Robbins Pathology - Chapter 6: Diseases of the Immune System PDF

CHAPTER 6: DISEASES OF THE IMMUNE SYSTEM  Capture protein antigens and display peptides for recognition by T...

CHAPTER 6: DISEASES OF THE IMMUNE SYSTEM  Capture protein antigens and display peptides for recognition by T lymphocytes; antigen presenting cells (APCs)  Endowed with receptors that sense microbes and cell damage   Immune system – vital for survival; protects us from infectious pathogens in the stimulate secretion of cytokines environment  Involved in initiation of innate immune responses  Capable of causing tissue injury and disease Natural Killer  Provide early protection against many viruses and intracellular o E.g., allergies, autoimmunity Cells bacteria Mast cells  Capable of producing many mediators of inflammation THE NORMAL IMMUNE SYSTEM  Also epithelial and endothelial cells Innate  Cells with the appearance of lymphocytes but w/ features more  Immunity – protection from infectious pathogens lymphoid cells like cells of innate immunity  Innate immunity – natural or native immunity  Contribute to early defense against microbes Proteins of  Plasma proteins that are activated by microbes using the o Refers to the mechanisms that are ready to react to infections even before complement alternative and lectin pathways in innate immune response they occur; have evolved to specifically recognize and combat microbes system  In adaptive immunity: activated by antibodies using classical o First line of defense pathway o Mediated by cells and molecules that recognize products of microbes and  Mannose-binding lectin and CRP  coat microbes and dead cells and induce rapid protective host reactions promote phagocytosis  Adaptive immunity – acquired or specific immunity  Lung surfactant – also a component of innate immunity provide o Consists if mechanisms that are stimulated by (“adapt to”) microbes protection against inhaled microbes o Capable of recognizing microbial and nonmicrobial substances o Develops later after exposure to microbrs and other foreign substances Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances o More powerful than innate immunity o “immune response”  Cells that participate in innate immunity are capable of recognizing certain microbial components that are shared among related microbes and are Innate Immunity often essential for infectivity (thus cannot be mutated to allow the microbes to evade the defense mechanism)  Innate immunity is always present, ready to provide defense against microbes and to o These microbial structures are called pathogen-associated molecular eliminate damaged cells patterns  Functions in stages:  Damaged-associated molecular patterns – where leukocytes recognize o Recognition of microbes and damaged cells molecules released by injured and necrotic cells o Activation of various mechanisms  Pattern recognition receptors – cellular receptors that recognize these molecules o Elimination of the unwanted substances  Pattern recognition receptors are located in all the cellular compartments where Components of Innate Immunity microbes may be present: o Plasma membrane receptors detect extracellular microbes  The major components of innate immunity are epithelial barriers that block o Endosomal receptors detect ingested microbes the entry of microbes, phagocytic cells (mainly neutrophils and o Cytosolic receptors detect microbes in the cytoplasm macrophages), dendritic cells, natural killer cells, and several plasma proteins of the complement system Toll-Like Receptors  Best-known of the pattern recognition receptors; Toll was discovered in Drosophila  10 TLRs in mammals; present in plasma membrane and Epithelia of  Provide mechanical barriers to the entry of microbes from the endosomal vesicles skin and GIT external environment  All these receptors signal by a common pathway that  Also produce antimicrobial molecules such as defensins, and culminates in the activation of two sets of transcription lymphocytes located in the epithelial combat microbes at these factors: sites o NF-kB – stimulates the synthesis and secretion of Monocytes  Phagocytes in blood; rapidly recruited at sites of infection cytokines and the expression of adhesion and  Macrophages – matured monocytes in tissues; “professional molecules neutrophils phagocytes”; sense and ingest invaders o Interferon regulatory factors (IRFs) – o Dominant cells in chronic inflammation stimulate the production of the antiviral cytokines, Dendritic cells  Specialized cell population present in epithelia, lymphoid organs, type I interferons and most tissues abmrmtmd NOD-Like  NLRs – cytosolic receptors; recognize wide variety of Adaptive Immunity Receptors and the substances including: Inflammasome o Products of necrotic cells (uric acid, released ATP)  The adaptive immune system consists of lymphocytes and their products, including o Ion disturbances (loss of K+) antibodies o Microbial products  Two types of adaptive immunity:  NLRs signal via a cytosolic multiprotein complex called o Humoral immunity – protects against extracellular microbes and their inflammasome, w/c activates enzyme (caspase-1) that cleaves IL-1 to generate active form toxins  IL-1 – mediator of inflammation that recruits leukocytes and  Mediated by B lymphocytes, antibodies or immunoglobulins (Ig) induce fever o Cell-mediated or cellular immunity – responsible for defense against  Gain-of-function mutations of NLRs lead to periodic fever intracellular microbes syndromes, called autoinflammatory syndromes  Mediated by T lymphocytes o Respond to treatment w/ IL-1 antagonist Other Receptors for  C-type lectin receptors (CLRs) – expressed on the Cells of the Immune System Microbial Products plasma membrane of macropahges and dendritic cells o Detect fungal glycans and elicit inflammatory reactions to fungi  Lymphocytes and other cells involved in immune response constantly circulate  RIG-like receptors (RLRs) – located on the cytosol of among lymphoid and other tissues via blood and lymphatic circulation most cell types and detect nucleic acids of viruses that o Promotes immune surveillance replicate in the cytoplasm  Naive cells – mature lymphocytes that have not encountered the antigen for which  These receptors stimulate the production of antiviral they are specific cytokines  Effector cells – differentiated lymphocytes after they are activated by recognition of  G protein coupled receptors on neutrophils, macrophage antigens and other signals; functions to eliminate microbes  recognize short bacterial peptides containing N- formylmethionyl residues  Memory cells – live in a state of heightened awareness; able to react rapidly and o GPCR enables neutrophils to detect bacterial strongly combat the microbe in case it returns proteins and stimulate chemotactic response  Mannose receptors – recognize microbial sugars and Lymphocyte