General Pathology - Diseases of the Immune System PDF

General Pathology Chapter 6: Diseases of the Immune System THE NORMAL IMMUNE RESPONSE...

General Pathology Chapter 6: Diseases of the Immune System THE NORMAL IMMUNE RESPONSE Pattern recognition receptors: cellular receptors that recognize these these Classic definition of immunity: molecules Protection from infectious pathogens - Located: cellular compartments; (+) microbes Mechanism of immunity fall into 2 categories: Toll-like receptors Innate immunity (natural,native immunity) - Intrinsic mechanisms that are posed to react immediately → first line of ✓ Toll – discovered in Drosophila as gene involved in defense development of gly Fly Adaptive immunity (acquired or specific immunity) ✓ Mammals: 10 TLRs - Consist of mechanisms that are stimulated by exposure to microbes and ✓ present(+) plasma membrane & endosomal vesicles foreign substances ✓ Common pathway: - Slowly develops than innate ▪ NF- KB: stimulates synthesis & secretion of cytokines & - More powerful in combating infections expression of adhesion molecules - - “Immune response” INNATE IMMUNITY ▪ IRFs: stimulate production of antiviral cytokines, Type 1 - interferon Always present, ready to provide immediate defense against microbes & - ❖ assoc with rare but serious immunodeficiency to eliminate damaged cells syndromes NOD-like receptors and the inflammasome (NLRs) Components of Innate Immunity Major components are: ✓ Cytosolic receptors named after founding member NOD-2 - Epithelial barriers that block entry of microbes ✓ Recognize wide variety of substances: released from necrotic or damaged cell (uric acid & ATP), loss of intracellular K+ ions, - Phagocytic cells (neutrophils and macrophages) microbial products - Dendritic cells, NK cells & other lymphoid cells & plasma proteins ✓ Signal via a cytosolic multiprotein complex called (complement system) inflammasome → activates enzyme (Caspase-1) → cleaves Epithelia of skin, precursor of cytokine IL-1 → bioactive form Act as mechanical barriers to the entry of GIT and microbes from the external environment ✓ IL-1: mediator of inflammation, recruits leukocytes and induces respiratory tract fever Produce antimicrobial molecules such as: o Definsins & lymphocytes ✓ Autoinflammatory syndromes ▪ Loss of fxn mutations in regulators of inflammasome → Monocytes and periodic fever syndrome Phagocytes in the blood that can be rapidly neutrophils recruited to any site of infection ▪ T & B lymphocyte reaxn against self antigens Monocytes – enter tissue and mature called ▪ Treatment: IL-1 antagonists macrophages ✓ Inflammasome pathway: Play a role in common disorders o Kupffer cells = liver ▪ Recognition of urate crystals by a class of NLRs o Microglia = brain ▪ Detection of lipids & cholesterols crystals result in o Alveolar macrophages = lungs inflammation in obesity-associated DM type 2 & Develop from yolk sac or fetal liver early in life atherosclerosis Macrophages → dominant cell of chronic Other receptor for microbial products inflammation C-type Lectin Receptors Expressed on the plasma membrane of (CLRs) > dendritic cells that detect fungal glycans Dendritic cells Cells present in epithelia, lymphoid organs & and elicit inflammatory reaction against most tissues fungi Capture protein antigens → display peptides for recognition by T lymphocytes Rig-like receptors (RLR) Located in the cytosol Antigen-presenting fxn: endowed with a rich collection of receptors that sense microbes & cell STING Pathway o - interferon - a Detect nucleic acids of viruses that damage & replicate in the cytoplasm of the infected "Interferonopathies" cells Serves as sentinels that detect danger & initiate innate immune responses These receptors stimulate the production of antiviral cytokines not Key participant in destruction of microbes Innate lymphoid G-Protein Coupled Those found in most leukocytes can Tissue resident lymphocytes, lack T-cell antigen cells (ICLs) Receptors recognize short bacterial peptides receptors – CANNOT respond to antigens containing N-formylmethionyl residues Activated by cytokines & mediators @ the site of damage These receptors enable the neutrophils to detect bacterial proteins & stimulate Sources of inflammatory cytokines during early chemotactic response of the cells phases of immune reactions (chemotaxis) Classified into groups Mannose Receptors Recognize microbial sugars which often - Groups 1,2,3 ICLs – many of the same cytokines contain mannose residues & induce as Th1, Th2, Th17 subsets of CD4+ T cells phagocytosis of the microbes - NK cells: type of ILC – provide early protection against many viruses & intracellular bacteria NATURAL KILLER CELLS (NK Cells) Function is to destroy severely stressed and abnormal cells. Other cell types Mast cells – capable of producing mediators of Make up approximately 5-10% of the peripheral lymphocytes. inflammation Do not express TCR or Igs. epithelial and endothelial cells NK cells are larger and contain abundant azurophilic granules. Can kill a variety of virus-infected cells and tumor cells without prior Plasma proteins Complement system exposure to or activation by microbes or tumors. Surface molecules used to identify NK Cells: - Plasma proteins that are activates by microbes - Activation may occur through the alternative & - CD16 – Fc receptor for IgG, confers the NK cell’s ability to lyse IgG coated targets, known as the antibody-dependent cell-mediated cytotoxicity lectin pathways as part of innate immune (ADCC). responses or through classical pathway The NK Cell is regulated by a balance between activating and Mannose-binding lectin & C-reactive protein b phagocytosis) inactivating signals from the receptors. Lung surfactant (coat microbes promote ↳ also component of innate immunity - NK inhibitory cell receptors recognize self MHC I molecules which are expressed in all healthy cells, which prevents NK Cells from killing CELLULAR RECEPTORS FOR MICROBES, PRODUCTS OF DAMAGED CELLS normal cells. AND FOREIGN SUBSTANCES NK Cells also release cytokines such as IFN-γ that activate Pathogen-associated molecular pattern macrophages to destroy ingested