Immunopathology I Lecture Notes PDF

IMMUNOPATHOLOGY I NWOKORO ONYEKACHI C. MB.BS, FMCPath Senior Lecturer, College of Medicine, University of Nigeria, Ituku-Ozalla campus, Enugu & Consultant Pathologist, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu...

IMMUNOPATHOLOGY I NWOKORO ONYEKACHI C. MB.BS, FMCPath Senior Lecturer, College of Medicine, University of Nigeria, Ituku-Ozalla campus, Enugu & Consultant Pathologist, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu 1  INTRODUCTION The immune system is vital for survival because it plays a key role in protection against infectious pathogens, mutant cells, tumour cells and foreign substances. Immune deficiencies therefore can predispose individuals to infections and diseases. On the other hand, the immune system is itself capable of causing tissue injury and disease. E.gs hypersensitivity reactions, autoimmune diseases. 2  INTRODUCTION contd.. Antigen (Ag)- a substance, usually protein in nature, which when introduced into living tissues, is capable of stimulating antibody (immunoglobulin) production. Hapten- small molecule which has no antigenic properties on its own, but on combination with a larger carrier molecule such as a protein, is capable of eliciting an immune response. Antibody (Ab)/ Immunoglobulin (Ig)- protein substance produced as a result of antigenic stimulation. There are five classes of Igs namely IgG, IgA, IgM, IgE and IgD. 3 THE NORMAL IMMUNE RESPONSE 4  THE NORMAL IMMUNE RESPONSE The mechanisms of immune response can be broadly classified into: – Innate (natural, native) immunity and – Adaptive (acquired, specific) immunity 5  INNATE IMMUNITY This is the first line of defense The major components of innate immunity include: – Epithelia: eg of skin, GIT, respiratory tract. These provide mechanical barriers to the entry of microbes from the external environment – Phagocytes: monocytes (macrophages, when present in tissues), and neutrophils – Dendritic cells – Natural killer cells – Innate lymphoid cells: these have recently been recognized. They are cells with the appearance of lymphocytes but lack typical lymphocyte receptors. They are thought to also contribute to the early defense against microbes. – Soluble proteins: eg complement proteins, C-reactive protein, mannose-binding lectin 6  INNATE IMMUNITY Contd.. The innate immune system provides host defense by – triggering inflammation following release of cytokines, products of complement and other mediators – release of type I interferons (produced by NK-cells in response to viruses) which activate enzymes that degrade viral nucleic acids and inhibit viral replication – stimulation of adaptive immune response which is stronger Innate immunity does not have memory or fine antigen specificity, unlike adaptive immunity 7 8  ADAPTIVE IMMUNITY The adaptive immune system consists mainly of lymphocytes and their products (eg antibodies, some cytokines), antigen presenting cells (eg macrophages, dendritic cells, B-lymphocytes) and other cells such as mast cells/basophils and eosinophils. There are two types of adaptive immunity namely; – Humoral immunity: mediated by B lymphocytes (bone marrow-derived) and protects against extracellular microbes and their toxins – Cell-mediated immunity: mediated by T-lymphocytes and protects against intracellular microbes 9  ADAPTIVE IMMUNITY Contd.. LYMPHOID ORGANS The lymphoid organs are generally divided into two categories namely: – Primary (generative or central) lymphoid organs: these are the bone marrow (where B cells develop) and the thymus (where T cells develop) – Secondary (peripheral) lymphoid organs: these include lymph nodes, spleen, mucosa associated lymphoid tissue (MALT) of the GIT and respiratory tract. 