B-Cell Development, Activation, Differentiation and Humoral Response PDF

B-Cell Development, Activation, Differentiation and Humoral Response Chapter 9+11 1  Production of plasma cells and memory B cells can be divided into three broad stages: 1. Generation of mature, immunocompetent B cells (maturation), 2. A...

B-Cell Development, Activation, Differentiation and Humoral Response Chapter 9+11 1  Production of plasma cells and memory B cells can be divided into three broad stages: 1. Generation of mature, immunocompetent B cells (maturation), 2. Activation of mature B cells when they interact with antigen, 3. Differentiation of activated B cells into plasma cells and memory B cells. 2  Overview of B-cell development  Antigen- independent maturation phase: A mature B cell leaves the bone marrow expressing membrane-bound immunoglobulin (mIgM and mIgD) with a single antigenic specificity. These naive B cells, which have not encountered antigen, circulate in the blood and lymph and are carried to the secondary lymphoid organs.  Only about 10% of the potential B cells reach maturity and exit the bone marrow.  Naive B cells in the periphery die within a few days unless they encounter Soluble protein antigen and activated TH cells.  Antigen dependent phase of B-cell development: If a B cell is activated by the antigen specific to its membrane-bound antibody, the cell proliferates (clonal expansion) and differentiates to generate a population of antibody- secreting plasma cells and memory B cells. In this activation stage, affinity maturation is the progressive increase in the average affinity of the antibodies produced and class switching is the change in the isotype of the antibody produced by the B cell from μ toϒ ,α , ε or. 3 Overview of B-cell development 4 Progenitor B Cells Proliferate in Bone Marrow Bone marrow Pro-B cell → precursor B cell Stromal cell in bone marrow secrete IL-7 that help development into immature B cells, heavy chain rearngment Pre-B cell Light chain rearrangement Immature B cell Is now committed to antigenic specificity and produces IgM B cell not fully functional, must first express both IgM AND IgD on membrane B-Cell Activation and Proliferation After export of B cells from the bone marrow, activation, proliferation, and differentiation occur in the periphery and require antigen 1. Thymus-independent antigens (TI) a. Type 1 thymus independent (TI-1) antigens. b. 2. Type 2 thymus-independent (TI-2) antigens 2. Thymus-dependent (TD) antigens B cell required direct contact with TH cell 7 1. Thymus-independent antigens (TI) a. Type 1 thymus independent (TI-1) The first type of response, is directed toward multivalent antigens such as lipopolysaccharide (LPS), expressed by gram-negative bacteria. This type of response is referred to as a T- independent response, and the antigens that elicit such responses are T independent (TI) antigens. TI-1 antigens bind to both Ig and innate receptors (TLR4/MD-2/CD14) on B cells, since B-cell stimulation in this instance is occurring through the innate receptor only a small minority of the antibodies produced will be able to bind directly to the TI-1 antigen. BUT being mitogenic (at high antigen concentrations) for all B cells bearing the relevant innate receptors lead to elicit a polyclonal, antibody-secreting response. 8 b. Type 2 thymus-independent (TI-2) In contrast, TI-2 antigens are highly multivalent to ntigenes such as capsular bacterial polysaccharides or polymeric flagellin, and bind only to Ig receptors. Their ability to cross-link a large fraction of the Ig receptors on the surface of a B cell allows them to deliver an activation signal in the absence of T-cell help. They do not elicit a polyclonal response at high concentrations. Rather, their capacity to activate B cells in the absence of T-cell help results from their ability to present antigenic determinants in a remarkably multivalent array, causing extensive cross- linking of the BCR. In addition, most naturally occurring TI-2 antigens are characterized by the ability to bind the complement fragments C3d. 9  B cell Activation  Membrane bound antibody have short cytoplasmic tails  Too short to generate signal by associating with tyrosine kinases and G proteins  Membrane Ig must be associated with B-cell receptor Ig-α/Ig-β 10  The initial stages of signal transduction by an activated B-cell receptor (BCR). The BCR comprises an antigen-binding mIg and one signal-transducing Ig-α/Ig-β heterodimer. Following antigen crosslinkage of the BCR, the immunoreceptor tyrosine-based activation motifs (ITAMs) interact with several members of the Src family of tyrosine kinases (Fyn, Blk, and Lck), activating the kinases. 11 B cell Activation 12 TH cells play essential role in B cell repsonse 13  TEM of interaction between B cell and T cell 15 In vivo sites for induction of humoral responses When an antigen is introduced into the body, it becomes concentrated in various peripheral lymphoid organs: Blood-borne antigen is filtered by spleen Antigen from tissue spaces filtered by lymph nodes  Antigen or antigen-antibody complexes enter the lymph nodes either alone or associated with antigen transporting cells (e.g., Langerhans cells or dendritic cells ) and macrophages.  Antigenic challenge leading to a humoral immune response involves a complex series of events, which take place within a lymph node.  Once antigen-mediated B-cell activation takes place, small foci of proliferating B cells form at the edges of the T-cell–rich zone. These B cells differentiate into plasma cells secreting IgM and IgG isotypes.  After few days the activated B cells with Th cells leave the foci to the primary follicles that then developed to secondary follicles. All the activated cells migrate to the center of secondary follicles forming germinal center. 16 T cells are green and B cells are red 18 Germinal Centers and Antigen- Induced B-Cell Differentiation  Germinal centers arise within 7-10 days after initial exposure to thymus-dependent antigen in lymph node  During the first stage of germinal-center formation, activated B cells undergo intense proliferation.  Three important B-cell differentiation events take place in germinal centers: Affinity maturation Class switching Formation of plasma and memory B cells 19  Overview of cellular events within germinal centers.  Antigen-stimulated B cells migrate into germinal centers, where they reduce expression of surface Ig and undergo rapid cell division and mutation of rearranged immunoglobulin V region genes within the dark zone.  Subsequently, division stops and the B cells migrate to the light zone and increase their expression of surface Ig. At this stage they are called centrocytes.  Within the light zone centrocytes must interact with follicular dendritic cells and T helper cells to survive.  