Diversity induce phagocytosis  Lymphocytes specific for a large number of antigen exist before exposure to antigen, and when an antigen enters, it selectively activates the antigen- specific cells  “clonal selection” Reactions of Innate Immunity o Lymphocytes express receptors for antigens and mature to competent cells before exposure to antigen  Innate immune system provides host defense by two main reactions o Clone – lymphocytes of the same specificity ; all members of a clone have identical antigen receptors  Antigen receptor diversity is generated by somatic recombination of the genes that Inflammation  Cytokines and products of complement activation are encode the receptor proteins produced during innate immune reactions and trigger the o All cells of the body contain antigen receptor genes in the germline vascular and cellular components of inflammation (inherited) configuration  consist of spatially separated segments that  Recruited leukocytes destroy microbes and ingest and cannot be expressed as proteins eliminate damaged cells o During lymphocyte maturation (thymus and MB), gene segments Antiviral defense  Type I interferons produced in response to viruses act on cells recombine, transcribed and translated into functional antigen receptors and activate enzymes that degrade viral nucleic acids and  Enzyme in developing lymphocytes that mediates recombination of these gene inhibit viral replication  inducing antiviral state segments is the product of RAG-1 and RAG-2 Others  Innate immunity provides the danger signals that stimulate o Inherited defects of RAG proteins  failure to generate mature lymphocytes more powerful adaptive immune response  Germline antigen receptor genes are present in all cells in the body, but only T and B cells contain recombined antigen receptor genes  TCR in T cells; Ig in B cells  TCR or Ig genes  marker of T or B lineage cells  Innate immunity does not have memory of fine antigen specificity  Analysis of antigen receptor gene rearrangements is a valuable assay for detecting o Uses about 100 different receptors to recognize 1,000 molecular patterns tumors derived from lymphocytes  Adaptive immunity uses two types of receptors (antibodies and T cell receptors) to recognize millions of antigens abmrmtmd T Lymphocytes B Lymphocytes  Have three major populations:  B lymphocytes are the only cells in the body capable of producing antibody 1. Helper T lymphocytes (HTL) – stimulate B lymphocyte to make molecules, the mediators of humoral immunity antibodies and activate other leukocytes to destroy microbes  B lymphocytes develop from bone marrow 2. Cytotoxic T lymphocytes (CTL) – kill infected cells o Mature B cells – 10-20% of the circulating peripheral lymphocyte 3. Regulatory T lymphocytes (RTL) – limit immune responses and prevent o Also present in peripheral lymphoid tissues such as lymph nodes, spleen, reaction against self antigens and MALT  T lymphocytes develop in the thymus  B cells recognize antigen via the B-cell antigen receptor complex  Mature T cells are found in the blood (60-70% of lymphocytes) and in T cell zones of  Membrane-bound antibodies of the IgM and IgD isotypes, present on the surface of peripheral lymphoid organs all mature, naive B cells, are the antigen-binding component of the B-cell receptor  T cell recognize an antigen by antigen-specific TCR complex o TCR consist of a disulfide-linked heterodimer made up of α & β o After stimulation by Ag and other signals, B cells develop into plasma cells polypeptide chain, each have a variable (antigen-binding) region and (factories for antibodies) constant region  Plasmablasts – antibody-secreting cells detected in human peripheral blood  The αβ TCR recognizes peptide antigens that are presented by MHC molecules on  B-antigen receptor complex also contains a heterodimer of two invariant proteins the surfaces of APC called Igα and Igβ (essential for signal transduction)  MHC restriction – limiting the specificity of T cells for peptides displayed by cell o Igα (CD&(a) surface MHC molecules; ensures that T cells see only cell associated antigens o Igβ (CD79Bb)  Each TCR is noncovalently linked to six polypeptide chains, w/c form the CD3  B cell also express type 2 complement receptor (CR2, or CD21)  recognizes complex and the ζ chain dimer complement products generated during innate immune responses to microbes o CD3 and ζ proteins are invariant or identical in all T cells  CD40 – receives signals from helper T cells o Involve in transduction signals  CR2 – also used by the EBV as a receptor to enter and infect B cells o Form TCR complex (TCR, CD3 and ζ protein)  Small population of mature T cells express TCR composed of γ and δ polypeptide chains  γδ TCR – recognizes peptides, lipids, and small molecules, w/o a requirement for Dendritic Cells display by MHC proteins  Dendritic cells – aka interdigitating dendritic cells; the most important APC o γδ T cells – aggregate at epithelial surfaces (skin and mucosa of GIT and for initiating T-cell responses against protein antigens urogenital tracts); these cells are sentinels that protect against microbes o Have numerous fine cytoplasmic processes that resembles dendrites that try to enter the epithelia o Langerhans cells – immature dendritic cells w/in epidermis  Another small subset of T cells expresses markers that are also found on NK cells   Features of dendritic cells as APC: called NK-T cells o (1) Located under the epithelia (common site of entry), and interstitial of all o NK-T cells – express a very limited diversity of TCRs; recognize tissues (where Ag are produced) glycolipids displayed by MHC like molecule CD1 o (2) Express many receptors for capturing and responding to microbes,  T cell express several other proteins that assist the TCR complex in functional including TLRs and lectins responses: CD4, CD8, CD28 o (3) They are recruited to the T-cell zones of lymphoid organs where they o CD4 and CD8 – expressed on subsets of αβ T cells; function as APC  Serve as coreceptors in T-cell activation; recognize part of the same ligand o (4) They express high levels of MHC and other molecules needed for  CD4+ - 60% of mature T cells presenting Ag to and activating T cells  CD8+ - 30%  Follicular dendritic cells– second type of cell w/ dendritic morphology; present in  CD4+ T cells – function as cytokine-secreting helper cells that assist macrophages the germinal centers of lymphoid follicles in spleen and lymph nodes and B cells to combat infections o Bear Fc receptors for IgG and receptors for C3b o Recognize and respond to antigen displayed only by class II MHC o Can trap antigen bound to antibodies or complement proteins  CD8+ T cells – functions as cytotoxic (killer) T lymphocytes (CTLs) to destroy host o Play a rle in humoral immune responses by presenting antigens to B cells cells harbouring microbes and