10 Gross photograph of a long bone showing marrow (blue arrow) within the medullary cavity 11  Adipocyte Bone trabeculae Haematopoietic cells Photomicrograph of normal bone marrow histology (H&E) 12 The thymus, a primary lymphoid organ, is shown; note its surrounding anatomic relations 13 A B The Spleen, a secondary lymphoid organ showing: A. External (capsular) surface B. Cut surface C. Normal histology (H&E) C 14 Photomicrograph of ileum showing mucosa associated lymphoid tissue, MALT, (yellow arrows), H&E. 15 Photomicrograph showing the histology of normal lymph node (H&E) 16 CELLS OF THE IMMUNE SYSTEM 17  CELLS OF THE IMMUNE SYSTEM LYMPHOCYTES In lymphoid organs, B- and T-lymphocytes are anatomically segregated in such a way that they interact with one another only when stimulated to do so by encounters with antigens and other stimuli. Eg in normal lymph nodes (B cells are located in the lymphoid follicle germinal centres and the medullary cords; T cells are located in the paracortical areas); in the spleen (B cells are seen in the red pulp, T cells in the white pulp), etc. Mature lymphocytes that have not encountered the antigen for which they are specific are said to be naive (immunologically inexperienced). After they are activated by recognition of antigens and other signals, lymphocytes differentiate into effector cells (which perform the function of eliminating microbes) and memory cells (which live in a state of heightened awareness and are able to react rapidly and strongly to combat the microbe in case it returns). 18  CELLS OF THE IMMUNE SYSTEM contd.. LYMPHOCYTES Contd.. The generation of antigen receptor diversity by lymphocytes is achieved through somatic recombination of the genes that encode the receptor proteins (ie the T-cell receptor [TCR] genes for T cells and the immunogobulin [Ig] genes for B cells) The enzyme in developing lymphocytes that mediates the recombination of these gene segments is a product of RAG-1 and RAG-2 genes (recombination activating genes) Inherited defects in RAG proteins result in a failure to generate mature lymphocytes. 19  CELLS OF THE IMMUNE SYSTEM contd.. LYMPHOCYTES Contd.. T lymphocytes develop in the thymus from precursors that arise from hematopoietic stem cells in the bone marrow. Mature T cells constitute 60% to 70% of circulating lymphocytes in the blood, and are also found in T-cell zones of peripheral lymphoid organs There are three major populations of T cells: – Helper T lymphocytes- stimulate B lymphocytes to make antibodies and activate phagocytes to destroy microbes – Cytotoxic T lymphocytes (CTLs)- kill infected cells, and – Regulatory T lymphocytes- limit immune responses and prevent reactions against self antigens. 20  CELLS OF THE IMMUNE SYSTEM contd.. LYMPHOCYTES Contd.. B lymphocytes develop from precursors in the bone marrow. Mature B cells constitute 10% to 20% of the circulating lymphocyte population and are also present in peripheral lymphoid tissues After stimulation by antigen and other signals, B cells develop into plasma cells which produce antibodies (immunoglobulins) 21 Structure of antibody (Immunoglobulin) 22  CELLS OF THE IMMUNE SYSTEM contd.. MACROPHAGES They are part of the mononuclear phagocyte system They phagocytose microbes and protein antigens, process the antigens and present peptide fragments to T cells. They are effector cells in some forms of cell-mediated immunity (T-cells activate the macrophages and enhance their ability to eliminate ingested microbes). In humoral immunity, macrophages also phagocytose and destroy microbes that are opsonized (ie coated- by IgG or C3b) 23  CELLS OF THE IMMUNE SYSTEM contd.. DENDRITIC CELLS Derive their name from presence of fine cytoplasmic processes that resemble dendrites There are two types of cells with dendritic morphology : – interdigitating dendritic cells- these cells are the most important antigen-presenting cells (APCs) for initiating primary T-cell responses against protein antigens. These cells are located under epithelia (the common site of entry of microbes and foreign antigens) and in the interstitia of all tissues; and express many receptors including TLRs and mannose receptors for capturing and responding to microbes – follicular dendritic cells- present in the lymphoid follicles in spleen, lymph nodes, etc; these cells have Fc receptors for IgG and receptors for C3b. They play a role in humoral immune response by presenting antigens to B cells. 