Follicular dendritic cells bind antigen-antibody complexes along their long extensions and the centrocytes must compete with each other to bind antigen. 20  Cellular events within germinal centers, Cont”.  B cells bearing high-affinity membrane immunoglobulin are most likely to compete successfully.  Those that fail this antigen-mediated selection die by apoptosis.  B cells that pass antigen selection and receive a second survival signal from TH cells differentiate into either memory B cells or antibody-secreting plasma cells.  The encounter with TH cells may also induce class switching.  A major outcome of the germinal center is to generate higher affinity B cells (Ka2) from B cells of lower affinity ( Ka1). 21  Cellular events in germinal centers 3 events in germinal centers Affinity maturation Class switching Formation of plasma and memory B cells Class Switching Dependent on:  cytokines to switch from IgM to other isotype  Thymus-dependent antigens Interaction of CD40 on B cell and CD40L on T cell is essential for the induction of class switching. The importance this interaction is illustrated by the X-linked hyper-IgM syndrome, an immunodeficiency disorder in which TH cells fail to express CD40L. Patients with this disorder produce IgM but not other isotypes. Such patients fail to generate memory cell populations, fail to form germinal centers, and their antibodies 24 25  The Humoral Response The humoral immune response is carried out by antibodies, which are produced by activated B-cells.  Primary and Secondary Responses Differ Significantly  a primary response to antigen is characterized by a lag phase, during which naive B cells undergo clonal selection, subsequent clonal expansion, and differentiation into memory cells or plasma cells  The memory B cells formed during a primary response stop dividing and enter the G0 phase of the cell cycle. Activation of memory cells by antigen results in a secondary antibody response that can be distinguished from the primary response in several ways 26 28 The presence of antibody can suppress response to antigen: antibody exerts feedback inhibition on its own production. Because of antibody mediated suppression, certain vaccines (e.g., those for measles and mumps) are not administered to infants before the age of 1 year. The level of naturally acquired maternal IgG, which the fetus acquires by trans-placental transfer, remains high for about 6 months after birth. If an infant is immunized with measles or mumps vaccine while this maternal antibody is still present, the humoral response is low and the production of memory cells is inadequate to confer long-lasting immunity 29 Regulation of the Immune Effector Response  Humoral and cell-mediated branches must be heavily regulated  Upon encountering an antigen, the immune system can either develop an immune response or enter a state of unresponsiveness called tolerance.  Cytokines play important role  Antigenic competition Previous encounter with antigen can render animal tolerant or may result in formation of memory cells 30  Major Histocompatibility Complex chapter 8 Introduction Antibodies can recognize antigen alone while T-cell receptors can only recognize antigen that has been processed and presented by Major Histocompatibility Complex (MHC) that involves, antigen processing and antigen presentation. Every mammalian species possesses a tightly linked cluster of genes, the major histocompatibility complex (MHC), whose products play roles in intercellular recognition and in discrimination between self and nonself antigens. The MHC participates in the development of both humoral and cell mediated immune responses.  Work carried out in the 1940s and 1950s by Gorer and George Snell established that antigens encoded by the genes in the group took part in the rejection of transplanted tumors and other tissue. Snell called these genes “histocompatibility genes”; their current designation as histocompatibility-2 (H-2) in mouse and in humans they are called Major Histocompatibility Complex (MHC). The concept that the rejection of foreign tissue is the result of an immune response to cell-surface molecules, now called histocompatibility antigens, originated from the work of Peter Gorer in the mid-1930s. General Organization and Inheritance of the MHC The major histocompatibility complex is a collection of genes arrayed within a long continuous stretch of DNA on chromosome 6 in humans and on chromosome 17 in mice. The MHC is referred to as the Human Leukocyte Antigens HLA complex in humans and as the H-2 complex in mice. MHC genes are organized into regions encoding three classes of molecules: 1. Class I MHC genes 2. Class II MHC genes 3. Class III MHC genes  Class I MHC genes encode glycoproteins expressed on the surface of nearly all nucleated cells; the major function of the class I gene products is presentation of peptide antigens to Tc cells. Class II MHC genes encode glycoproteins expressed primarily on antigen-presenting cells (macrophages, dendritic cells, and B cells), where they present processed antigenic peptides to Th cells. Class III MHC genes encode, in addition to other products, various secreted proteins that have immune functions, including components of the complement system C4, C2, BF and inflammatory cytokines, including tumor necrosis factor (TNF) and heat-shock proteins.  Class I MHC molecules encoded by the regions A, B, and C loci in humans that are called classical genes. Also they encode the non classical genes as (HLA-F, - G, -H, -X, -E, -J). class II MHC molecules are encoded by the DP, DQ, and DR regions in humans. Class III products include the complement components C4, C2, BF, and inflammatory cytokines, including tumor necrosis factor (TNF) and heat-shock proteins.  Human Class I MHC are red Telomeric end of HLA complex Class II MHC are blue Centromeric end of HLA complex Organization of the major histocompatibility complex (MHC) in the mouse and human General features of MHC Genes MHC class I and class II genes, encode two groups of structurally distinct but homologous proteins. Class I molecules present peptides and recognized by CD8 T cells, and class II present peptides to CD4 T cells. The two types of MHC (class I and class II) genes are highly polymorphic genes present in the genome of every species analyzed; that is, many alternative forms of the gene, or alleles, exist at each locus among the population. MHC genes are codominantly expressed in each individual, both maternal and paternal gene products are expressed in the same cells.  