selecting the B cells that have the highest affinity for the antigen, thus o Recognize cell-bound antigens only in association with class I MHC improving the quality of the antibody produced molecule  CD4 or CD8 coreceptors initiates signals needed for activation of T cells  Integrins – adhesion molecules that promote the attachment of T-cells to APCs  T cells have to recognize antigen-MHC complexes and signals provided by APC  CD28 abmrmtmd Macrophages Tissue of the Immune System  Part of the mononuclear phagocyte system  Important functions in the induction and effector phases of adaptive immune  Consist of: response: o Generative (primary or central) lymphoid organs – T and B lymphocytes mature and become competent to respond to antigens  Macrophages that have phagocytosed microbes and protein Ags process the Ags and o Peripheral (secondary) lymphoid organs – adaptive immune responses present peptide fragments to T cells. Thus, macrophage function as APC in T-cell activation to microbes are initiated  Macrophages are key effector cells in certain forms of cell-mediated immunity, the reaction that serves to eliminate intracellular microbes. In this response, T cells Generative Lymphoid Organs activate macrophages and enhance their ability to kill ingested microbes  Thymus – where T cells develop  Macrophages participate in the effector phase of humoral immunity. They  Bone marrow – the site of productionof all blood cells and where B lymphocytes phagocytose, and destroy microbes that are opsonized mature Natural Killer Cells Peripheral Lymphoid Organs  The function of NK cells is to destroy irreversibly stressed and abnormal  Organize to concentrate antigens, APC, and lymphocytes in a way that cells, such as virus-infected cells and tumor cells optimizes interactions among this cells and the development of adaptive immune  5-10% of peripheral blood lymphocytes response  They do not express TCRs or Ig o Lymph nodes  Larger than lymphocytes and contain abundant azurophilic granules o Spleen  Have the ability to kill virus-infected cells and tumor cells w/o prior exposure to or o Mucosal and Cutaneous lymphoid tissues activation by these microbes or tumors o Early line of defense against viral infections and tumors Lymph nodes  Nodular aggregates of lymphoid tissues located along  CD16 and CD56 – commonly used to identify NK cells lymphatic channels  CD16 – is an Fc receptor for IgG; confers on NK cells the ability to lyse IgG-coated  Dendritic cells pick up and transport transport antigens of target cells  called antibody-dependent cell-mediated toxicity (ADCC) microbes from epithelia via lymphatic vessels to lymph nodes  The functional activity of NK cells is regulated by a balance between signals from  Antigens of microbes that enter through the epithelia or activating and inhibitory receptors colonize tissues become concentrated in draining lymph nodes  NKG2D family – activating receptor; recognize surface molecules induced by various Spleen  Abdominal organ; functions like lymph nodes kinds of stress (e.g., infection, DNA damage)  Blood entering the spleen flows through a network of sinusoids  NK cell inhibitory receptors recognize self class I MHC molecules (in healthy cells)  Blood-borne Ags are trapped by dendritic cells and o Prevent NK cells from killing normal cells macrophages in the spleen  Infection or neoplasm  enhance expression of activating receptors and reduces Cutaneous  Located under the epithelia of skin and GIT and respiratory expression of class I MHC molecules  balance is tilted toward activation and infected and mucosal tract, respectively or tumor cell is killed lymphoid  Respond to Ags that enter through branches in the epithelium  NK cells also secrete cytokines: systems  Pharymgeal tonsils and Peyer’s patches – anatomically defined o IFN-y – activates macrophages to destroy ingested microbes; thus NK cells mucosal lymphoid tissues provide early defense against intracellular microbial infections  More than half the body’s lymphocytes are in the mucosal  NK cells activity is regulated by many cytokines: tissues, mostly are memory cells o IL-2 & IL-5 – stimulate proliferation if NK cells o IL-12 - activates killing and secretion of IFN-y  Within peripheral lymphoid organs, T an B lymphocytes are segregated into regions  Follicles – located around the periphery or cortex or each lymph node; where B cells Innate Lymphoid Cells (ILC) are concentrated  Lack TCRs but produce cytokines similar to T cells o Contain follicular dendritic cells – involved in the activation of B cells  NK cells – first defined ILC  Germinal centers – central region contained in a follicle if the B cells have recently  Other ILC produce: IFN-y, IL-5, IL-17, IL-22 responded to an antigen  Functions:  Paracortex – adjacent to the follicles; where T cells are concentrated o Early defense against infections o Contains dendritic cells that present antigens to T lymphocytes o Recognition and elimination of stressed cells (“stress surveillance”)  Periarteriolar lymphoid sheaths (PALS) – located in spleen surrounding small o Shaping the later adaptive immune response, by providing cytokines that arterioles; where T lymphocytes are located influence the differentiation of T cells o Follicles – where B cell resides abmrmtmd Lymphocyte Circulation Class II MHC  Encoded in a region called HLA-D  has three subregions:  Lymphocytes constantly recirculate between tissues and home to particular sites; molecules HLA-DP, HLA-DQ, HLA-DR o Naive lymphocytes traverse the peripheral lymphoid organs where  Heterodimer w/ noncovalently associated α and β chain, both immune responses are initiated are polymorphic o Effector lymphocytes migrate to sites of infection and inflammation o Extracellular portions of α & β chains both have two  Plasma cells remain in lymphoid organs and the bone marrow domain: α1, α2, β1, β2 o Do not need to migrate to sites of infection because they secrete antibodies  Crystal structure have peptide binding clefts facing outward that are carried to distant tisues o Cleft is formed by interaction of α1 and β1 domains  portion that most class II differs  Polymorphism is asso.w/ differential binding of antigenic Major Histocompatibility Complex (MHC) Molecules: The Peptide Display System of peptides  Class II MHC molecules present antigens that are internalized Adaptive Immunity into vesicles, and are typically derived from extracellular microbes and soluble proteins  The function of MHC molecules is to display peptide fragments of protein o Internalized proteins are digested in endosomes or antigens for recognition by antigen-specific T cells lysosomes o Fundamental to the recognition of antigens by T cells o Peptides then asso.w/ class II heterodimers in the o Linked to autoimmune diseases vesicles  the stable peptide-MHC complexes are  Human leukocyte antigens – MHC in