24  CELLS OF THE IMMUNE SYSTEM contd.. NATURAL KILLER (NK) CELLS They are also called large granular lymphocytes due to the abundant azurophilic granules in their cytoplasm They are morphologically larger than small lymphocytes and make up 5% - 10% of peripheral blood lymphocytes Do not express TCRs or Ig They have an innate ability to kill a variety of tumour cells and virus-infected cells without prior sensitization (part of innate immunity) 25  CELLS OF THE IMMUNE SYSTEM contd.. NATURAL KILLER (NK) CELLS Contd.. They are CD16 and CD56 positive. CD16 is FcR for IgG and enables killing of IgG-coated target cells by antibody dependent cell-mediated cytotoxicity (ADCC). The role of CD 56 is yet unknown. Their functions are regulated by the balance between signals from activating and inhibiting receptors. Activating receptors stimulate killing by recognizing ill defined molecules on cells. Inhibitory receptors act by recognizing MHC class I molecules found in all nucleated cells. Absence of inhibitory signals and presence of activating signals are required to trigger killing Eg of an activating receptor is NKG2D, the expression of which increases with viral infections and neoplastic transformation. Both conditions also decrease MHC class I expression. 26 MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) 27  MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) MOLECULES: STRUCTURE AND FUNCTION MHC molecules are fundamental to the recognition of antigens by T cells They function to display peptide fragments of protein antigens for recognition by antigen specific T cells. Play important role in determining tissue compatibility between individuals, hence their name. The MHC molecules are also called human leukocyte antigens (HLA) in humans because they were initially detected on leukocytes. The genes encoding MHC (HLA) molecules are clustered on a segment of chromosome 6 There are many alleles of MHC genes in humans (therefore these genes are said to be polymorphic) and each individual’s alleles differ from most others in the population. This poses a challenge in organ transplantation. 28  MHC MOLECULES Contd.. MHC molecules are classified into three on the basis of their structure and tissue distribution, namely: Class I MHC - expressed on all nucleated cells and platelets Class II MHC- mainly expressed on antigen presenting cells (macrophages, B-lymphocytes, and dendritic cells) The MHC locus also contains genes that encode some complement components, cytokines [eg tumor necrosis factor (TNF) and lymphotoxin], as well as some other proteins. These are sometimes called class III MHC molecules. 29  CLASS I MHC Expressed on all nucleated cells and platelets. They are heterodimers consisting of a polymorphic α (heavy) chain (44-kD) linked noncovalently to a 12-kD nonpolymorphic protein called β2-microglobulin (not encoded in the MHC complex). The α chain is encoded by HLA-A, HLA-B and HLA-C genes. The extracellular region of the α heavy chain is divided into three domains: α1,α2,α3. The cleft or groove where peptides bind is formed by the α1 and α2 domains. 30 31  CLASS I MHC Contd.. In general, MHC class I molecules bind and display peptides that are derived from proteins, such as viral or tumour antigens, located in the cytoplasm and usually produced within the cell (endogenous). They present these peptides to CD 8+ T-lymphocytes. CD 8+ T-lymphocytes recognise peptides only in complex with MHC class I, and are therefore class I restricted. The generation of peptides and their binding with class 1 MHC molecules and transportation to the surface is a complex process as follows: Proteolytic complexes (proteasomes) digest antigenic proteins into short peptides. Transport proteins ferry these from the cytosol to the endoplasmic reticulum ER. Within the ER they bind to the groove of newly synthesized class I MHC. The complex then associates with β2-microglobulin to form a stable trimer that is transported to the cell surface for presentation to CD8+ cytotoxic lymphocytes which has a binding site for the α3 domain. 