HLA INHERETENCE They are inherited as a unit that called haplotype (it’s the set of MHC alleles present on each chromosome). HLA genes are codominantly expressed in each individual. Each individual expresses the MHC alleles on both chromosomes that are inherited from both parents. MHC Molecules general features Class I and class II MHC molecules are membrane-bound glycoproteins that are closely related in both structure and function. Each MHC molecule consist of an extracellular peptide-binding cleft, or groove, followed by a pair of immunoglobulin Ig-like domains and anchored to the cell by transmembrane and cytoplasmic tail. The polymorphic residues of MHC molecules are located in and adjacent to peptide-binding cleft. The nonpolymorphic Ig-like Class I MHC Class I MHC molecules composed of two polypeptide chains the α chain that called heavy chain associated noncovalently β2- macroglobulin molecule that called light chain. The interaction between α1 and α2 domain form what is called peptide binding cleft, where the antigen is located and this is the most polymorphic residue of the molecule. This peptide-binding cleft is located on the top surface of the class I MHC molecule, and it is large enough to bind a peptide of 8–10 amino acids. α3 domain it has the binding site of CD8 T cell receptor. Class II Molecules Class II MHC molecules contain two heavy polypeptide chains, a α chain and a β chain. Both α1 and β 1 domain interact to form the peptide binding cleft for processed antigen. In class II molecules, the ends of the peptide-binding cleft are open, so that peptides of 30 residues or more can fit. The β2 domain has the binding site of CD4 T cells receptors. Peptide Interactions with MHC 16 Cellular Distribution of MHC Molecules In general, the classical class I MHC molecules are expressed on most nucleated cells, but the level of expression differs among different cell types. The highest levels of class I molecules are expressed by lymphocytes. In contrast, fibroblasts, muscle cells, liver hepatocytes, and neural cells express very low levels of class I MHC molecules. Because of individual allelic differences in the peptide-binding clefts of the class I MHC molecules, different individuals within a species will have the ability to bind different sets of viral peptides. Unlike class I MHC molecules, class II molecules are expressed constitutively only by antigen-presenting cells, primarily macrophages, dendritic cells, and B cells; thymic epithelial cells and some other cell types can be induced to express class II molecules and to function as antigen- presenting cells under certain conditions and under stimulation of some cytokines. MHC Restriction CD8+ Tc cells are MHC Class I restricted Can only recognize antigen presented by MHC Class I molecules Therefore, cells with MHC Class I are called “target cells”, killed by cytotoxic T cells CD4+ TH cells are MHC Class II restricted Cells with MHC Class II are called antigen-presenting cells (APCs) Antigen Processing and Presentation The formation of these peptide-MHC complexes requires that a protein antigen be degraded into peptides by a sequence of events called antigen processing. The degraded peptides then associate with MHC molecules within the cell interior, and the peptide-MHC complexes are transported to the membrane, where they are displayed (antigen presentation). Class I MHC molecules bind peptides derived from endogenous antigens that have been processed within the cytoplasm of the cell (e.g., normal cellular proteins, tumor proteins, or viral and bacterial proteins produced within infected cells). Class II MHC molecules bind peptides derived from exogenous antigens that are internalized by phagocytosis or endocytosis and processed within the endocytic pathway. Self-MHC Restriction of T Cells Both CD4 and CD8 T cells can recognize antigen only when it is presented by a self-MHC molecule, an attribute called self-MHC restriction. so, antigen recognition by the CD4 Th cell is class II MHC restricted, and antigen recognition by CD8 Tc cells is class I MHC restricted. Major Histocompatibility Complex (MHC) that involves: antigen processing antigen presentation Processing and Presentation of Antigen Different experiments suggest that antigen processing is a metabolic process that digests proteins into peptides, which can then be displayed on the cell membrane together with a class I or class II MHC molecule. cells that display peptides associated with class I MHC molecules to CD8 Tc cells are referred to as target cells; Because nearly all nucleated cells express class I MHC molecules, virtually any nucleated cell is able to function as a target cell presenting endogenous antigens to Tc cells. Most often, target cells are cells that have been infected by a virus or some other intracellular microorganism. cells that display peptides associated with class II MHC molecules to CD4 Th cells are called antigen-presenting cells (APCs). APCs present antigens to naïve T cells during the recognition phase of immune responses.  Three cell types are classified as professional antigen-presenting cells: dendritic cells, macrophages, and B lymphocytes. These cells differ from each other in their mechanisms of antigen uptake: Dendritic cells are the most effective of the APCs. Because these cells express a high level of class II MHC molecules and they can activate naive Th cells. Macrophages must be activated by phagocytosis of particulate antigens before they express class II MHC molecules the co- stimulatory B7 membrane molecules. B cells constitutively express class II MHC molecules but must be activated before they express the co-stimulatory B7 molecule. Antigen Presenting Pathways The immune system uses two different pathways to eliminate intracellular and extracellular antigens. 1. Endogenous antigens (those generated within the cell) are processed in the cytosolic pathway and presented on the membrane with class I MHC molecules to Tc cells; Endogenous antigens are degraded into peptides within the cytosol by proteasomes and assemble with class I molecules in the RER. 2. Exogenous antigens (those taken up by endocytosis) are processed in the endocytic pathway and presented on the membrane with class II MHC molecules to TH cells. Exogenous antigens are internalized and degraded within the acidic endocytic compartments and subsequently pair with class II molecules.  