human; small segment of chromosome 6 transported to the cell surface o Highly polymorphic o Class II β2 domain has a binding site for CD4  recognize by CD4+ (fxnx as helper cells) o Formidable barrier in organ transplant  CD4+ T cells  class II MHC-restricted  MHC has two major products:  Class II MHC molecules are mainly expressed on cells o Class I MHC molecules that present ingested Ags and respond to T-cell help o Class II MHC molecules (macrophages, B lymphocytes, dendritic cells) MHC locus  Contains genes that encode some complement components Class I MHC  Expressed on all nucleated cells and platelets and the cytokine TNF and lymphotoxin molecules  Heterodimers w/ polymorphic α, or heavy, chain (44kD) linked noncovalently to a smaller (12kD) nonpolymorphic protein called B2-microglobulin  HLA haplotype – combination of HLA alleles in each individual  α chains are encoded by three genes: HLA-A, HLA-B, HLA- o 1 set of HLA from each parent C  lie close to one another in the MHC locus  No two individuals (other than identical twins) are likely to express the same MHC  Extracellular region of α chain is divided into three domain: molecules α1, α2, α3 o α1 & α2 domains – form a cleft or groove, where  MHC molecules play several key roles in regulating T cell-mediated immune peptides bind responses:  Class I MHC molecules display peptides that are derived from o (1) an individual mounts an immune response against a protein Ag only if proteins, such as viral and tumor Ags, that are located in the he or she inherits the genes for those MHC molecules that can bind peptides cytoplasm and usually produced in the cell derived from Ag and present it to T cells o Class-I associated peptides are recognized by o (2) by segregating cytoplasmic and internalized antigens, MHC molecules CD8+ T lymphocytes  Cytplasmic proteins are degraded in proteasomes  ensure that the correct immune response is mounted against different peptides are transported in ER and bind to class I molecules microbes – CTL-mediated killing cells harbouring microbes, and helper T o Peptide-loaded MHC associate w/ B2- cell-mediated antibody and macrophage activation to combat extracellular microglobulin  form a stable trimer  microbes transported to cell surface  A number of autoimmune and other diseases are associated with the inheritance of o α3 domain has a binding site for CD8+  particular HLA alleles recognized by CD8+ (CTLs) o TCR recognize MHC-peptide complex and CD8 molecule (coreceptor) binds to class I heavy chain  CD8+ T cells  class I MHC-restricted o Eliminate virus  all nucleated cells express class I HLA that can be surveyed by CD8+ abmrmtmd Cytokines: Messenger Molecules of the Immune System Cell-Mediated Immunity: Activation of T Lymphocytes and Elimination of Intracellular Microbes  Many cellular interactions and functions of leukocytes are mediated by secreted  Naive T lymphocytes are activated by Ag and costimualtors in peripheral lymphoid proteins called cytokines organs and proliferate and differentiate into effector cells that migrate to site of  Interleukins – molecularly defined cytokines; mediate communications between antigens  Secretion of IL-2 – earliest responses of CD4+ cells and expression of high-affinity meukocytes receptors for IL-2  Majority of cytokines act on the cells that produce them (autocrine reactions) or on  IL-2 – growth factor that acts on these T lymphocytes and stimulates their neighboring cells (paracrine) and rarely at a distance (endocrine) proliferation, leading to increase in number of antigen-specific lymphocytes  Cytokines contribute to different types of immune responses.  Functions of helper T cells are mediated by the combined actions of CD40L and  In innate immune response, cytokines are produced rapidly after encounter w/ cytokines microbes and other stimuli o When CD4+ helper T cells recognize antigens displayed by macrophage or B cells, the T cells express CD40L w/c engages CD40 on macrophages or B o Function to induce inflammation and inhibit virus replication cells and activates these cells o TNF, IL-1, IL-12, type I IFNs, IFN-y, chemokines  major source:  Some of the activated CD4+ cells differentiate into effector cells that secrete different macrophages, dendritic cells, NK cells; also epithelial cells sets of cytokines and perform different functions  In adaptive immune responses, cytokines are produced mainly by CD4+ T  IFN-y – potent macrophage activator secreted by TH1 lymphocytes o Combination of CD40- and IFN-y mediated activation results in “classical o Functions to promote lymphocyte proliferation and differentiation and macrophage activation “  lead to destruction of ingested microbes activate effector cells  IL-2, IL-4, IL-5, IL-17, IFN-y  TH2 produces: o IL-4 – stimulates B cells to differentiate into Ig-E secreting plasma cells o Some cytokines limit and terminate immune responses TGF-b, IL-10 o IL-5 – activates eosinophils  Some cytokines stimulate hematopoiesis  colony-stimulating factors  Eosinophils and mast cells bind to IgE-coated microbes (helminthic parasites) and o Stimulate formation of blood cell colonies from BM eliminate o Increase leukocyte numbers during immune and inflammatory responses  TH2 also induce “alternative pathway” of macrophage activation  asso.w/ o Produced by: marrow stromal cells, T lymphocytes, macrophages tissue repair and fibrosis o E.g., CSFs such as GM-CSF, IL-7  TH17 cells – releases IL-17 w/c recruit neutrophils and monocytes and destroy extracellular bacteria and fungi, also involved in inflammatory diseases  Activated CD8+ T lymphocytes differentiate into CTLs  kills microbes in cytoplasm Overview of Lymphocyte Activation and Immune Responses o CTLs eliminate the reservoirs of infection  Steps in developing an adaptive immune response: 1. Antigen recognition Humoral Immunity: Activation of B Lymphocytes and Elimination of Extracellular 2. Activation of specific lymphocytes to proliferate and differentiate into effector and Microbes memory cells  Upon activation, B lymphocytes proliferate and then differentiate into 3. Elimination of the antigen plasma cells that secrete different classes of antibodies with distinct 4. Decline of the response (memory cells being the long-lived survivors) functions  Antibody responses to most protein antigens require T cell help  T-dependent Display and Recognition of Antigens o In these responses, B cells ingest Ags into vesicles and degrade them, and  Microbes and their protein antigens are captured by dendritic cells display peptides bound to class II MHC for recognition by helper T cells o They carry their antigenic cargo to draining lymph nodes  Ag are o Helper T cells are activated, express CD40L and secrete cytokines  processed and displayed w/ MHC molecules on the cell surface  antigens stimulate B cells are recognized by T cells  Many polysaccharide