32 MHC Class I and CD 8+ T-lymphocyte interaction 33  CLASS II MHC Encoded in the HLA-D region with three subregions- HLA-DP, HLA-DQ, and HLA-DR. Class II molecules are heterodimers and consist of non-covalently associated α chain and β chain, both of which are polymorphic. The α and β chains both have two extracellular domains designated α1 and α2; β1 and β2, respectively. The antigen binding groove for the class II MHC molecule is formed by the α1 and β1 domains. 34 35  CLASS II MHC Contd.. The nature of the binding antigens are different. Class II molecules present exogenous antigens and soluble proteins that are first internalized and processed in endosomes or lysosomes. The resulting peptides are then associated with newly formed MHC class II that are assembled in the vesicles and transported to the cell surface. The peptide fragments presented by Class II MHC molecules are recognized by CD4+ Helper T cells. Therefore, CD 4+ cells are MHC class II restricted. The class II MHC β2 domain has a binding site for CD4, and therefore, is recognized by CD4+ T cells. Class II MHC molecules are expressed by antigen presenting cells e.g macrophages, dendritic cells, and B-cells, but can also be induced on several other cell types eg endothelium and fibroblasts, by the action of IFN-γ. 36 37  HLA AND DISEASE A variety of diseases have been associated with certain HLA alleles eg: - Ankylosing spondylitis and HLA-B27: >90fold chance of developing the disease. - Inherited errors of metabolism such as 21-hydroxylase deficiency (HLA-B47) - Autoimmune diseases including endocrinopathies associated with certain HLA-DR locus alleles. 38  Activation of T Lymphocytes and Elimination of Intracellular Microbes (Cell-Mediated Immunity) 39  Activation of T Lymphocytes and Elimination of Intracellular Microbes (Cell-Mediated Immunity) Naive T lymphocytes are activated in peripheral lymphoid organs by antigen and co-stimulators (the co-stimulators are CD 28 on T cells and B7 proteins {CD 80 and CD 86} on APCs). The T cells proliferate and differentiate into effector and memory cells that migrate to any site where the antigen (microbe) is present. Activated CD4+ T cells differentiate into various effector cells (eg TH1, TH2, and TH17) which secrete different sets of cytokines with different functions. Eg: TH1 subset secrete the cytokine IFN-γ: leading to classical macrophage activation TH2 cells produce IL-4: stimulates B cells to differentiate into IgE-secreting plasma cells; ↑IL-5 (activates eosinophils); TH2 cells also lead to alternative macrophage activation TH17 (produces IL 17): recruits neutrophils and monocytes Activated CD8+ T lymphocytes differentiate into CTLs which kill cells harboring microbes in the cytoplasm, eliminating the reservoirs of infection 40 41  Activation of B Lymphocytes and Elimination of Extracellular Microbes (Humoral Immunity) 42  Activation of B Lymphocytes and Elimination of Extracellular Microbes (Humoral Immunity) Antibody responses of B lymphocytes to most proteins require T-cell help and are said to be T-cell dependent. In these processes B-cells ingest protein antigens into vesicles, degrade them, and display peptides bound to class II MHC molecules for recognition by helper T-cells. The helper T cell is then activated and expresses CD 40L which binds to CD40 on the B cell surface and activates the B lymphocyte. 43  Activation of B Lymphocytes and Elimination of Extracellular Microbes (Humoral Immunity) contd.. B-cell activation leads to their proliferation and then differentiation into plasma cells that produce various types of antibodies (immunoglobulins). The B lymphocyte undergoes isotype switching (eg into IgG, IgA, or IgE) induced by the cytokines produced by the helper T-cells (eg IFN gamma and IL-4). Helper T cells also stimulate the production of antibodies with high affinity for the antigen, called affinity maturation. Isotype switching and affinity maturation occurs in the germinal centres of lymphoid follicles. The helper T-cells that stimulate these processes in B lymphocytes migrate to and reside in the germinal centers and are called follicular helper T cells (TFH). Note: B-cell activation and response to many polysaccharide and lipid antigens is T-independent and generates a weaker immune response than the T-dependent response to protein antigens. 