Cell-Mediated Effector Responses chapter 14 Introduction The effectors of the humoral branch are secreted antibodies, highly specific molecules that can bind and neutralize antigens on the surface of cells and in the extracellular spaces. The principal role of cell-mediated immunity is to detect and eliminate cells that harbor intracellular pathogens. Cell-mediated immunity also can recognize and eliminate cells, such as tumor cells, that have undergone genetic modifications so that they express antigens not typical of normal cells. Both antigen-specific and -nonspecific cells can contribute to the cell- mediated immune response. Specific cells include CD8+cytotoxic T lymphocytes (TC cells or CTLs) and cytokine-secreting CD4+ TH cells that mediate delayed-type hypersensitivity (DTH). Nonspecific cells include NK cells and non lymphoid cell types such as macrophages, neutrophils, and eosinophils. Effector Responses Cell-mediated immune responses can be divided into two major categories according to the different effector populations that are mobilized. effector cells that have direct cytotoxic activity. The various cytotoxic effector cells can be grouped into two general categories: one comprises antigen-specific cytotoxic T lymphocytes (CTLs) and nonspecific cells, such as natural killer (NK) cells and macrophages. The other group is a subpopulation of effector CD4+ T cells that mediates delayed-type hypersensitivity reactions(DTH). Cytotoxic T Cells Cytotoxic T lymphocytes, or CTLs, are generated by immune activation of T cytotoxic (TC) cells. These effector cells have lytic capability and are critical in the recognition and elimination of altered self-cells (e.g., virus-infected cells and tumor cells) and in graft- rejection reactions. In general, CTLs are CD8+ and are therefore class I MHC restricted. Since all nucleated cells in the body express class I MHC molecules, CTLs can recognize and eliminate almost any altered body cell.  The CTL-mediated immune response can be divided into two phases, reflecting different aspects of the response. The first phase activates and differentiates naive TC cells into functional effector CTLs. In the second phase, effector CTLs recognize antigen–class I MHC complexes on specific target cells, which leads them to destroy the target cells. The first phase Naive TC cells are incapable of killing target cells (infected cells/tumor cell) and are therefore referred to as CTL precursors (CTL-Ps). Generation of CTLs from CTL-Ps appears to require at least three sequential signals: 1. An antigen-specific signal 1 transmitted by the TCR complex upon recognition of a peptide–class I MHC molecule complex. 2. A co-stimulatory signal transmitted by the CD28-B7 interaction of the CTL-P and the target cell. 3. The third signal induced by the interaction of IL-2 with the high-affinity IL-2 receptor, resulting in proliferation and differentiation of the antigen- activated CTL-P into effector CTL. TH cell provide the IL-2 necessary for proliferation of an antigen-activated CTL-P when it binds to the APC. Generation of effector CTLs from precursor CTLs The second phase The primary events in CTL-mediated death are conjugate formation, membrane attack, CTL dissociation, and target cell destruction. T-cell receptors on a CTL interact with processed antigen-class I MHC complexes on an appropriate target cell, leading to formation of a CTL/target-cell conjugate. The Golgi stacks and granules in the CTL reorient towards the point of contact with the target cell, and the granule’s contents are released by exocytosis. The two granule proteins that are important for cytolysis are perforin and granzymes. After dissociation of the conjugate, the CTL is recycled and the target cell dies by apoptosis. Stages in CTL-mediated killing of target cells Three mechanisms of CTLs to kill the target cell 1. By using perforin: perforin is exocytosed in CLT granules and polymerizes in the target cell membrane to form pores that allow the entry of water and ions and result in target cell death. 2. By granzymes: granzymes are exocytosed in CTL granules, enter target cells through perforin pores and induce target cell apoptosis. Both 1+2 mechanisms called apoptosis by osmotic lysis of cell. 3. By using Fas ligands (FasL): FasL is expressed on activated CTLs, engages Fas on the surface of target cells and induce apoptosis. Natural Killer Cells (NK) The cells, which were named natural killer (NK) cells for their nonspecific cytotoxicity, make up 5%–10% of the recirculating lymphocyte population. These cells are involved in immune defenses against viruses and tumors. NK cells produce a number of immunologically important cytokines, they play important roles in immune regulation and influence both innate and adaptive immunity. NK activity is stimulated by IFN-α, IFN-β, and IL-12. NK cells are the first line of defense against virus infection, controlling viral replication during the time required for activation, proliferation, and differentiation of CTL-P cells into functional CTLs at about day 7.  Natural killer cells appear to kill tumor cells and virus infected cells by processes similar to those employed by CTLs. NK cells bear FasL on their surface and readily induce death in Fas- bearing target cells. The cytoplasm of NK cells contains numerous granules containing perforin and granzymes. After an NK cell adheres to a target cell, degranulation occurs with release of perforin and granzymes at the junction of the interacting cells. The roles of perforin and granzymes in NK-mediated killing of target cells by apoptosis are believed to be similar to their roles in the CTLmediated process. The NK-cell response generates no immunologic memory. NK Cells Have Both Activation and Inhibition Receptors NK cells do not express antigen-specific receptors, instead NK cells employ two different categories of receptors, one that delivers inhibition signals to NK cells, and another that delivers activation signals. opposing-signals model: It is the balance between activating signals and inhibitory signals that is believed to enable NK cells to distinguish healthy cells from infected or cancerous ones. This balance allows NK to distinguish between self and nonself. C-type lectin, CD2, and CD16 kind of receptors found on NK cells that has activation properties. three additional proteins, NKp30, NKp44, and NKp46, appear to play significant roles in the activation of human NK cells.  Two major groups of inhibitory receptors have been found on NK cells. One of these is a family of C-type-lectin–inhibitory receptors (CLIR) as CD94/NKG2. The other is a group of Ig superfamily–inhibitory receptors (ISIR) known as the killer cell–inhibitory receptors (KIR). Because signals from inhibitory receptors have veto power type, can block the lysis of target cells by NK cells over signals from activating receptors, a negative signal from any inhibitory receptor, whether of the CD94/NKG2 or KIR.  Receiving both inhibitory and activating signals Only receiving activating signal NK cells do not have capability of recognizing MHC and antigen like T cell; they recognize altered cell surface molecules, possibly lowered Class I MHC 17 Opposing-signals model of how cytotoxic activity of NK cells is restricted to altered self-cells. An activation receptor (AR) on NK cells interacts with its ligand on normal and altered self-cells, inducing an activation signal that results in killing. However, engagement of inhibitory NK cell receptors such as KIR and CD94/NKG2 by class I MHC molecules delivers an inhibitory signal that counteracts the activation signal. Expression of class I molecules on normal cells thus prevents their destruction by NK cells. class I expression is often decreased on altered self-cells, the killing signal predominates, leading to their destruction. NK cells are activated by recognition of three types of target cells 1. ADCC 2. they can bind to the target cell by adhesion molecules and other unknown ligands. 