and lipid antigens cannot be recognized by T cells but have  B lymphocytes use their Ag receptors (membrane-bound antibody molecules) to multiple antigenic determinants (epitopes) that are able to engage many antigen recognize Ags of many different chemical types (e.g., protein, polysaccharides, lipids) receptor molecules on each B cell and initiate the process of B-cell activation  T-  Adjuvants – microbial mimics; given w/ the antigen and stimulate innate immune independent response (e.g., immunizations)  Polysaccharides and lipids stimulate secretion mainly of IgM antibody o Activates APCs to express molecules called costimulators and to secrete  Protein antigens (thru CD40L- and cytokine mediated helper T cell actions) induce cytokines that stimulate the proliferation and differentiation of T cells production of antibodies IgG, IgA, IgE o Principal costimulators for T cells are the B7 proteins (CD80 and CD86)  Isotype switching – induced by cytokines IFN-y and IL-4  expressed on APCs and recognize by CD28 receptor on naive T cells  Helper T cells also stimulate production of antibodies w/ high affinities for the Ag  Signal 1 (antigens) and costimulatory molecules produced during innate immune o Called affinity maturation  improves quality of humoral response responses to signal 2 (microbes) function cooperatively to activate antigen-specific  Isotype switching and affinity maturation occur mainly in germinal centers lymphocytes  Follicular helper T cells (TFH) – helper T cells that stimulate these processes in B lymphocytes migrate to and reside in the germinal centers abmrmtmd   IgG  opsonises microbes and target them for phagocytosis (neutrophils and  CD4+ helper T cells help B cells to make antibodies, activate macrophages to destroy macrophages  has receptors for Fc tails of IgG) ingested microbes, stimulate recruitment of WBC, and regulate all immune responses o Crosses the placenta; protects newborn until immune system matures to protein antigens. The function of CD4+ T cells are mediated by secreted proteins o Half-life: 3 weeks (plasma cells have months or years in BM) called cytokines. CD8+ cytotoxic T lymphocytes kill cells that express antigens in the  IgG and IgM  activate classical pathway cytoplasm that are seen as foreign and can also produce cytokines  IgA  secreted from mucosal epithelia and neutralizes microbes in the lumens of  Antibodies secreted by plasma cells neutralize microbes and block their infectivity, and respiratory and GIT promote phagocytosis and destruction of pathogens. Antibodies also confer passive  IgE and eosinophils  kills parasites thru granules immunity to neonates o TH2 cytokines stimulate production of IgE and activate eosinophils HYPERSENSITIVITY: IMMUNOLOGICALLY MEDIATED TISSUE INJURY Decline of Immune Responses and Immunologic Memory  Majority of effector lymphocytes die by apoptosis after elimination of microbes   Hypersensitivity – injurious immune reactions; basis of the pathology asso.w/ returns the immune system to its resting state immunologic diseases  Initial activation of lymphocytes also generates memory cells  survive for years o Individuals who have been previously exposed to an antigen manifest after the infection detectable reactions to that antigen  sensitized  Memory cells expanded pool of antigen-specific lymphocytes; respond faster and more effectively when reexposed to antigen than do naive cells (important in o Excessive or harmful reaction to antigen vaccination  Hypersensitivity reactions can be elicited by exogenous environmental antigens (microbial and nonmicrobial) or endogenous self antigens o Allergy – most common reaction to environmental antigens KEY CONCEPTS: The Normal Immune Response: Cells, Tissues, Receptors, Mediators, o Autoimmune diseases – immune responses against self or autologous and Overview antigens  The innate immune system uses several families of receptors, notably the Toll-like  Hypersensitivity usually results from an imbalance between the effector mechanisms receptors, to recognize molecules present in various types of microbes and produced of immune responses and the control mechanisms that serve to normally limit such by damaged cells responses  Lymphocytes are the mediators of adaptive immunity and the only cells that produce specific and diverse receptors for antigens  The development of hypersensitivity diseases (both allergic and autoimmune) is often  T lymphocytes express antigen receptors called TCR that recognize peptide fragments asso.w/ the inheritance of particular susceptibility genes of protein antigens that are displayed by MHC molecules on the surface of APCs  The mechanisms of tissue injury in hypersensitivity reaction are the same as the  B lymphocytes express membrane-bound antibodies that recognize wide variety of effector mechanisms of defense against infectious pathogens antigens. B cells are activated to become plasma cells, w/ secrete antibodies  Natural killer cells kill cells that are infected by microbes, or are stressed and damaged Classification of Hypersentivity Diseases beyond repair. NK cells express inhibitory receptors that recognize MHC molecules that are normally expressed on healthy cells, and are thus prevented from killing  Classified based on the immunologic mechanism that mediates the diseases normal cells  Antigen presenting cells (APCs) capture microbes and other antigens, transport them to lymphoid organs, and display them for recognition by lymphocytes. The most 1. Type I hypersensitivity (immediate hypersensitivity) efficient APCs are dendritic cells (live in epithelial and most tissues) o Injury is caused by TH2 cells, IgE, mast cells and other leukocytes  The cells of the immune system are organized in tissues, some of w/c are the sites of 2. Type II hypersensitivity (antibody-mediated disorders) production of mature lymphocytes (generative lymphoid organs: thymus and BM) and o Secreted IgG and IgM antibodies injure cells by promoting their others are the sites of immune responses (peripheral lymphoid organs: lymph nodes, phagocytosis or lysis and injure tissues by inducing inflammation spleen, mucosal lymphoid tissues) 3. Type III hypersensitivity (immune-complex mediated disorders)  The early reaction to microbes is mediated by innate immunity. Includes epithelial barriers, phagocytes, NK cells, plasma proteins of the complement system. Reaction of o IgG and IgM antibodies bind antigens usually in the circulation, and the Ag- innate immunity is often manifested as inflammation. Does not have fine antigen Ab complexes deposit in tissues and induce inflammation specificity or memory 4. Type IV hypersensitivity (cell-mediated immune disorders)  Defense reactions of adaptive immunity develop slowly, but are more potent and o Sensitized T lymphocytes (TH1 and TH17 cells and CTLs) are the cause of specialized the tissue injury  