44 General Structure of an Antibody 45 DECLINE OF IMMUNE RESPONSES AND IMMUNOLOGIC MEMORY 46  DECLINE OF IMMUNE RESPONSES AND IMMUNOLOGIC MEMORY After elimination of microbe, most of the effector lymphocytes die by apoptosis (with the immune system back to its resting state). However, during initial activation, there is also the generation of memory cells which are long-lived, and will respond faster and more effectively following re-exposure to the initial antigen. The generation of memory cells is an important goal of vaccination 47 48 DISORDERS OF THE IMMUNE SYSTEM 49 DISORDERS OF THE IMMUNE SYSTEM These include: - Hypersensitivity Reactions - Autoimmune diseases - Immune deficiency syndromes 50 HYPERSENSITIVITY REACTIONS 51  HYPERSENSITIVITY REACTIONS General Features Defined as excessive, exaggerated immune response to antigens with associated damage or harm to normal host tissue. The triggering antigens can be exogenous or endogenous. Exogenous antigens include dust, drugs, pollen, microbes, and various chemicals. Hypersensitivity reactions have a wide range of manifestations, from trivial symptoms like itching, to potentially fatal diseases like bronchial asthma. Immune responses against self, or endogenous, antigens, result in autoimmune diseases 52  General Features of Hypersensitivity Reactions Contd.. Usually results from an imbalance between the effector mechanisms of immune responses and the control mechanisms Often associated with the inheritance of particular susceptibility genes: HLA genes and many non-HLA genes have been implicated The mechanisms of tissue injury are the same as the effector mechanisms of defense against infectious pathogens, only that in hypersensitivity, these reactions are poorly controlled, excessive, or misdirected (e.g., against normally harmless environmental and self antigens). 53 Classification Of Hypersensitivity Reactions 54  CLASSIFICATION OF HYPERSENSITIVITY REACTIONS Generally classified into 4 types: Type I (Immediate) hypersensitivity Type II (Antibody-mediated) hypersensitivity Type III (Immune-complex mediated) hypersensitivity Type IV (Cell-mediated) hypersensitivity 55 IMMEDIATE (TYPE I) HYPERSENSITIVITY 56  IMMEDIATE (TYPE I) HYPERSENSITIVITY The injury is mainly due to TH2 cells, IgE antibodies, mast cells and other leukocytes It is a rapidly developing immunologic reaction, occurring within minutes after the combination of an antigen with IgE antibody bound to the surface of mast cells in an individual previously sensitized to the antigen. The reactions are called allergies and the eliciting antigens are called allergens It could be systemic eg bee sting, ending up in anaphylactic shock, or local (skin allergy, hives and allergic rhinitis, bronchial asthma or allergic conjunctivitis). 57  Type I Hypersensitivity Reaction contd.. Has two (2) well defined phases: – The immediate or initial response, evident within 5-30mins after exposure to an allergen and characterized by vasodilation, vascular leakage, smooth muscle contractions and glandular secretion; subsides in about 1hr. – Late phase, which sets in 2-24 hours later without additional exposure to the antigen (allergen) and may last several days; characterized by infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells, with mucosal epithelial cell damage (tissue damage) 58 Phases of Type I reaction 59  Pathogenesis of Type I Reaction Most immediate (type I) hypersensitivity reactions are caused by excessive TH2 responses, and these cells play a central role by stimulating IgE production and promoting inflammation. The sequence of events is as follows: The first step in the generation of TH2 cellular response is the presentation of antigen (allergen) to naive CD4+ helper cells, probably by dendritic cells that capture the antigen from the site of entry. 