3. activated by target cell lacking class I MHC complex molecules. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Among the cells that can mediate ADCC are NK cells, macrophages, monocytes, neutrophils, and eosinophils. Antibody-dependent cell-mediated cytotoxicity (ADCC). Nonspecific cytotoxic cells are directed to specific target cells by binding to the Fc region of antibody bound to surface antigens on the target cells. Various substances (e.g., lytic enzymes, TNF, perforin, granzymes) secreted by the nonspecific cytotoxic cells then as a result of recognition NK cells lyse target cell mediate target cell destunction.  Cell-mediated immunity Humoral immunity It’s the mechanism of defense It’s the mechanism of defense against against intracellular microbes that extracellular microbes and their toxins. either survive in phagocytes or Mediated by antibodies produced by infect non phagocytic cells. lymphocyte. Mediated by T cells. B cells activated by 2 type of cell-mediated reaction 1. protein antigens with signals provided by helper T cells (CD40) and cytokines 1. T cells of both CD4 and CD8 receptors stimulate the proliferation recognize peptide antigens of and differentiation into antibody- phagocytosed microbes and producing cells. activate the phagocytes to destroy the microbes. 2. By nonprotein antigens, without requirement for t cell help. 2. CD8 Cytolytic T cells (CLTs) Differentiated B cells eliminate microbes recognize peptide antigen of by various mechanisms as opsonization microbes in the cytosol of cells and phagocytosis or complement and kill the infected cells. activation. Vaccination chapter 18 1 Active and Passive Immunization Immunity to infectious microorganisms can be achieved by active or passive immunization. Immunity can be acquired either by natural processes (usually by transfer from mother to fetus or by previous infection by the organism) or by artificial means such as injection of antibodies or vaccines 2 3 Passive immunization, in which preformed antibodies are transferred to a recipient, occurs naturally by transfer of maternal antibodies across the placenta to the developing fetus. Maternal antibodies to many microorganisms like diphtheria, tetanus, streptococci, rubella, mumps, and poliovirus all afford passively acquired protection to the developing fetus. Maternal antibodies present in colostrum and milk also provide passive immunity to the infant Passive immunization can also be achieved by injecting a recipient with preformed antibodies. Because passive immunization does not activate the immune system, it generates no memory response and the protection provided is transient 4  Conditions that require the use of passive immunization: Deficiency in synthesis of antibody as a result of congenital or acquired B-cell defects, alone or together with other immunodeficiencies. Exposure or likely exposure to a disease that will cause complications or when time does not permit adequate protection by active immunization (immunocompromised patients exposed to microorganisms) Infection by pathogens whose effects may be ameliorated by antibody. For example, if individuals who have not received up-to-date active immunization against tetanus suffer a puncture wound. 5 6 Unlike passive immunization that provide transient protection or alleviation of an existing condition, the goal of active immunization is to elicit protective immunity and immunologic memory. Active immunization can be achieved by natural infection with a microorganism, or it can be acquired artificially by administration of a vaccine. the immune system plays an active role—proliferation of antigen-reactive T and B cells results in the formation of memory cells. 7 8 9 * 10  Designing Vaccines for Active Immunization Several factors must be kept in mind in developing a successful vaccine. 1. The development of an immune response does not necessarily mean that a state of protective immunity has been achieved. Which branch of the immune system is activated, vaccine designers must recognize the important differences between activation of the humoral and the cell-mediated branches. 2. The need to develop of immunologic memory. The role of memory cells in immunity depends, in part, on the incubation period of the pathogen. 11 12 1. Whole-Organism Vaccines A. Attenuated Viruses and Bacteria Microorganisms can be attenuated so that they lose their ability to cause significant disease (pathogenicity) but retain their capacity for transient growth within an inoculated host. Provide prolonged immune-system exposure to the individual epitopes on the attenuated organisms, resulting in increased immunogenicity and production of memory cells e.g. measles, mumps, and rubella (MMR), tuberculosis 13 14 15 B. Inactivated whole Pathogenic Organisms Inactivation of the pathogen by heat or by chemical means so that it is no longer capable of replication in the host. It is critically important to maintain the structure of epitopes on surface antigens during inactivation. Heat inactivation would denature proteins, chemical inactivation requires the use of formaldehyde. It elicits only humoral immune response, booster doses are required e.g. cholera, influenza , hepatitis A, plague 16  2. Purified Macromolecules as Vaccines A. Bacterial Polysaccharide Capsules  The virulence of some pathogenic bacteria depends primarily on the antiphagocytic properties of their hydrophilic polysaccharide capsule. Coating of the capsule with antibodies and/ or complement greatly increases the ability of macrophages and neutrophils to phagocytose such pathogens. These findings provide the rationale for vaccines consisting of purified capsular polysaccharides. Streptococcus pneumonia (pneumococcal pneumonia) and Neisseria meningitides (meningitis). One limitation of polysaccharide vaccines is their inability to activate T cells. They activate B cells in a thymus independent H type 2 (TI-2). No class switching and no memory cells. 17 Haemophilus influenzae type b (Hib) vaccine  is a conjugate vaccine that combines the polysaccharide antigen to some sort of protein carrier  It is more immunogenic than the polysaccharide alone, and because it activates TH cells, it enables class switching from IgM to IgG  Although this type of vaccine can induce memory B cells, it cannot induce memory T cells specific for the pathogen. 18 19 The vaccine is prepared by conjugating the surface polysaccharide of Hib to a protein molecule 20 B. Toxoids  Some bacterial pathogens, including those that cause, diphtheria and tetanus vaccines, can be made by purifying the bacterial exotoxin and then inactivating the toxin with formaldehyde to form a toxoid.  