitivity (anaphylaxis) may require immediate treatment with epinephrine Type II Hypersensitivity Reactions Type II hypersensitivity reactions are rare and take anywhere from 2 to 24 h to develop These types of reactions occur when IgG and IgM antibodies bind to the patient’s own cell-surface molecules, forming complexes that activate the complement system This, in turn, leads to opsonisation, red blood cell agglutination (process of agglutinating or “clumping together”), cell lysis and death Some examples of type II hypersensitivity reactions include: Erythroblastosis fetalis Goodpasture syndrome Autoimmune anemia Type III Hypersensitivity Reactions Type III hypersensitivity reactions occur when IgG and IgM antibodies bind to soluble proteins (rather than cell surface molecules as in type II hypersensitivity reactions) forming immune complexes that can deposit in tissues, leading to complement activation, inflammation, neutrophil influx and mast cell degranulation This type of reaction can take days, or even weeks, to develop and treatment generally involves anti inflammatory agents and corticosteroids Examples of type III hypersensitivity reactions include: Systemic lupus erythematosus (SLE) Serum sickness Reactive arthritis Type IV Hypersensitivity Reactions Unlike the other types of hypersensitivity reactions, type IV reactions are cell-mediated and antibody-independent They are the second most common type of hypersensitivity reaction and usually take 2 or more days to develop These types of reactions are caused by the overstimulation of T cells and monocytes/ macrophages which leads to the release of cytokines that cause inflammation, cell death and tissue damage In general, these reactions are easily resolvable through trigger avoidance and the use of topical corticosteroids An example of this is the skin response to poison ivy Types of Hypersensitivity Reactions Type Examples Mediators I – Allergy (immediate) Atopy IgE – Anaphylaxis – Asthma – Allergic rhinitis – Angioedema – Food allergy II – Cytotoxic (antibody- Erythroblastosis fetalis IgG, IgM dependant) Goodpasture syndrome Autoimmune anemias, thrombocytopenias III – immune complex disease Systemic lupus erythematosus Aggregation of Serum sickness antigens Reactive arthritis IgG, IgM Arthrus reaction Complement proteins IV – delayed hypersensitivity Contact dermatitis T cells, monocytes, (cell mediated, antibody Tuberculosis macrophages dependant) Chronic transplant rejection Autoimmunity Autoimmunity involves the loss of normal immune homeostasis such that the patient produces an abnormal response to its own tissue The hallmark of autoimmunity is the presence of self-reactive T cells, auto-antibodies, and inflammation Prominent examples of autoimmune diseases include: Celiac disease Type 1 diabetes mellitus Addison’s disease Graves’ disease Inflammation Poorly regulated inflammatory responses and tissue damage as a result of inflammation are often immunopathological features Defects in immune regulation are associated with many chronic inflammatory diseases, including: rheumatoid arthritis, psoriasis, inflammatory bowel disease and asthma Classical features of inflammation are heat, redness, swelling and pain Inflammation can be part of the normal host response to infection and a required process to rid the body of pathogens, or it may become uncontrolled and lead to chronic inflammatory disease The overproduction of inflammatory cytokines (such as TNF, IL-1 and IL-6) as well as the recruitment of inflammatory cells (such as neutrophils and monocytes) through the function of chemokines are important drivers of the inflammatory process Additional mediators produced by recruited and activated immune cells induce changes in vascular permeability and pain sensitivity Immunodeficiency Immunodeficiency refers to a state in which the immune system’s ability to fight infectious disease is compromised or entirely absent Immunodeficiency disorders may result from a primary genetic defect (primary immunodeficiency – which can effect either innate or acquired immune function through inhibition of selected immune cells or pathways, or it may be acquired from a secondary cause (secondary immunodeficiency), such as viral or bacterial infections, malnutrition, autoimmunity or treatment with drugs that induce Immunosuppression Certain diseases can also directly or indirectly impair the immune system such as leukaemia and multiple myeloma Immunodeficiency is also the hallmark of acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV) – HIV directly infects Th cells and also impairs other immune system responses indirectly Summary Summary Innate immunity is the first immunological, nonspecific mechanism for fighting against infections This immune response is rapid, occurring minutes or hours after aggression and is mediated by numerous cells including phagocytes, mast cells, basophils and eosinophils, as well as the complement system Adaptive immunity develops in conjunction with innate immunity to eliminate infectious agents; it relies on the tightly regulated interplay between T cells, APCs and B cells A critical feature of adaptive immunity is the development of immunologic memory or the ability of the system to learn or record its experiences with various pathogens, leading to effective and rapid immune responses upon subsequent exposure to the same or similar pathogens There is a great deal of synergy between the adaptive immune system and its innate counterpart, and defects in either system can lead to immunopathological disorders, including autoimmune diseases, immunodeficiencies and hypersensitivity reactions Defining Features of Innate & Adaptive Immunity Innate System Adaptive System Cells Hematopoietic cells: Hematopoietic cells: Macrophages, Dendritic cells, Mast T cells, B cells cells, Neutrophils, Basophils, Eosinophils, NK cells, T cells Non-hematopoietic cells: Epithelial cells (skin, airways, gastrointestinal tract) Molecules Cytokines Antibodies (Ig) Complement Cytokines Proteins and glycoprotein Response times Immediate Delayed by hrs to days Immunologic memory None: responses are the same with Responsiveness enhanced by each exposure repeated antigen exposure Thank you!