60  Pathogenesis of Type I Reaction contd.. For reasons not fully understood only certain antigens called allergens elicit such strong TH2 responses. In response to these allergens, cytokines such as IL-4,are produced in the local site that stimulates differentiation of the CD4+ cells into TH2 effector cells. Following this, the TH2 cells then release more IL-4, in addition to IL-5 and IL-13. IL-4 also acts on B-lymphocytes to promote class switching to IgE; IL-5 is an eosinophil growth factor; and IL-13 enhances IgE production and mucus secretion. 61  Pathogenesis Of Type I Reaction contd.. Sensitization and stimulation of mast cells The next critical step is the sensitization and stimulation of mast cells Mast cells are central to the development of immediate type hypersensitivity. They are marrow derived cells that are widely distributed in subepithelial tissues. Mast cells have cytoplasmic membrane-bound granules containing various mediators. Mast cells also express high-affinity receptors, called FcεRI, specific for the Fc portion of IgE and therefore avidly binds IgE antibodies. Such IgE-coated mast cells are said to be sensitized. When a sensitized mast cell is exposed to the same antigen subsequently, the cell is activated, leading eventually to degranulation and release of powerful mediators, responsible for the clinical features of immediate hypersensitivity reactions. 62 Illustration. 63 64  Sensitization and stimulation of mast cells contd.. Sensitized mast cells are activated on re-exposure to the antigen, by crosslinking (bridging) of high affinity IgE Fc receptors by antigen-bound surface IgE molecules, leading to degranulation. They may also be triggered by several other stimuli e.g C3a and C5a (anaphylatoxins), IL-8 ,bee sting, drugs such as mellitin and codeine, and physical stimuli eg extremes of temperature (non-atopic allergy). 65 Sensitization and stimulation of mast cells contd.. The bridging of IgE molecules by multivalent allergens leads to degranulation of mast cells with: discharge of preformed granules (primary mediators) de novo synthesis and release of secondary mediators 66 Sensitization and stimulation of mast cells contd.. The primary mediators include: Vasoactive amines- the most important is histamine; causes intense smooth muscle contraction, increased vascular permeability, and increased mucus secretion by nasal, bronchial, and gastric glands. Enzymes eg neutral proteases (chymase, tryptase) and acid hydrolases. Proteoglycans eg heparan and chondroitin sulfate; these package and store the amines in the granules Secondary mediators include Lipid mediators and Cytokines. 67  Sensitization and stimulation of mast cells contd.. The lipid mediators are arachidonic acid derivatives. Reactions in mast cell membranes lead to activation of phospholipase A2 which breaks down membrane phospholipids forming arachidonic acid 5-lipooxygenase and cyclooxygenase enzymes act on arachidonic acid yielding leukotrienes and prostaglandins respectively Leukotrienes C4 and D4 are very potent vasoactive and spasmogenic agents; much more active than histamine in increasing vascular permeability and causing bronchial smooth muscle contraction. Leukotriene B4 is highly chemotactic for neutrophils, eosinophils, and monocytes. Prostaglandin D2 causes intense bronchospasm and increased mucus secretion Platelet-activating factor (PAF): another lipid mediator, causes platelet aggregation, release of histamine, bronchospasm, increased vascular permeability, and vasodilation. Cytokines released by mast cells include: TNF,IL-1,IL-3,IL-4,IL-5,IL-6 and GM-CSF as well as MIP-1α and MIP-1β. 68 Mast cell sensitization and stimulation 69  Examples of disorders caused by type I hypersensitivity reactions include: systemic disorders e.g anaphylaxis local disorders e.g bronchial asthma, allergic rhinitis and sinusitis (hay fever), food allergies 70 TYPE II (ANTIBODY-MEDIATED) HYPERSENSITIVITY REACTION 71  TYPE II (ANTIBODY-MEDIATED) HYPERSENSITIVITY REACTION Mediated by Antibodies (Ab) directed towards antigens present on cell surfaces or extracellular matrix. The antigenic determinants may be intrinsic to the cell membrane or matrix, or they may take the form of an exogenous antigen that is adsorbed on the cell membrane surface or matrix. Cause disease by destroying these cells, triggering inflammation, or interfering with normal functions. Three different antibody dependent mechanisms are involved namely: opsonisation, with complement and Fc receptor- mediated phagocytosis Complement and Fc Receptor-Mediated Inflammation Antibody-Mediated Cellular dysfunction. 