Vaccination with the toxoid induces anti-toxoid antibodies, which are also capable of binding to the toxin and neutralizing its effects.  Large quantities of the exotoxin can be produced, purified, and subsequently inactivated by recombinant DNA technology. 21 C. Proteins from Pathogens Produced by Recombinant Techniques  Recombinant DNA technology has been used to successfully produce vaccines for a number of genes encoding surface antigens from viral, bacterial, and protozoan pathogens. The first such recombinant antigen vaccine approved for human use is the hepatitis B vaccine. Cloning the gene for the major surface antigen of hepatitis B virus (HBsAg) and expressing it in yeast cells. The yeast cells are harvested and disrupted by high pressure, releasing the recombinant HBsAg, which is then purified by conventional biochemical techniques. 22 Recombinant-Vector Vaccines  Genes that encode major antigens of especially virulent pathogens can be introduced into attenuated viruses or bacteria. The attenuated organism serves as a vector, replicating within the host and expressing the gene product of the pathogen.  Vaccinia virus, the attenuated vaccine used to eradicate smallpox, has been widely employed as a vector vaccine. This large, complex virus, with a genome of about 200 genes, can be engineered to carry several dozen foreign genes without impairing its capacity to infect host cells and replicate. The genetically engineered vaccinia expresses high levels of the inserted gene product, which can then serve as a potent immunogen in an inoculated host. 23 Production of vaccinia vector vaccine.  The gene that encodes the desired antigen is inserted into a plasmid vector adjacent to a vaccinia promoter and flanked on either side by the vaccinia thymidine kinase (TK) gene.  When tissue culture cells are incubated simultaneously with vaccinia virus and the recombinant plasmid, the antigen gene and promoter are inserted into the vaccinia virus genome by homologous recombination at the site of the nonessential TK gene, resulting in a TKrecombinant virus.  Cells containing the recombinant vaccinia virus are selected by addition of bromodeoxyuridine (BUdr), which kills TK cells. 24 26 DNA Vaccines plasmid DNA encoding antigenic proteins is injected directly into the muscle of the recipient. Muscle cells take up the DNA and the encoded protein antigen is expressed, leading to both a humoral antibody response and a cell-mediated response. The encoded protein is expressed in the host in its natural form—there is no denaturation or modification. The immune response is therefore directed to the antigen exactly as it is expressed by the pathogen. DNA vaccines also induce both humoral and cell-mediated immunity; DNA vaccines cause prolonged expression of the antigen, which generates significant immunological memory. 27 28 29 hypersensitivity reaction Chapter 16 Introduction An immune response mobilizes a battery of effector molecules that act to remove antigen by various mechanisms described in previous chapters. Generally, these effector molecules induce a localized inflammatory response that eliminates antigen without extensively damaging the host’s tissue. This inflammatory response can have deleterious effects, resulting in significant tissue damage or even death. This inappropriate immune response is termed hypersensitivity or allergy. Hypersensitivity Reactions May develop in course of humoral OR cell-mediated response Immediate hypersensitivity Anaphylactic Initiated by antibody-antigen complexes Symptoms manifests in minutes Delayed-type hypersensitivity May occur in days  There are four types of hypersensitivity: (1) immediate hypersensitivity (Type-I) (2) Cytotoxic hypersensitivity (Type-II) (3) Immune complex hypersensitivity (Type-III) (4) Delayed or cell-mediated hypersensitivity (Type-IV) 4 Type I – IgE-Mediated Hypersensitivity Induced by antigens referred to as allergens Induces humoral response but induces high secretion of IgE Fc portion of IgE binds with Fc receptors on mast cells and basophils. Mast cells and basophils coated by IgE are said to be sensitized. Allergen cross-links the membrane-bound IgE on sensitized mast cells and basophils, causing degranulation of these cells.  Common components of type I  Allergens ○ Atopy: hereditary predisposition to development of immediate hypersensitivity reactions to common environmental antigens ○ Allows nonparasitic antigens to induce IgE response The term allergen refers specifically to nonparasitic antigens capable of stimulating type I hypersensitive responses in allergic individuals.  IgE ○ Normally lowest of all antibody classes in serum ○ Half-life is 2-3 days but once bound to mast cells or basophils, can last for weeks  The cells that bind IgE are mast cells and basophils IgE binding receptors: The reaginic activity of IgE depends on its ability to bind to a receptor specific for the Fc region of the ε heavy chain ○ High affinity receptors (FCεRI) Low affinity receptors (FCεRII): activate B cells, alveolar macrophages, and eosinophils. IgE cross-linkage initiates degranulation IgE-mediated degranulation begins when an allergen crosslinks IgE that is bound (fixed) to the Fc receptor on the surface of a mast cell or basophil. Once cross-linkage of antigen has occurred, intracellular signaling result in mast cell degranulation ○ Cooperation among protein and lipid kinases, phosphatases, rearrangement of the cytoskeleton and Ca++ influx. The increase of Ca2+ promotes the assembly of microtubules and the contraction of microfilaments, both of which are necessary for the movement of granules to the plasma membrane. The importance of the Ca2+ increase in mast-cell degranulation is high lighted by the use of drugs, such as disodium cromoglycate (cromolyn sodium), that block this influx as a treatment for allergies. Pharmacologic agents that mediate Type I Primary mediators Are produced before degranulation and are stored in the granules The most significant primary mediators are: Histamine, proteases, eosinophil chemotactic factor, heparin. Early phase 2-3 min. to 6 hr. Secondary mediators either are synthesized after target-cell activation or are released by the breakdown of membrane phospholipids during the degranulation process. Include: Platelet-activating factor, leukotrienes, prostaglandins, bradykinins, some cytokines and chemokines. Late phase 6 hr. - 24 hr. Histamine Formed by decarboxylation of amino acid Histidine Major component of granules accounting for about 10% of granule weight. Because it is stored—preformed—in the granules, it’s biological effect effects observed in minutes. Contraction of smooth muscle (intestinal and bronchial), increase permeability of venules, increased mucus secretion by goblet cells Leukotrienes and prostaglandins As secondary mediators, the leukotrienes and prostaglandins are not formed until the mast cell undergoes degranulation and the enzymatic breakdown of phospholipids in the plasma membrane. It therefore takes a longer time for the biological effects Their effects are more pronounced and longer lasting, however, than those of histamine. Bronchoconstriction, vascular permeability, mucus production CYTOKINES: Human mast cells secrete IL-4, IL-5, IL-6, and TNF-α. These cytokines alter the local microenvironment, eventually leading to the recruitment of inflammatory cells such as neutrophils and eosinophils. Type 1 can be systemic or localized Type 1 can be systemic or localized 1. Systemic anaphylaxis:  It is a shock like and often fatal, Quick (starts within minutes).  