microbes. - Cells that participate in innate immunity → recognizes certain NK Cell activity is regulated by many cytokines such as: components that are shared among related microbes & often essential for o IL-2, IL-15 – stimulates proliferation of NK Cell infectivity → cannot be mutated to allow microbes to evade defense o IL-12 – activates killing and secretion of IFN-γ mechanism target cells damage-associated molecular patterns - Leukocytes → recognizes molecules released by injured & necrotic cells Page 1 of 15 | NEXILIS  General Pathology Chapter 6: Diseases of the Immune System REACTIONS OF THE INNATE IMMUNITY T- LYMPHOCYTES Innate immunity provides host defense by two main reactions: Three major population of T-lymphocyte: - Inflammation – cytokines & products of the complement activation triggers - Helper T-lymphocyte: the vascular & cellular components of inflammatory process stimulate B lymphocytes to make antibodies & activate other - Antiviral defense – type 1 interferons produced in response to viruses act leukocytes (phagocytes) to destroy microbes on infected and uninfected cells, & activates the enzymes that degrade - Cytotoxic T-lymphocyte: viral nucleic acid Kill infected cells ▪ NK cells recognize virus-infected cells - Regulatory T-lymphocyte - Innate immune system also provide danger signals to stimulate the Limit immune response & prevent reactions against self antigens adaptive immune response Develop in the thymus from precursors that arise from hematopoietic stem Innate immunity does not have memory or fine antigen specificity. Uses 100 cells (HSCs) different receptors to recognize 1,000 molecular patterns. Adaptive Found in blood, 60-70% of lymphocytes & T-cell zones of secondary immunity uses two types of receptors (antibodies & T-Cell receptors) lymphoid organs Produce in bone marrow but matures in the thymus Recognizes a specific cell-bound antigen by means of an antigen-specific ADAPTIVE IMMUNITY TCR (T-cell receptor) → a disulfide-linked heterodimer made up of α and Consists of lymphocytes & their products including antibodies beta polypeptide chain (variable & constant region) Two types of adaptive immunity: - Humoral The αβ TCR recognizes peptide antigens presented by major Mediated byB lymphocytes (bone marrow) histocompatibility complex (MHC) molecules on the surfaces of Fxn against extracellular microbes & toxins antigen-presenting cells (APCs). Secrete antibodies (aka Immunoglobulines) - Cell-Mediated Mediated by T lymphocytes (thymus) Fxn against intracellular microbes & cancer - Both have highly specific receptors for a wide variety of substances called antigens CELLS OF THE ADAPTIVE IMMUNE SYSTEM B and T lymphocytes: - Morphologically unimpressive, but they are remarkable heterogeneous and specialized in molecular properties and functions Lymphocytes & other cells involved in the immune system are not fixed in a particular tissue but constantly circulate among lymphoid & other tissues via lymphatic circulation Allows immune surveillance of the lymphocytes Lymphoid organs: different classes of lymphocytes are arranged in a way that they interact with one another only when stimulated - Naive lymphocytes: mature lymphocytes, have not encountered the antigen for which they are specific MHC Restriction – limits the specificity of the T-cells for peptides displayed by the MHC molecules, ensures that T cells see only cell-associated Effector cells: naive lymphocytes that are activated by recognition antigens. of antigens & other signals CD3 and ζ proteins Memory cells: live in a state of heightened awareness & able to react rapidly & strongly upon re-exposure - Invariant, same in all T-cells - Involved in transduction of signals into the T-cell that are triggered LYMPHOCYTE DIVERSITY by the binding of the antigen. Lymphocyte specific for a large number of antigens exists before - TCR + CD3-ζ = TCR COMPLEX exposure to antigen – antigen appears it selectively activates antigen- γδ polypeptide chains specific cells - Expressed by a small population of T-cells. - Recognizes peptides, lipids, and small molecules without the requirement of the MHC proteins. - Tends to aggregate in mucosal and epithelial linings, suggesting that these are sentinels that protect against microbes that invade the A epithelia. I CD4 and CD8 proteins C expressed on subsets of CBT cells) - Acts as co-receptors in T-cell activation. A - CD4 (expressed in 60%) binds to MHC II molecules, and functions as cytokine secreting helper cells that help macrophages and B lymphocytes. - CD8 (expressed in 30%) binds to MHC I molecules, and functions as cytotoxic T-lymphocytes (CTL) that destroy cell harboring microbes. Integrins – adhesion molecules that attach T-cells to APC. CD28 – binds to CD80 or CD86 in the APC. B-LYMPHOCYTES CLONAL SELECTION The only cell that can produce - Lymphocytes express specific receptors for Ags & mature into functionally antibodies which are competent cells before exposure to Ags mediators of the humoral - lymphocyte s of the same specificity constitute a CLONE, expressing immunity. identical antigen receptors Develop and mature in the - Number of cells specific for any one antigen is very small, fewer than 1 in bone marrow, constitutes 10- 100,00 lymphocytes 20% of the population of the circulating lymphocytes. Antigen receptor diversity is generated by somatic recombination of the genes that encode the receptor proteins Present in peripheral lymphoid tissues such as spleen, lymph nodes, and mucosa-associated lymphoid tissues. Lymphocyte progenitors and most cells in the body contain Ags-receptor gene which has spatially separated segments that cannot be expressed IgM and IgD isotypes are present in the surface of naïve B cells, which in mRNAs serves as its antigen-binding component. of BCR complex Lymphocyte maturation: gene segments are assembled by recombination After stimulation, it matures to a Plasma Cell which produces Ab & DNA sequence variation is introduced @ sites where gene segments are Antibody-secreting cells detected in the peripheral blood of humans are joined called plasmablasts. RAG-1 and RAG-2 – enzymes responsible for