72 Type II Hypersensitivity Reaction 73  Type II hypersensitivity reaction contd.. Opsonisation, and Complement and Fc receptor- mediated Phagocytosis Cells coated with IgG antibodies (opsonized) become attractive to phagocytes and are recognized by specific Fc receptors of the phagocytes If they are coated with IgM or IgG, these may activate complement generating C3b and C4b (opsonins), which are deposited on the surface of the cells and recognized by phagocytes that express the receptors leading to phagocytosis Complete activation of complement generates membrane attack complex (MAC) which “drills holes” in cell membrane leading to cell death by osmotic lysis. Antibody mediated destruction of cells may occur by another process called ADCC (antibody-dependent cell-mediated cytotoxicity). Coated cells are lysed mainly by NK cells without phagocytosis. In most instances ADCC involves IgG coated antigens. Clinically, antibody-mediated cell destruction and phagocytosis occur in the following situations: transfusion reactions, erythroblastosis foetalis, autoimmune haemolytic anaemia, certain drug reactions. 74 75  Type II hypersensitivity reaction contd.. Complement and Fc receptor-mediated Inflammation Occurs when antibodies deposit in extracellular tissues, such as basement membranes and the matrix The deposited antibodies cause complement activation, generating by-products C5a and C3a, which recruit neutrophils and monocytes, as well as causing increased vascular permeability The recruited inflammatory cells release many injurious substances such as enzymes and reactive oxygen species with resultant tissue destruction. eg some forms of glomerulonephritis 76  Type II hypersensitivity reaction contd.. Antibody mediated cellular dysfunction Here antibodies directed against cell surface receptors impair or dysregulate the function of the receptors without causing injury or inflammation e.g myasthenia gravis, pemphigus vulgaris, Graves disease. 77 Type II Hypersensitivity 78 79 80 TYPE III (IMMUNE COMPLEX MEDIATED) HYPERSENSITIVITY REACTION 81  TYPE III (IMMUNE COMPLEX MEDIATED) HYPERSENSITIVITY REACTION The pathologic reaction is usually initiated when antigen combines with antibody in the circulation, forming immune complexes which typically deposit in vessel walls and other sites. The antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition. Sometimes, the complexes may be formed at sites where antigen has been “planted” previously (in situ immune complexes) eg some forms of glomerulonephritis The antigens may be exogenous (eg injected foreign protein or from an infectious microbe), or endogenous (self antigens -autoimmunity) Common sites of immune complex deposition include kidney (glomerulonephritis), joints (arthritis), and small blood vessels (vasculitis) 82  Type III Hypersensitivity Reaction contd.. Pathogenesis of Immune Complex Disease Involves three phases: Formation of immune complexes- presence of antigen in the circulation triggers formation and release of antibodies into the circulation which reacts with the antigen to form immune complexes Deposition of immune complexes- the circulating antigen-antibody complexes are deposited in various tissues. In general, complexes that are of medium size, formed in slight antigen excess, are the most pathogenic. Small complexes are usually cleared by the kidneys and large complexes are phagocytosed by macrophages. Inflammation and tissue injury- deposited immune complexes trigger inflammatory response leading to tissue injury Immune complexes bind and activate complement via the classical pathway Immune complex diseases can be systemic eg acute serum sickness (from a single large exposure to antigen); chronic