Microbes and other foreign antigens are captured by dendritic cells and transported to o TH2 cells induce lesions that are part of type I reaction (nor part of type IV) lymph nodes, where antigens are recognized by naive lymphocytes. Lymphocytes are activated to proliferate and differentiate into effector and memory cells  Cell-mediated immunity is the reaction of T lymphocytes, designed to combat cell- associated microbes. Humoral immunity is mediated by antibodies and is effective against extracellular microbes (in circulation and mucosal lumens) abmrmtmd TYPE MECHANISM HISTOPATHOLOGIC PROTOTYPICAL  Most immediate hypersensitivity disorders are caused by excessive TH2 responses LESION DISORDERS and these cells play a central role by stimulating IgE production and promote Type I Prdxn of IgE  release of Vascular dilation, Anaphylaxis; inflammation. (immediate) vasoactive amines and other edema, smooth muscle allergies; bronchial mediators from mast cells; contraction, mucus asthma (atopic Activation of TH2 cells and Production of IgE Antibody later recruitment of production, tissue injury, forms) inflammatory cells inflammation  First step in generation of TH2 cells is the presentation of the Ag to naive CD4+ helper T cells by dendritic cells Type II Prdxn of IgG, IgM  binds to Phagocytosis and lysis Autoimmune o In response to Ag, and also IL-4 produced at local site, T cells differentiate (antibody- Ag on target cell or tissue  of cells; inflammation; haemolytic anemia; into TH2 cells medaited) phagocytosis or lysis of functional derangements Goodpasture o New TH2 cells produce cytokines upon encounter w/ antigen  IL-4, IL-5, target cell by activated w/o cell injury syndrome IL-13 complement or Fc receptors; recruitment of WBC  IL-4 – acts on B cells to stimulate class switching to IgE and Type III Deposition of Ag-Ab complex Inflammation, SLE, some forms of promotes the development of additional TH2 cells (immune-  complement activation  necrotizing vasculatits glomerulonephritis;  IL-5 – involved in the development and activation of eosinophils complex recruitment of WBC by (fibrinoid necrosis) serum sicknesss; (important effector of Type I hypersensitivity) mediated) complement products and Fc Arthus reaction  IL-13 – enhances IgE production and acts on epithelial cells to receptors  release of stimulate mucus secretion enzymes and other toxic  TH2 cells also produce chemokines to attract more TH2 cells molecules Type IV Activated T lymphocytes  Perivascular cellular Contact dermatitis; (cell- infiltrates; edema; multiple sclerosis; Sensitization and Activation of Mast Cells (1) release of cytokines, mediated) inflammation and granuloma formation, type 1 DM, macrophage activation; (2) cell destruction tuberculosis  Mast cells – BM-derived cells; widely distributed in the tissues T-cell mediated cytotoxicity o Abundant near blood vessels and nerves and in subepithelial tissues o Have cytoplasmic membrane-bound granules that contain active mediators  Granules also contain acidic proteoglycans that bind basic dyes Immediate (Type I) Hypersensitivity (toluidine blue) o Basophils – circulating counterpart  Immediate or type I hypersensitivity  rapid immunologic reaction occurring in  Mast cells (and basophils) are activated by the cross-linking of high-affinity IgE Fc a previously sensitized individual that is triggered by the binding of an antigen to IgE receptors on the surface of mast cells o Can also be triggered by C5a and C3a (anaphylatoxins)  act by o Often called allergy binding to receptors on mast cell membrane  Allergen – antigen that caused the allergy  Other mast cell secretagogues: chemokines (IL-8), drugs (codeine, morphine,  May occur as systemic or local reaction adenosine, melittin in venom), and physical stimuli (heat, cold, sunlight) o Systemic reaction – most often follows injection of an Ag (e.g., bee sting)  Basophils – similar w/ mast cells in terms of IgE Fc receptors and granules or ingestion (e.g., peanut allergens) o Differes in location; basophils are present in citculating blood o Sometimes, w/in minutes the patient goes into a stae of shock  fatal  FcεRI – high-affinity receptors found on mast cells and basophils; specific for the Fc o Local reaction – diverse and may vary; localized cutaneous rash or blisters portion of IgE (skin allergy, hives), nasal and conjunctival discharge (allergic rhinitis,  IgE coated mast cells are said to be sensitized, because they are sensitive to conjunctivitis), hay fever, bronchial asthma, allergic gastroenteritis (food subsequent encounter w/ specific Ag allergy)  When a mast cell, armed w/ IgE antibodies, is exposed to the same Ag, the cell is  Local type I hypersensitivity reactions have two phases: activated, leading eventually to the release of an arsenal of powerful mediators 1) Immediate reaction – cxd by vasodilation, vascular leakage, smooth responsible for immediate hypersensitivity reactions muscle spasm or glandular secretions; evident w/in minutes after exposure  In the first step of mast cell activation, Ag binds to IgE antibodies. Multivalent Ags to allergen; subside in a few hours bind and cross-link adjacent IgE antibodies. Receptors (FcεRI) are brought together 2) Late-phase reaction – sets in 2-24 hrs later w/o additional exposure to and activate signal transduction pathway. Signal leads to production of mediators Ag and may last for several days; cxd by infiltration of tissues w/ responsible for symptoms of immediate hypersensitivity eosinophils, neutrophils, basophils, monocytes, CD4+ cells, and tissue destruction (mucosal epithelial cell damage abmrmtmd Mediators of Immediate Hypersensitivity  These mediators are responsible for the manifestations of immediate hypersensitivity reactions  Mast cell activation leads to degranulation, w/ the discharge of preformed o E.g., histamine and leukotrienes – released rapidly, responsible for intense (primary) mediators stored in granules, and de novo synthesis and release of immediate reactions cxd by: edema, mucus secretion smooth muscle spasm secondary mediators, including lipid products and cytokines Late Phase Reaction Preformed  Contained w/in mast cell granules; first to be released Mediators  Divided in three categories  In the late-phase reaction, leukocytes are recruited that amplify and sustain Vasoactive  Histamine – most important mast-cell the inflammatory response w/o additional exposure to the triggering amines derived amine; causes: antigen o Intense smooth muscle contraction  Eosinophils – abundant WBC in this reaction o Increased vascular permeability o Increased mucus secretion by o Recruited by eotaxin nasal, bronchial, and gastric  IL-5 – produced by TH2 cells; most potent eosinophil-activating cytokine glands  Upon activation eosinophils liberate proteolytic enzymes and two unique proteins: Enzymes  Contained in the