recombination of antigen- The receptor also contains a heterodimer of two invariant proteins Igα receptor genes. Inherited defects results in a failure to generate mature (CD79a) and Igβ (CD79b), which are essential for signal transduction lymphocytes through the antigen receptor. NOTE: germline antigen receptor genes are present in all cell in the bod CR2 or CD21 is a type-2 complement receptor which recognizes BUT only T & B cells contain recombined antigen receptor genes (TCR in complement products during innate immune response to microbes. T cells and Ig in B cells) CD40 receives signals from Helper T-cells. CR2 is used by the Epstein - Barr virus to enter and infect B Cells. T or B cell & clona progeny have unique DNA rearrangement → possible to distinguish polyclonal (nonneoplastic) lymphocyte proliferations from monoclonal (neplastic) lymphoid tumors Assay that assess clonality of antigen receptor gene rearrangements: diagnosing lymphoid neoplasm Page 2 of 15 | NEXILIS  General Pathology Chapter 6: Diseases of the Immune System DENDRITIC CELLS LYMPHOCYTE RECIRCULATION Sometimes called Interdigitating Dendritic Cells. The most important antigen-presenting cell for initiating T-cell response Lymphocytes constantly recirculate between tissues & home to particular against protein antigens. sites Have numerous fine cytoplasmic processes. Naive lymphocytes traverse the secondary lymphoid organs where These cells are located under the epithelia and interstitium , which is a immune responses are initiated → effector lymphocytes migrate to site of common site of entry of antigens and microbes to capture them. infection & inflammation (Langerhan Cells – immature dendritic cells within the epidermis) Naive T cells need this process because they have to circulate through the Express many receptors (e.g. TLRs and Lectins) for capturing peripheral lymphoid organs where most antigens are concentrated These cells are recruited to the T-cell zones of the lymphoid organs to Activated or Effector T-cells, because of antigens, go to the peripheral present the captured antigens to the T-cells. circulation and exert their effects These cells also express high levels of MHC needed for antigen- Plasma cells stay in the lymphoid organs and produce antibodies presentation. Follicular Dendritic Cells are present in the germinal centers of the Major Histocompatibility Complex Molecules: the Peptide Display System of lymphoid follicles which bear Fc receptors for IgG and receptors for C3b. Adaptive Immunity - They can trap antigen bound to antibodies or complement proteins MHC Displays peptide fragments of protein antigens for recognition MACROPHAGES MHC molecules are fundamental to antigen recognition by T cells and Part of the mononuclear phagocyte system. are linked to many autoimmune disease Important functions in the induction and effector phases of the adaptive MHC is a product of genes that evoke rejection of transplanted organs, immune response: and their name derives from their role in determining tissue compatibility a.k.a Human Leukocyte Antigen - Macrophages that have phagocytose microbes & protein antigen process the antigens and present peptide fragments to T-cells APC in T-cell activation - highly pleomorphic, meaning there are many alleles of MHC genes in humans & as a result each individual’s HLA allele differ from those inherited - Macrophages are key effector cells in certain forms of cell-mediated immunity, by most other individuals the reaction that serves to eliminate intracellular microbes Class I MHC molecules - Macrophages also participate in the effector phase of humoral immunity Expressed in all nucleated cells and platelets I phagocytosed destroy microbes opsonized by 196 or 23B Contains polymorphic α-chain (heavy) and a non-polymorphic β2 TISSUES OF THE IMMUNE SYSTEM microglobulin, α chain is encoded by HLA-A, B, and C Consist of: Extracellular region of a-chains is divided into three domains: - Primary (generative or central) lymphoid organs a1,a2, a,3 T and B lymphocytes mature & become competent to respond a1&a2 domains form a cleft, or grove where peptides bind to antigens Displays peptides that are derived from proteins, such as normal proteins - Secondary (peripheral) lymphoid organs & virus and tumor-specific antigens which are all recognized bound to class Adaptive immune responses to microbes are initiated I MHC molecules by CD8+ T cells Cytoplasmic proteins are degraded by proteasomes, and peptides are Primary Lymphoid Organs transported into the Endoplasmic Reticulum. Principal primary lymphoid organs: It is in the endoplasmic reticulum where the peptide binds to synthesized - Thymus – T cells develop class I molecules. - Bone marrow – production of other blood cells, including naive B The peptide-loaded MHC associates with β2 microglobulin to form a cells trimer and is then transported to the cell surface. The α3 domain has a binding site for CD8+ T Cells, which functions as a Secondary lymphoid organs Cytotoxic T-Cell. - Secondary lymphoid organs: TCR recognizes the MHC-peptide complex and the CD8 molecule – acting Lymph nodes, spleen & mucosal & cutaneous lymphoid tissues as a coreceptor bind to the class I heavy chain → adaptive immune response occur This makes CD8+ Cells, Class I MHC Restricted. - Promote the generation of adaptive immunity: All nucleted cells epxress class I MHC molecules and can be surveyed by CD8+ T cells antigens are concentrated in these organs Naive lymphocytes circulate through them by searching Class II MHC molecules antigens\ - Encoded in a region called HLA-D (HLA-DP, -DP, -DR) Lymph Nodes - Each molecule is a heterodimer consisting of a noncovalently associated a - Nodular aggregates of tissues located along lymphatic channels. chain & B chain Extracellular portions of the a & B chains: a1 & a2; B1 & B2 - APCs in the nodes are able to sample antigens that may enter into the - Crystal structure of class II molecules epithelia and be carried in the lymphatic circulation. (+) peptide-binding clefts facing outward - Dendritic cells may also pick up and transport antigen from the tissues to ▪ Formed by an interaction of a1 & B1 domains the lymph nodes via the lymphatic circulation. - Present antigens derived from extracellular microbes & proteins following - Thus, these antigens become concentrated in the draining lymph nodes. their internalization into endosomes or lysosomes - Internalized CHONs → digested → (+) peptides associate with Class II heterodimers (vesicles) → transport: cell surface as stable peptide-MHC complexes Pathologists do not use the inguinal lymph nodes to detect pathologies because - Class II B2 domain they are drainage areas hence what are present are mostly destroyed cells. It (+) CD4 binding site – recognized by CD4+ T cells (helper cells) is preferable to get from the cervical or axillary area. CD4+ T cells can recognize only in the context of self class II Spleen: molecules = class II MHC restricted - Mainly expressed on cells that present ingested antigens & respond to T- - An abdominal organ that serves the same role in immune response to blood cell help (macrophages, B lymphocytes, and DCs) borne antigen because lymph nodes only responds to lymph borne antigens Overview of Lymphocyte Activation and Immune Responses - Blood borne antigens are trapped by dendritic cells and macrophages in the spleen Cell Mediated Immunity: Activation of T Lymphocyte and elimination of Cutaneous and mucosal-associated lymphoid tissues intracellular Microbes - Present in the GIT, Epithelium of the Respiratory Tract Naïve T lymphocytes are activated by antigen and co-stimulators in - Respond to antigens that enter the breaches of the epithelium peripheral lymphoid organs, and proliferate and differentiate into effector cells that migrate to any site where microbial antigens are present - Pharyngeal Tonsils and Peyer’s Patches of the intestines Earliest response of CD4+ is secretion of cytokine IL-2 = acts as a growth Within these peripheral organs B cells and T cells are segregated into different regions: factor that stimulates T-cell proliferation. Th are mediated by CD40L and Cytokines - Lymph nodes: Some of the activated CD4+ T cells differentiate into effector cells that B cells are concentrated in the cortex of follicles secrete distinct sets of cytokines and perform different functions If B cells have already responded to an antigen, the follicles contain Th 1 secrete IFN-y (potent macrophage activator) a central region called the germinal centers CD40L+IFN-y-mediated activation =classical macrophage activation. T lymphocytes are located in the paracortex of follicles Th2 produce IL-4 (stimulates B-cells to diff into IgE plasma cells) - Spleen Th 2 also induces the Alternative pathway T cells are located in the periarteriolar lymphoid sheaths (PALS) surrounding small arterioles Th 17 (signature cell: IL-17) recruits neutrophils and monocytes = destroys EXTRACELLULAR bacteria, fungi and part of some inflammatory disease. B cells reside in the follicles CD8+ T-cells diff into CTL CTLs destroy reservoirs of infection Page 3 of 15 | NEXILIS  General Pathology Chapter 6: Diseases of the Immune System Humoral Immunity: Activation of B Lymphocytes and Elimination of Local reactions Extracellular Microbes - Diverse & vary depending on the portal of entry of the allergen Upon activation, B lymphocytes proliferate and then differentiate into Cutaneous rash/ blisters (skin allergy, hives) plasma cells that secrete different classes of antibodies with distinct Nasal & conjunctival discharge (allergic rhinitis & conjunctivitis) functions Immediate reaction: Antibody responses to most protein antigens require T cell help and are - (+) vasodilation, vascular leakage said to be T-dependent - Changes evident within minutes after exposure & subside in a few hours B cells that recognize protein Ags by their Ig receptors endocytose these Late-phase reaction: Ags into vesicles, degrade them, and display peptides bound to MHC II - 2-24 hours later without exposure to Antigen & may last for several days - (+) infiltration of tissues with eosinophils, neutrophils, basophils, for recognition by Th cells monocytes & CD4+ T cells Th1 Th2 Th17 Most immediate hypersensitivity disorders are caused by excessive Th2 Cytokines IFN-γ IL-4, IL-5, IL-13 IL-4, IL-5, IL-13 responses – stimulate IgE production & promote inflammation produced Cytokines that Activation of Th2 Cells & Production of IgE Antibody TG F-β, IL-6, IL-1, induce this IFN-γ, IL-12 IL-4 IL-23 Generation of Th2 cells = presentation of the Ag to naïve CD4+ Th Cells subset Stim. of IgE IL-4 Acts on B cells to stimulate class switiching to IgE & promotes the Immunological production, Recruitment of development of additional Th2 cells Macrophage reactions activation of neutrophils, IL-5 Involved in the development & activation of eosinophils activation triggered mast cells and monocytes IL-13 Enhances IgE production and acts onC epithelial cells to stimulate eosinophils mucus secretion Host defense Intracellular Helminthic Extracellular Th2 cells against microbes parasites bacteria, fungi - Produce chemokines that attract more Th2cells, as well as other WBCs, to Immune- the reaction site Immune-mediated - (+) Chronic atopic diseases sometimes classified as Th2-high & Th2-low mediated chronic Asthma Role in chronic Allergies inflammatory Atopic dermatitis disease inflammatory diseases (often - Antagonists of Th2 cytokines (IL-4, IL-5) = most effective in the Th2-high diseases (often autoimmune) group autoimmune) Sensitization & Activation of Mast Cells Mast Cells Its - Bone-marrow derived cells - Location explains why local immediate hypersensitivity reactions often occur in these sites Small blood vessels Nerves Subepithelial tissues - (+) cytoplasmic membrane-bound granules: “metachromatic granules” (+) biologically active mediators (+) acidic proteoglycans that bind basic dyes (Toluidine Blue) - Activated by the cross-linking of high-affinity IgE Fc Receptors - Be triggered by complement components = anaphylatoxins C5a C3a - Mast cell secretagogues: Protein antigens, by virtue of CD40L- and cytokine-mediated helper T-cell Chemokines: IL-8 actions, induce the production of antibodies of different classes, or isotypes Codeine & Morphine (IgG, IgA, IgE) = isotype switching Bee venom: (+) Adenosine melittin Helper T cells also stimulate the production of antibodies with high affinities Physical stimuli: heat, cold, sunlight for the antigen = affinity maturation - Basophils - Improves the quality of humoral immune response Similar to mast cells but not normally present in tissues Both express a high-affinity receptor FcERI HYPERSENSITIVITY: IMMUNOLOGICALLY MEDIATED TISSUE INJURY ▪ specific for the Fc portion of IgE & avidly binds IgE antibodies HYPERSENSITIVITY Mediators of Immediate Hypersensitivity Injurious immune reactions that are responsible for the pathology Mast cell activation = degranulation associated with immunologic diseases Granule Contents This term arose from the idea that individuals who have been previously Vasoactive amines Histamine exposed to an antigen manifest detectable reaction to that antigen & are - Intense smooth muscle contraction therefore said to be sensitized - Increases vascular permeability Excessive or harmful reaction to an antigen - Stimulates mucus secretion (nasal, General Features: bronchial & gastric glands) Enzymes Chymase, Tryptase, Acid Hydrolases Can be elicited by exogenous environmental antigens (microbial or - Cause tissue damage nonmicrobial) or endogenous self antigens - Generation of kinins & activated - (+) itching of the skin, anaphylaxis (fatal) components of complement (C3a) Imbalance between the effector mechanisms of immune responses and the Proteoglycans - Not directly involved control mechanism that serve to limit such responses Heparin, Chondroitin Sulfate Development is usually associated with the inheritance of particular - Package & store the amines in the susceptibility genes (HLA and non-HLA genes) granules The problem is that these reactions are poorly controlled, excessive or Lipid Mediators misdirected - Arachidonic acid-derived products - Associated with activation of phospholipase A2 Classification: Hypersensitivity Reactions – based on the underlying immunologic mechanism Leukotrienes Leukotrienes C4 & D4 - Most potent vasoactive & spasmogenic agents - Increasing vascular permeability - (+) bronchial smooth muscle contraction Leukotriene B4 - Highly chemotactic for neutrophils, eosinophils & monocytes Prostaglandin D2 - Most abundant mediator produced in mast cells by the cyclooxygenase pathway - Intense bronchospasm - Increase mucus secretion Platelet-Activating Factor - Lipid mediator produced by some Type 1 Hypersensitivity: Immediate Hypersensitivity (PAF) mast cell populations that is not derived from arachidonic acid Rapid immunologic reaction occurring in a previously sensitized individual - (+) platelet aggregation that is triggered by the binding of an Ag to IgE antibody on the surface - (+) histamine release of mast cells - (+) bronchospasm Systemic disorder - Increased vascular permeability - Injection/ Ingestion of an antigen into a sensitized individual - vasodilation Bee sting Peanut allergens Page 4 of 15 | NEXILIS  General Pathology Chapter 6: Diseases of the Immune System Cytokines - play an important role at several stages of immediate hypersensitivity Local Immediate Hypersensitivity Reactions reactions TNF Promote leukocyte recruitment 10-20% of the population suffers DTH morphology IL-1 - typical: late-phase reaction from allergies involving localized Accumulation of Chemokines reactions to common environmental mononuclear cells IL-4 Amplifies Th2 response allergens (CD4+ T cells & (+) Urticaria, Allergic Rhinitis (Hay macrophages) Fever), Bronchial Asthma, Atopic Perivascular “cuffing” Dermatitis, Food allergies Venules – endothelial hypertrophy Type 2 Hypersensitivity: Antibody-Mediated Hypersensitivity Antibodies that react with antigens present on cell surfaces or in the ECM Histamine & leukotrienes cause disease by destroying these cells, triggering inflammation, or - Released rapidly from sensitized mast cells interfering with normal functions - Trigger intense immediate reactions: Antibodies may be specific for normal cell/ tissue antigens Edema (autoantibodies) or for exogenous antigens (chemical/ microbial proteins) Mucus secretion Opsonization & Phagocytosis Smooth muscle spasm Chemokines Phagocytosis - Set the stage for the late-phase response by recruiting additional WBCs - Largely responsible for depletion of cells coated with antibodies - Also cause epithelial cell damage - Opsonized by IgG - IgG/IgM Epithelial cells Deposited on cell surfaces - Also produce soluble mediators (chemokines) May activate complement pathway (classical pathway) ▪ Activation: formation of Membrane Attack Complex (MAC) ▪ Disrupts membrane attack complex → disrupts the membrane by “drilling holes” → osmotic lysis ▪ Effective: cells & microbes with thin cell walls Antibody-Dependent Cellular Cytotoxicity (ADCC) Cells that are coated with IgG antibody are killed by NK cells & macrophages - Bind to the target by their receptor for the Fc Fragment of IgG - (+) cell lysis (-) phagocytosis ADCC & Phagocytosis occur in the following situations: 1. Transfusion reactions – incompatibility 2. Hemolytic Disease of the Fetus & Newborn (Erythroblastosis Fetalis) Late-Phase Reaction Rh (-) Mother = maternal IgG against Rh (+) Fetus Leukocytes are recruited that amplify and sustain the inflammatory 3. Autoimmune Hemolytic Anemia (AIHA), Agranulocytosis, Thrombocytopenia response without additional exposure to the triggering antigen Produce antibodies against their own blood cells Eosinophils 4. Certain drug reactions - Abundant WBC population in these reactions Inflammation - Recruited to sites of immediate hypersensitivity by chemokines, eotaxin - IL-5: most potent eosinophil-activating cytokine Antibodies deposit: - (+) Charcot-Leyden Crystals - Basement membrane & ECM (+) protein galecin-10 - Result: injury d/t inflammation Sometimes released into the extracellular space C5a (+) sputum of asthmatic patients - Direct the migration of granulocytes (BEN) and monocytes, & Promote inflammation & enhance Th2 response = allergic reactions anaphylatoxins (C5a & C3a) = ↑ vascular permeability Major cause of symptoms in some Type 1 Hypersensitivity