It is usually initiated by an allergen introduced directly into the bloodstream or absorbed into the circulation from the gut or skin.  It starts as sudden skin redness and intense itching and hives.  Symptoms include a precipitous drop in blood pressure leading to anaphylactic shock, followed by contraction of smooth muscles leading to defecation, urination, and bronchiolar constriction causing labored respiration.  Within minutes, if the allergen is inhaled or ingested, the airways will be severely constricted and the patient might die of suffocation. If the allergen enters through skin, anaphylactic shock will be produced through vasodilation and severe drop in blood pressure leading to death. E.g. venom from bee, wasp, hornet, and ant stings; drugs such as penicillin, insulin; foods such as seafood and nuts; and latex. 2. Localized Hypersensitivity Reactions (atopy) The reaction is limited to specific target tissue or organ, usually involving the epithelial surface of the site of allergen entry. It’s include: 1. Allergic Rhinitis , commonly known as , “hay fever”. The symptoms include watery exudation of the conjunctivae, nasal mucosa, and upper respiratory tract, as well as sneezing and coughing. 2. Asthma: Like hay fever, allergic asthma (extrinsic asthma) is triggered by degranulation of mast cells with release of mediators, but instead of occurring in the nasal mucosa, the reaction develops in the lower respiratory tract. The asthmatic response can be divided into early and late responses. The early response occurs within minutes of allergen exposure and primarily involves histamine, leukotrienes (LTC4), and prostaglandin (PGD2). The effects of these mediators lead to bronchoconstriction, vasodilation, and some buildup of mucus. The late response occurs hours later and involves additional mediators, including IL-4, IL-5, IL- 16,TNF-α. It recruits inflammatory cells, including eosinophils and neutrophils, into the bronchial tissue. In other individuals an asthma attack can be induced by exercise or cold, independently of allergen stimulation (intrinsic asthma). 3. Food allergies: Allergen crosslinking of IgE on mast cells along the upper or lower gastrointestinal tract can induce localized smooth-muscle contraction and vasodilation and thus such symptoms as abdominal pain vomiting and/or diarrhea. Mast-cell degranulation along the gut can increase the permeability of mucous membranes, so that the allergen enters the bloodstream. 4. Atopic dermatitis (allergic eczema) is an allergic inflammatory disease of skin, that is frequently associated with a family history of atopy. The affected individual develops a rash, erythematous (red) skin eruptions that can fill with pus if there is an accompanying bacterial infection. The skin lesions in atopic dermatitis contain Th 2 cells and an increased number of eosinophils. Clinical Methods to detect Type 1 Type I hypersensitivity is commonly identified and assessed by skin testing. Small amounts of potential allergens are introduced at specific skin sites either by intradermal injection or by superficial scratching. If a person is allergic to the allergen, local mast cells degranulate and the release of histamine and other mediators produces a wheal and flare within 30 min. Another method of assessing type I hypersensitivity is to determine the serum level of total IgE antibody by the radio immunosorbent test (RIST), highly sensitive technique, based on the radioimmunoassay levels of IgE.  Type I Hypersensitivities Can Be Controlled: 1. Avoiding contact with known allergens. Often the removal of house pets, dust-control measures, or avoidance of offending foods can eliminate a type I response. 2. Immunotherapy includes: Desensitization: Subcutaneous injections of allergens causes shift to IgG production instead of IgE. IgG competes for the allergen, binds to it, and forms a complex that can be removed by phagocytosis. Oral immunotherapy (OIT) consists of feeding children gradually increasing doses (beginning with extremely small amounts) of the food allergens with the goal of establishing desensitization. Monoclonal anti-human IgE: These antibodies bind to IgE, but only if IgE is not already bound to FcRI. Omalizumab, has been approved by the U.S. Food and Drug Administration. Omalizumab binds the Fc region of IgE and prevents the IgE from binding to FcεRI and triggering mast cell degranulation. 20  3. Drug therapies 21  3. Drug therapies Allergic rhinitis (Antihistamines, Leukotriene antagonists); Leukotriene antagonists. skin allergic reactions (such as for insect bites), topical creams (usually hydrocortisone) are available over-the-counter Asthma attacks: corticosteroids (often just referred to as steroids) Inhalation therapy with low-dose corticosteroids such as Flonase and Nasacort (now available without a prescription) reduces inflammation by inhibiting innate immune cell activity and has been used successfully to reduce the frequency and severity of asthma attacks. Also available as pills or liquids (ingested corticosteroids usually require prescriptions) can cause side effects. Epinephrine agonists like albuterol, do this by binding to G protein–coupled receptors, which initiate signals that generate cAMP. Theophylline, another commonly used drug in the treatment of asthma, does this by antagonizing phosphodiesterase (PDE), an enzyme that normally breaks down cAMP Type II -Antibody-Mediated Cytotoxic Hypersensitivity Type II hypersensitivity reactions involve antibody-mediated destruction of cells by IgG and IgM immunoglobulins. Antibody bound to a cell-surface antigen can induce death of the antibody bound cell by three distinct mechanisms. First, certain immunoglobulin subclasses can activate the complement system, creating pores in the membrane of a foreign cell. Second, antibodies can mediate cell destruction by antibody-dependent cell-mediated cytotoxicity (ADCC), in which cytotoxic cells bearing Fc receptors bind to the Fc region of antibodies on target cells and promote killing of the cells. Finally, antibody bound to a foreign cell also can serve as an opsonin, enabling phagocytic cells with Fc receptors or (after complement has been activated by the bound antibodies) receptors for complement fragments such as C3b to bind and phagocytose the antibody-coated cell.   