granule matrix o Major basic protein (MBP)  Include neutral proteases (chymase, o Eosinophils cationic protein (ECP) tryptase) and acid hydrolase  Late phase reaction is a major cause of symptoms in some type 1  Cause tissue damage and lead to generation hypersensitivity disorders (e.g., allergic asthma) of kinins and activated components of complement (C3a)  Treatment: steroids Proteoglycans  Heparin – anticoagulant  Chondroitin sulfate Development of Allergies  Serve to package and store the amines in the granules  Susceptibility to immediate hypersensitivity reactions is genetically determined  Atopy – increased propensity to develop immediate hypersensitivity reactions Lipid  Major lipid mediators are arachidonic acid-derived products o Atopic individuals have higher serum IgE levels and more IL-4-producing Mediators  Reactions in mast cell membranes  activates PLA2  converts TH2 cells membrane phospholipids to arachidonic acid  Studies in px w/ asthma reveal linkage to polymorphisms in genes  Arachidonic acid – parent compound of: o 5q31 region o Leukotrienes (5-lipoxygenase pathway) o Prostaglandins (cyclooxygenase pathway) o Encodes IL-3, IL-4, IL-5, IL-9, IL-13, GM-CSF Leukotrines  Leukotrines C4 and D4  most potent  Environmental factors are also important in the development of allergic reactions vasoactive and spasmogenic agents; more o Predisposing factor for allergy  exposure to pollutants active than histamine  Nonatopic allergy – immediate hypersensitivity reactions triggered by non-antigenic  Leukotriene B4  highly chemotactic for stimuli (e.g., temperature extremes, exercise) and do not involve TH2 cells or IgE neutrophils  The incidence of many allergic diseases is increasing in developed countries Prostaglandin  Most abundant mediator by COX pathway o Hygiene hypothesis – early childhood exposure to microbial antigens D2  Cause intense bronchospasm and increased mucus secretion educates immune system in such a way that pathologic responses against PAF  Platelet-activating factor allergens are prevented  Lipid mediator produced by mast cells, not derived from arachidonic acid Systemic Anaphylaxis  Causes platelet aggregation, release of histamine, bronchospasm, increased vascular  Systemic anaphylaxis is characterized by: permeability, vasodilation o Vascular shock o Widespread edema Cytokines  TNF, IL-1, chemokines o Difficulty in breathing  Chemokines – promote WBC recruitment; typical of late-phase reaction  It may occur in sensitized individuals,  IL-4 – amplifies TH2 response o In hospital setting (after administration of foreign proteins (entisera),  Cause further mast cell degranulation hormones, enzymes, polysaccharides, drugs (antibiotic penicillin) o Community setting (exposure to food allergen or insect toxin) abmrmtmd   Within minutes after exposure, itching, hives, and skin erythema appear o Complement system generates C3b and C4b  deposited on the surfaces of o Followed by contraction of respiratory bronchioles and distress the cells and recognize by phagocytes  phagocytosis and opsonization o Laryngeal edema  hoarsness  compromise breathing o Complement activation also leads to formation of membrane attack complex o Vomiting, abdominal cramps, diarrhea, and laryngeal obstruction follow  “drill holes”  osmotic lysis of cells (e.g., Neisseria bacteria) o Patient may go into shock and die w/in an hour  Antibody-dependent cellular cytotoxicity (ADCC)  antibody-mediated destruction of cells Local Immediate Hypersensitivity Reactions o Cells coated w/ IgG are killed by different effector cells: NK cells, macrophages, etc.  E.g., pollen, animal dander, house dust, foods  ADCC and phagocytosis occur in following situations:  Urticaria, allergic rhinitis (hay fever), bronchial asthma, food ellergies 1) Transfusion reactions 2) Haemolytic disease of the newborn (erythroblastosis fetalis) Examples of Disorders Caused by Immediate Hypersensitivity 3) Autoimmune haemolytic anemia, agranulocytosis, thrombocytopenia Clinical Syndrome Clinical and Pathologic Manifestations Anaphylaxis (drugs, Fall in BP (shock) caused by vascular dilation; airway obstruction due 4) Certain drug reactions (drugs acts as a”hapten”) bee sting, food) to laryngeal edema Bronchial asthma Airway obstruction caused by bronchial smooth muscle hyperactivity; Inflammation inflammation and tissue injury caused by late-phase reaction Allergic rhinitis, Increased mucus secretion; inflammation of upper airways, sinuses  When antibodies deposit in fixed tissues (e.g., basement membrane, ECM)  sinusitis (hay fever) resultant injury is due to inflammation Food allergies Increased peristalsis due to contraction of intestinal muscles  Deposited antibodies activate complement (chemotactic agent C5a, anaphylatoxins C5a and C3a), increase vascular permeability  Leukocytes are activated  results in production of substances that damage tissues KEY CONCEPTS: Immediate (Type 1) Hypersensitivity such as lysosomal enzymes, protease (digest basement membrane, collagen, elastin,  Also called allergic reactions, or allergies cartilage, ROS)  Induced by environmental antigens (allergens) that stimulate strong TH2 responses and IgE production in genetically susceptible individuals  Antibody-mediated inflammation  glomerulonephritis, vascular rejection  IgE coats mast cells by binding to Fcε receptors; reexposure to the allergen leads to cross linking of the IgE and FcεR, activation of mast cells, and release of mediators Cellular Dysfunction  The principal mediators are histamine, proteases, and other granule contents, prostaglandins, and leukotrienes, and cytokines  In some cases, antibodies directed against cell surface receptors impair or dysregulate  The mediators are responsible for the immediate vascular and smooth muscle function without causing cell injury or inflammation reactions and the late-phase reaction (inflammation)  Myasthenia gravis – antibodies reactive w/ acetylcholine receptors in the motor end  The clinical manifestations may be local or systemic, and range from mildly annoying plates of skeletal muscles block neuromuscular transmission and cause muscle rhinitis to fatal anaphylaxis weakness  Graves disease – antibody-mediated stimulation of cell function; antibodies against Antibody-Mediated (Type II) Hypersensitivity the thyroid stimulating hormone receptor on thyroid epithelial cells stimulate the cells, resulting in hyperthyroidism  Antibodies that react w/ antigens present on cell surfaces or in the extracellular matrix cause disease by destroying these cells, triggering inflammation, or interfering w/ Examples of Antibody-Mediated Diseases (Type II Hypersensitivity) Disease Target Antigen Mechanism of Clinicopathologic normal functions Disease Manifestation  Antibodies may be specific for normal cell or tissue antigens (autoantibodies) or for Autoimmune RBC membrane proteins