disorders Release of substances from WBCs that damage tissues: (allergic asthma) - Lysosomal Enzymes (Proteases) Tx: broad-spectrum anti-inflammatory drugs (steroids) > antihistamine Basement membrane, collagen, elastin & cartilage - Generation of ROS Development of Allergies Antibody-Mediated Inflammation Susceptibility to immediate hypersensitivity reactions is genetically - Glomerulonephritis determined - Vascular rejection (Organ grafts) Atopy Cellular Dysfunction - Propensity to develop immediate hypersensitivity reactions - Atopic individuals Antibodies directed against cell surface receptors impair function without causing cell injury or inflammation Higher serum IgE levels More IL-4-producing Th2 cells - Myasthenia Gravis → muscle weakness (+) 50% have a family history of allergy - Graves Disease → Hyperthyroidism Environmental Factors - Pollen, cat hair, dust mites Nonatopic Allergy - 20-30% of immediate hypersensitivity reactions are triggered by non- antigenic stimuli Temperature extremes Exercise - Do not involve Th2 cells or IgE - Mast cells are abnormally sensitive to activation by various nonimmune stimuli Systemic Anaphylaxis Characteristics: - Vascular shock - Widespread edema - - Difficulty in breathing Extremely small doses of antigen may trigger Type 3 Hypersensitivity: Complex-Mediated Hypersensitivity anaphylaxis Antigen-antibody complexes produce tissue damage mainly by eliciting - Within minutes after inflammation at the sites of deposition exposure to allergens - Initiated when Ag combines with Ab in the circulation = Immune complexes (+) itching, hives & that typically deposit in vessel walls skin erythema - Less frequently, formed at site where Ag has been “planted” previously (in (+) contraction of bronchioles & respiratory distress situ immune complexes) Laryngeal Edema Antigen that form immune complexes: ▪ Hoarseness - Exogenous ▪ Compromises breathing Foreign protein that is injected/ produced by infectious microbe (+) vomiting, abdominal cramps, diarrhea, & laryngeal obstruction - Endogenous ▪ Patient may go on shock & die within the hour Individual produces antibody against self-antigens (autoimmunity) Tend to be systemic - Kidney = glomerulonephritis - Joints = arthritis - Small blood vessels = vasculitis Page 5 of 15 | NEXILIS  General Pathology Chapter 6: Diseases of the Immune System Systemic Immune Complex Disease Responses of Differentiated Effector T Cells Serum Sickness On repeat exposure to an antigen, Th1 cells secrete cytokines (IFN-y) - Prototype of a systemic immune complex disease responsible for many of the manifestations of DTH - Administration of large amounts of foreign serum or antibodies from other Classically Activated Macrophages individuals/ species - IFN-y-activated Pathogenesis: 3 Phases Ability to phagocytose & kill microorganism is markedly augmented Formation of - Introduction of protein Ag = formation of Abs (1 Express more class II MHC molecules = enhance Ag presentation Immune week after Ag exposure) Secrete TNF, IL-1 and chemokines = promote inflammation Complexes - Abs secreted into the blood, react with the Ag = Produce more IL-12 = ↑ Th1 response (+) immune complexes - Serve to eliminate the offending antigen Deposition of - Circulating immune complexes are deposited in - Activation sustained + continued inflammation = (+) tissue injury Immune vessels = (+) tissue deposition Activated Th17 cells > - neutrophils & monocyty Complexes - Complexes (medium-sized) = under conditions of - Secrete IL-17, IL-22, chemokines & other cytokines slight Ag excess are the most pathogenic - Recruit neutrophils & monocytes to the reaction = promote inflammation - Organs where blood is filtered at high pressure to Clinical Examples: CD4+ T Cell-Mediated Inflammatory Reactions (DTH) form fluids (urine & synovial fluid) are sites where immune complexes become concentrated & tend to Tuberculin Reaction deposit (Glomeruli & Joints) - Intracutaneous injection of purified protein (tuberculin) Inflammation & - Once complexes are deposited in tissues = (+) - In a previously sensitized individual Tissue Injury acute inflammatory reaction (+) reddening & induration of the site: 8-12 hours - Clinical features: 10 days after Ag administration Peak: 24-72 hours → slowly subside ✓ Fever - Persistent/ Nondegradable Antigens (MTB) ✓ Urticaria Macrophage infiltration in the lungs over a period of 2-3 weeks ✓ Joint pain Sustained activation: ✓ Lymph node enlargement ▪ Macrophage → epitheloid cells → (+) granulomas = chronic ✓ Proteinuria inflammation (granulomatous inflammation) - Complement proteins can be detected at the site Helminthic Infections of injury, during the active phase of the disease: - Schistosomiasis Consumption of complement = ↓C3 (serum Worms lay eggs that elicit granulomatous reactions levels) – used to monitor disease activity Rich in eosinophils – elicited by strong Th2 responses Calternative pathways MORPHOLOGY Contact Dermatitis Acute Vasculitis - Contact with urushiol (poison ivy/ oak) - Principal morphologic manifestation if Immune complex injury - Itchy, vesicular dermatitis - (+) Fibrinoid Necrosis – seen in IF microscopy; deposits along the - Same mechanism for drug reactions – (+) skin rashes glomerular basement membrane Rheumatoid arthritis Acute Serum Sickness Chronic Serum Sickness Multiple Sclerosis - Single exposure to a large - Repeated/ prolonged Inflammatory Bowel Disease amount of antigen exposure to an antigen - Lesion tends to resolve as a - SLE – persistent antibody CD8+ T Cell-Mediated Cytotoxicity result of catabolism of the response to autoantigens Kill antigen-expressing target cells immune complexes Play an important role in graft rejection In a virus-infected cell, viral peptides are displayed by class I MHC Local Immune Complex Disease molecules, and the complex is recognized by the TCR of the CD8+ T lymphocytes Arthus reaction - Localized area of tissue necrosis resulting from acute immune complex Killing of infected cells lead to elimination of the infection = responsible vasculitis (skin) for cell damage that accompanies the infection - Reaction can be produced experimentally