serum sickness (from repeated or prolonged exposure to antigen eg SLE) local eg Arthus reaction 83 84 Immune complex vasculitis 85 86 Examples of Type III Hypersensitivity diseases 87 TYPE IV (T-CELL MEDIATED) HYPERSENSITIVITY REACTION 88  TYPE IV (T-CELL MEDIATED) HYPERSENSITIVITY REACTION It is initiated by antigen-sensitized T lymphocytes and includes: CD 4+ T-cell mediated delayed type hypersensitivity (DTH) and CD 8+ T-cell mediated cytotoxicity The injury in cell-mediated type of hypersensitivity is caused by inflammation, resulting from cytokines produced by CD4+ T cells and cell killing by CD8+ T cells 89  Type IV Hypersensitivity Reaction contd.. CD 4+ T-Cell Mediated Delayed Type Hypersensitivity (DTH) DTH is the prototype of CD 4+ T-cell mediated inflammation. Naïve CD4+ T cells recognize peptides displayed by APCs (eg dendritic cell) and secrete IL-2 (an autocrine growth factor which causes proliferation of the T cells). The CD 4+ T-cells then differentiate into TH1 or TH17 cells depending on the cytokines produced by the APC If the APCs produce IL-12, this induces differentiation of CD4+ T cells to the TH1 subset; whereas IL-1, IL-6, and IL-23 produced by APCs induce differentiation to the TH17 subset. TH17 effector cells release IL-17, IL-22 and other chemokines, which recruits neutrophils and monocytes causing inflammation and tissue injury. Also IL- 21 secreted by the TH17 cells amplifies the response. 90  CD 4+ T-Cell Mediated Delayed Type Hypersensitivity (DTH) Contd.. TH1 cells secrete mainly IFN-γ, which is responsible for many of the manifestations of DTH IFN-γ causes classical activation of macrophages, which eliminates the offending agent. The IFN-γ-activated macrophages: ✔show augmented phagocytic ability ✔express more class II MHC molecules on the surface, thus enhancing antigen presentation ✔secrete TNF and IL-1, which promote inflammation ✔Produce more IL-12, thereby amplifying the TH1 response 91  DTH contd.. However, if the activation is sustained as occurs with certain persistent or non-degradable antigens, such as tubercle bacilli or some foreign bodies, IFN-γ induces a morphologic transformation of macrophages into epithelioid cells (large epithelium-like cells with abundant cytoplasm) A microscopic aggregation of epithelioid cells, is called a granuloma. The epithelioid cells may be surrounded by lymphocytes, plasma cells, fibroblasts and multinucleated giant cells. This pattern of inflammation is called granulomatous inflammation (eg tuberculous lymphadenitis, pulmonary tuberculosis) and is typically associated with a strong TH1-cell activation and high-level production of cytokines such as IFN-γ. 92 Granuloma formation in Type IV hypersensitivity reactions 93 DTH: Granulomatous Inflammation 94 DTH: Tuberculous lymphadenitis 95  DTH contd.. Other clinical examples of DTH include: tuberculin reaction- when purified protein derivative (PPD or tuberculin), a protein-containing antigen of the tubercle bacillus, is injected intracutaneously in a previously sensitized individual, a hardening and an induration occurs within 8-12 hrs and reaches a peak in 24-72 hours. Thereafter it slowly subsides. contact dermatitis drug reactions 96  IHC demonstrating CD4+ T cells DTH in skin eg contact dermatitis 97  Type IV Hypersensitivity Reaction contd.. CD 8+ T-Cell Mediated Cytotoxicity A variant of T-cell mediated hypersensitivity Here, sensitized CD8+ T cells (CTLs) kill antigen-bearing target cells. Cytotoxic T-lymphocytes (CTLs) directed against cell surface histocompatibility antigens play an important role in graft rejection. They are also important in resistance against viruses and host response against transformed (tumour) cells. CTLs release granules containing perforins and granzymes which enter the target cells by endocytosis. Within the target cell, perforins stimulate the release of granzymes which activates caspases and induce apoptosis of the target cell. Activated CTLs also express Fas ligand, a molecule which can bind to Fas expressed on target cells and trigger apoptosis 98 Type IV Hypersensitivity Reactions 99 100