Opsonisation and Hemolysis, anemia exogenous antigens, such as chemical or microbial proteins, that bind to a cell surface Hemolytic Anemia (Rh blood group Ags, I phagocytosis of RBC or tissue matrix Ag) Autoimmune Platelet membrane Opsonisation and Bleeding Opsonization and Phagocytosis thrombocytopenic proteins (GpIIb-IIIa phagocytosis of purpura integrin) platelets  Phagocytosis – largely responsible for depletion of cells coated with antibodies Pemphigus Proteins in intercellular Ab-mediated Skin vesicles (bullae)  Deposition of IgG or IgM antibodies on surfaces of cells  activate complement vulgaris junctions of epidermal activation of system by classical pathway cells (epidermal proteases, disruption cadherin) of intracellular adhesions abmrmtmd Vasculitis caused Neutrophil granule Neutrophil Vasculitis 2) Deposition of immune complexes by ANCA proteins (released from degranulation and  Circulating Ag-Ab complex is deposited in tissues activated neutrophils) inflammation  Often affects glomeruli and joints Goodpasture Noncollagenous protein Complement- and Nephritis, lung 3) Inflammation and tissue injury syndrome in basement Fc- receptor hemorrhage  Deposition initiates acute inflammation membranes of mediated glomeruli and alveoli inflammation  During this phase (10 days after Ag administration), clinical Acute rheumatic Streptococcal cell wall Inflammation, Myocarditis, arthritis features such as fever, urticaria, joint pains (arthralgias), lymph fever Ag; Ab cross-reacts w/ macrophage node enlargement, and proteinuria appear myocardial Ag activation  Resultant inflammatory lesion: vasculitis, glomerulonephritis, Myasthenia Acetylcholine receptor Ab inhibits Ach Muscle weakness, arthritis Gravis binding, down- paralysis  Complement-fixing Abs (IgG, IgM) and Abs that bind to leukocyte Fc receptor (IgG) modulates receptors induce pathologic lesions of immune complex disorders Graves Disease TSH receptor Ab-mediated Hyperthyroidism o Consumption of complement leads to a decreased on C3 levels stimulation of TSH receptors o C3 levels can be used to monitor disease activity Insulin-resistant Insulin Receptor Ab inhibits binding Hyperglycemia,  Principal morphologic manifestation of immune complex injury  vasculitis asso.w/ diabetes of insulin ketoacidosis necrosis or the vessel wall and intense neutrophilic infiltration Pernicious Intrinsic factor of Neutralization of IF, Abnormal o Fibrinoid necrosis – smudgy eosinophilic area compose of necrotic tissue anemia gastric parietal cells decreased erythropoiesis, and deposits of immune complexes, complement and plasma protein absorption of B12 anemia o Kidney (IF microscopy)  appears granular lumpy deposits of immunoglobulin and complement o EM  electron-dense deposits along the glomerular basement membrane Immune Complex-Mediated (Type III) Hypersensitivity Local Immune Complex Disease (Arthus Reaction)  Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition  Arthus reaction – localized area of tissue necrosis resulting from acute immune  Pathologic reaction is initiated when antigen complexes w/ antibody in the circulation complex vasculitis, usually elicited in the skin  created immune complexes that deposits in vessel walls o Cause by intracutaneous injection of Ag in a previously immunized animal  Antigens that form immune complexes may be: that contains circulating Abs against Ag o Exogenous – foreign protein that is injected or produced by an infectious o As Ag diffuses to vascular wall, it binds the preformed Ab, and large microbe immune complexes are formed locally o Endogenous – if individual produces antibody against self antigens o Precipitate in vessel walls and cause fibrinoid necrosis, and superimposed (autoimmunity) thrombosis worsens the ischemic injury  Immune complexes-mediated diseases tend to be systemic, but often preferentially involve the kidney (glomerulonephritis), joint (arthritis), and small blood vessels KEY CONCEPTS: Pathogenesis of Diseases Caused by Antibodies and Immune (vasculitis) Complexes  Antibodies can coat (opsonised) cells, with or without complement proteins, and Systemic Immune Complex Disease target these cells for phagocytosis vy phagocytes (macrophages), w/c expresses receptors for the Fc tails of IgG and for complement proteins. The result is depletion  Acute serum sickness – prototype of a systemic immune complex disease of the opsonised cells o Frequent sequela to administration of large amount of proteins  Antibodies and immune complexes may deposit in tissues or blood vessels, and elicit o Seen in px who receive antibodies from other individuals or species an acute inflammatory reaction by activating complement, w/ release of breakdown products, or by engaging Fc receptors of leukocytes. The inflammatory reaction  Pathogenesis of systemic immune complex disease can be divided in three phases: causes tissue injury 1) Formation of immune complexes  Antibodies can bind to cell surface receptors or other essential molecules and cause  Protein Ag triggers Ab formation (a week after) and Abs are functional derangements (inhibition or unregulated activation) without cell injury secreted into blood where it reacts w/ the Ag still present in the circulation  forms Ag-Ab complexes abmrmtmd  Examples of Immune Complex-Mediated Diseases microorganisms is markedly augmented, express more class II Disease Antigen Involved Clinicopathologic MHC, facilitate further Ag presentation; secrete TNF, IL-1, Manifestations chemokines (promote inflammation); produce more IL-12  SLE Nuclear Ags (circulating or Nephritis, skin lesions, arthritis, etc amplify TH1 response “planted” in kidney)  Activated TH17 cells secrete IL-17, IL-22, chemokines, Poststreptococcal Streptococcal cell wall Ag; may Nephritis and cytokines  recruit neutrophils and monocytes  glomerulonephritis be “planted” in GBM prmote inflammation Polyarteritis Hepatitis B virus Ag in some Systemic vasculitis  TH17 also produce IL-21  amplifies TH17 response nodosa cases Clinical  Tuberculin reaction – caused by intracutaneous injection of Reactive arthritis Bacterial Ag (e.g., Yersinia) Acute arthritis examples of PPD (contain tubercle bacillus Ag) Serum sickness Various proteins (e.g., foreign Arthritis, vasculitis, nephritis CD4+ T cell- o Appears 8-12 hrs (peaks 24-72 hrs) serum protein (horse Mediated  DTH – cxd by accumulation of mononuclear cells, mainly CD4+ antithymocyte globulin) Inflammatory T cells and macrophages around venules, producing perivascular Arthus reaction Various foreign proteins Cutaneous vasculitis Reactions “cuffing”  marked endothelial hypertrophy (experimental)  Macrophage transform into epitheloid cells with sustained activation  granuloma (microscopic aggregation of epitheloid cells, surrounded by a collar of lymphocytes)  granulomatous inflammation T Cell-Mediated (Type IV) Hypersensitivity