by intracutaneous injection of Involves perforins & granzymes, preformed mediators contained in the Ag in a previously immunized animal that contains circulating antibodies lysosome-like granules of CTLs against the antigen - Perforin – facilitates the release of the granzymes from the complex - As the antigen diffuses into the vascular wall, it binds the preformed - Granzymes – proteases that cleave & activate caspases = (+) apoptosis antibody, and large immune complexes are formed locally - Complexes precipitate in the vessel walls & cause fibrinoid necrosis Imposed thrombosis worsens the ischemic injury * in 17 only Type 4 Hypersensitivity: T-Cell Mediated Hypersensitivity Cell-mediated hypersensitivity is caused by inflammation resulting from cytokines produced by CD4+ T cells AUTOIMMUNE DISEASES CD4+ T cell-mediated - Environmental & self-antigens Autoimmunity – immune reactions against self antigens Hypersensitivity - Autoimmune & chronic inflammatory It should be noted that the mere presence of autoantibodies does not diseases indicate that an autoimmune disease exists – older age groups CD8+ T cells (Cell - Dominant mechanism of tissue injury – Ideally, at least 3 requirements should be met before a disorder is Killing) follow viral infections categorized as truly caused by autoimmunity: 1. Presence of an immune reaction specific for some self antigen or self CD4+ T Cell-Mediated Inflammation tissue 2. Evidence that such a reaction is not secondary to tissue damage but Produced by T cells induce inflammation that may be chronic & destructive is of primary pathogenic significance The prototype of T cell-mediated inflammation is delayed-type 3. The absence of another well-defined cause of the disease hypersensitivity (DTH) Organ-Specific Disease Systemic Disease An antigen administered into the skin of a previously immunized individual Immune responses directed against a Diseases in which the autoimmune - Detectable: 24-48 hrs single organ or tissue reactions are against widespread - (+) Inflammatory reaction contribute to organ-specific diseases antigens Th1 – activated macrophages - Type 1 DM - SLE Th17 – greater neutrophil component - Multiple sclerosis - Goodpasture syndrome Activation of CD4+ T cells Naïve CD4+ T cells recognize peptides displayed by DCs & secrete IL-2 - Stimulate proliferation of the antigen-responsive T cells APCs produce: - IL-12 Induce differentiation of CD4+ T cells to the Th1 Subset - IFN-y Promotes further Th1 development = amplify reaction - IL-1, IL-6, IL-23 (close relative of IL-12) Induce differentiation to the Th17 subset Some of the differentiated effector cells enter the circulation & join the pool of memory T cells – persist for long periods (years) Page 6 of 15 | NEXILIS  General Pathology Chapter 6: Diseases of the Immune System Immunologic Tolerance Phenomenon of unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen Self-tolerance - Lack of responsiveness to an individual’s own antigens - Our ability to live in harmony with our cells & tissues SELF-TOLERANCE: 2 GROUPS Central Tolerance - Immature self-reactive T & B Lymphocyte clones that recognize self antigens during their maturation in the central (primary, or generative) lymphoid organs [T cells: Thymus; B cells: Bone Marrow] are killed - Negative Selection (Clonal Deletion) ✓ When immature T cells expressing TCRs specific for self antigen encounter these antigens in the thymus, signals are produced that result in killing of the cells (apoptosis) ✓ AIRE (autoimmune regulator) Critical for deletion of immature T cells specific for these antigens Germline loss-of-function mutations in the AIRE gene = autoimmune polyendocrine syndrome – destruction of multiple endocrine organs Association of Non-MHC Genes with Autoimmune Diseases - Receptor Editing PTPN22 ✓ When developing B cells strongly recognize self antigen in the - Encodes a protein tyrosine phosphatase bone marrow, many of the cells reactivate the machinery of - (+) polymorphism: the Ag receptor gene rearrangement & begin to express new Rheumatoid Arthritis – high prevalence Ag receptors, not specific for self antigens Type 1 Diabetes ✓ If receptor editing does not occur – self-reactive cells undergo - Non-HLA gene that is most frequently implicated in autoimmunity apoptosis NOD2 Peripheral Tolerance - (+) polymorphism: Crohn Disease - Several mechanisms silence autoreactive T & B cells Inflammatory bowel disease Anergy Ineffective at sensing gut microbes, including commensal bacteria, - If the antigen is presented to T cells without adequate levels of resulting in entry of & chronic inflammatory responses against these costimulators, the cells become anergic normally well-tolerated organisms - T cells that recognize self antigens receive an inhibitory signal from IL-2 receptor (CD25) receptors - (+) polymorphism: multiple sclerosis - CTLA-4 = Binds to B7 molecules Inherited mutations lead to systemic inflammatory diseases - PD-1 = binds to 2 ligands: PD-L1 & PD-L2 P I - CTLA-4 & PDL-1 = “knockout” I - Some tumors & viruses use the same pathways of immune regulation to C evade immune attack This realization has led to the development of Abs that block CTLA-4, PD-1 & its ligand, PD-L1 for tumor immunotherapy By removing the brakes on the immune response, these antibodies promote responses against tumors Epitheliais Suppression by regulatory T cells - The best-defined regulatory T cells are CD4+ cells that express high levels of CD25 (a-chain of IL-2 receptor & FOXP3) - Regulatory T cells prevent immune responses not only against self antigens but also against the fetus & commensal microbes Roles of Infections & Other Environmental Factors Deletion by apoptosis - T cells receive signals that promote their death by apoptosis Autoimmune reactions may be triggered by infections - T cells recognize self antigens – Bim (pro-apoptotic member of the Bcl - Infections may upregulate the expression of APC costimulators family) = Unopposed Bim triggers apoptosis If they present self antigens, the result may be a breakdown of - Fas-Fas Ligand System anergy & activation of T cells specific for the self antigens Lymphocytes express the death receptor Fas (CD95) + FasL = Some microbes express antigens that share amino acid sequences apoptosis with self antigens Mutations: (+) autoimmune lymphoproliferative syndrome (ALPS) - Molecular Mimicry – immune responses against microbial antigens may result in the activation of self-reactive lymphocytes Rheumatic Heart Disease Infections may protect against some autoimmune diseases - Infections promote low-level IL-2 production Essential for maintaining regulatory T cells - The display of tissue antigens also may be altered by a variety of environmental insults: UV radiation – cell death; exposure of nuclear antigens which elicit pathologic immune responses in lupus Smoking – a risk factor for RA = leads to chemical modification of self antigens - Autoimmunity has a strong gender bias – more common in women General Features of Autoimmune Diseases Autoimmune diseases tend to be chronic, sometimes with relapses & remissions - Sample amplification mechanisms exacerbate & prolong the injury The clinical & pathologic manifestations of an autoimmune disease are determined by the nature of the underlying immune response - Most chronic inflammatory diseases are caused by abnormal & excessive Th1 & Th17 responses Mechanisms of Autoimmunity: General Principles Systemic Lupus Erythematosus (SLE) Defective tolerance or regulation Abnormal display of self antigens Involving multiple organs characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANA), in which injury is caused by Inflammation or an initial innate immune response mainly by deposition of immune complexes as is binding of antibodies Role of Susceptibility Genes to various cells & tissues Most autoimmune diseases are complex multigenic disorders Hallmark: production of autoantibodies to dsDNA & the smith antigen (Anti-dsDNA and Anti-sm) are virtually diagnostic The incidence of many autoimmune diseases is greater in twins of affected individuals than in the general population ANAs – 4 categories based on their specificity for: - Monozygotic > dizygotic twins 1. DNA DANN Association of HLA Alleles with Disease 2. Histones 3. Nonhistone proteins bound to RNA HLA genes – greatest contributor to autoimmunity 4. Nucleolar Antigens - Class I HLA allele have a 100- to 200-fold greater chance of developing the disease compared with hose who do not carry HLA-B27 (Ankylosing spondylitis) - Most common HLA allele = DRBI – involved in many diseases DR Beta 1 pressor Page 7 of 15 | NEXILIS  General Pathology Chapter 6: Diseases of the Immune System the most widely used method for detecting ANAs is indirect Neuropsychiatric Manifestations immunofluorescence - Attributed to antibodies that cross the BBB and react with neurons or - the pattern of nuclear fluorescence suggests the type of antibody present receptors for various neurotransmitters in the patient’s serum Homogenous/ Diffuse Nuclear - reflects antibodies to Staining chromatin, histone & ds-DNA Rim/ Peripheral Staining - indicative of antibodies to ds- DNA & to nuclear envelope proteins Speckled pattern - presence of uniform/ variable-sized speckles - least specific - (+) non-DNA nuclear constituents (Sm antigen, RNPs, SS-A & SS-B) Nucleolar pattern - Few spots of fluorescence within the nucleus - Antibodies to RNA - Systemic sclerosis Centromeric pattern - Specific for centromeres - Systemic sclerosis MORPHOLOGY - The most characteristic lesions result from immune complex deposition in blood vessels, kidneys, CT, & skin Blood Vessels Acute necrotizing vasculitis Antiphospholipid antibodies Undergo fibrous thickening Present in 30-40% of lupus patients Antibodies against the phospholipid-B2-glycoprotein complex also binds to cardiolipin antigen, used in syphilis serology - Lupus patients may have a false positive test result for syphilis Pathogenesis The fundamental defect in SLE is a failure of the mechanisms to maintain self-tolerance Kidney Genetic Factors Glomerulonephritis – 50% SLE patients Family members – 1st degree relatives of SLE - d/t deposition of immune complexes on the glomerular basement patients have autoantibodies & other immune membrane abnormalities 6 Patterns of Glomerular Disease: SLE Higher rate of concordance (>20%) in Class I: Minimal mesangial lupus nephritis monozygotic twins compared with dizygotic twins - Very uncommon (1-3%) - Immune complex deposition in mesangium Specific alleles of the HLA-DQ locus Class II: Mesangial proliferative lupus nephritis Deficiencies of complement components: C2, C4 - Mesangial cell proliferation or C1q Class III: Focal lupus nephritis Immunologic Failure of self-tolerance in B cells - Involvement fewer than 50% of glomeruli factors Activation of CD4+ helper T cells specific for - Lesions: nucleosomal antigens that escape tolerance segmental (only a portion of the glomerulus) TLR engagement by nuclear DNA & RNA global (entire glomerulus) - May activate B lymphocytes Class IV: Diffuse Lupus Nephritis - May get second signals from TLRs & may be - Most common & severe form of lupus nephritis activated = ↑ ANA production - Half or more of the glomeruli are affected Type 1 Interferons play a role in lymphocyte - (+) “wire loop” structures on L/M activation in SLE - Usually symptomatic: - High levels of circulating type 1 interferons ✓ Hematuria Environmental Exposure to UV light exacerbates the disease ✓ Proteinuria Factors The gender bias of SLE - HTN: mild to severe renal insufficiency - X-chromosome, independent of hormone effects Class V: Membranous Lupus Nephritis Drugs: - Thickening of the capillary walls - Hydralazine HPD - Immune complexes accompanied by production of basement- - Procainamide membrane like material - D-penicillamine Class VI: Advanced Sclerosing Lupus Nephritis - Sclerosis of more than 90% of the glomeruli - End-stage renal disease Mechanisms of Tissue Injury Spleen Most of the systemic lesions are caused by immune complexes (type III Splenomegaly hypersensitivity) Lungs - LE Bodies or hematoxylin bodies = LE cell Pleuritis & pleural effusions Any phagocytic leukocyte (neutrophil/ macrophage) has engulfed Other organs & tissues the denatured nucleus of an injure