Examples of type II hypersensitivity: Mismatched blood transfusion. Hemolytic disease of the newborn. Certain drug induced hypersensitivity. It can also be seen in certain viral infections and in rheumatoid fever. 24   Mismatched blood transfusion. (Transfusion reactions are Type II Reactions) Different genes encode for many proteins and glycoproteins in blood, those would be different from person to person. RBCs have different antigen, but the most important are A and B antigens (used for blood grouping ABO). Blood groups are named according to the presence of antigens A and B. Blood group A antigen A Blood group B antigen B Blood group AB antigens A, B Blood group O no antigens (A, B) 25  Antibodies to the A, B, and O antigens, called isohemagglutinins, are usually of the IgM class 26 Type II – Antibody-Mediated Cytotoxic Hypersensitivity Individuals have antibodies to blood types not their own IF blood group B is transfused to a patient with blood group A, Antibodies against the antigen B will be produced, mismatched blood transfusion occurs and the patient develops type II hypersensitivity. In transfusion reaction, antibody attaches to RBC and initiates complement system to lyse RBC  After lysis: ○ Hemoglobin detected in plasma, starts to filter through kidneys and found in urine (hemoglobinuria) ○ Hemoglobin converted to bilirubin – toxic at high levels ○ Typical symptoms include: Fever, chills, blood clotting within blood vessels, pain in the lower back  Treatment involves prompt termination of the transfusion and maintenance of urine flow with a diuretic, because the accumulation of hemoglobin in the kidney can cause acute tubular necrosis Reactions that begin immediately are most commonly associated with ABO blood-group incompatibilities, which lead to complement mediated lysis triggered by the IgM isohemagglutinins. Antibodies to other blood-group antigens such as Rh factor may result from repeated blood transfusions because minor allelic differences in these antigens can stimulate antibody production. These antibodies are usually of the IgG class. These incompatibilities typically result in delayed hemolytic transfusion reactions that develop between 2 and 6 days after transfusion. 28  Hemolytic disease of the newborns (erythroblastosis fatalist) Hemolytic Disease of the Newborn Is Caused by Type II Reactions Rh antigen is also found on RBCs so we have either Rh+ or Rh-. If a mother is Rh- and the fetus is Rh+, the fetal blood will cross placenta before or at delivery. These fetal red blood activate Rh-specific B cells, resulting in production of Rh- specific plasma cells and memory B cells in the mother. The secreted IgM antibody clears the Rh+ fetal red cells from the mother’s circulation, but the memory cells remain. Activation of these memory cells in the next pregnancy results in the formation of IgG anti-Rh antibodies, which cross the placenta and damage the fetal red blood cells Administration of anti Rh+ antibodies (Rhogam) to the mother within 24–48 h after the first delivery. These antibodies, bind to any fetal red blood cells that enter the mother’s circulation at the time of delivery and facilitate their clearance before B-cell activation and ensuing memory-cell production can take place.  Drug induced Hemolytic anemia is a Type II Response Certain antibiotics (penicillins,cephalosporins and streptomycin), as well as other well known drugs (including ibuprofen and naproxen), can adsorb nonspecifically to proteins on red blood cell membranes, forming a drug- protein complex. These complexes induce antibody formation and activates complement mediated lysis of RBCs. 31  Type III – Immune complex-mediated hypersensitivity Antibody-antigen complexes are usually removed from blood by phagocytosis. However, large amount of complexes with intermediate size might escape phagocytosis or removal through kidney filtration. After sensitization, these complexes might deposit in different tissues leading to tissue damage reactions (Type III hypersensitivity). 32  Type III can be localized Injection of antigen intradermally or subcutaneously into animal that has high level of antibody for that antigen leads to formation of localized immune complexes, which mediate an acute Arthus reaction within 4–8 h. Inflammation at the site of an Arthus reaction is characterized by swelling and localized bleeding, followed by fibrin deposition. Uncleared immune complexes bind to mast cells, neutrophils, and macrophages via Fc receptors, triggering the release of vasoactive mediators and inflammatory cytokines, which interact with the capillary epithelium and increase the permeability of the blood vessel walls. 33  Development of a localized Arthus reaction (type III hypersensitive  reaction). 1.Complement initiates mast cell degranulation 2.Neutrophils are chemotactically attracted to the site 3.Neutrophils release lytic enzyme after failed attempts to endocytose the immune complex. 4.Leads to tissue damage 35  Type III can be generalized  Serum sickness After receiving antiserum (serum from another animal that may contain antitoxins for treatment, initially during the use of horse anti-diphtheria toxin antibodies in the treatment of diphtheria in the early 1900s) an individual begins to manifest a combination of symptoms that are called serum sickness. These symptoms include fever, weakness, generalized vasculitis (rashes) with edema and erythema, lymphadenopathy, arthritis, and sometimes glomerulonephritis. A more recent manifestation of the same problem occurred in patients who received therapeutic mouse-derived monoclonal antibodies designed to treat cancers. some patients generated their own antibodies against the foreign monoclonals and developed serum sickness–like symptoms. To avoid this response, current therapeutic antibodies are genetically engineered to replace the mouse-specific regions of antibody proteins with the corresponding human sequences (they are then called humanized antibodies) 36  Type III can be generalized Formation of circulating immune complexes contributes to the pathogenesis of a number of conditions other than serum sickness. These include the following:  Autoimmune diseases  Systemic lupus erythmatosis, Rheumatoid arthritis  Drug reactions  Allergy to Penicillin, sulfonamides  Infectious disease Post-streptococcal glomerulonephritis , Meningitis, Hepatitis, Mononucleosis, 37 Malaria, Trypanosomiasis  Type IV – Delayed-type Hypersensitivity (Cell mediated) The reaction develops when antigen activates sensitized TDTH (subpopulation of TH1 and some TC cells). Recent studies indicate that TH 17 and CD8 cells can also play a role. It is a delayed reaction because it takes more than 10 hrs. to be produced. It is important defense mechanism against parasites and bacteria living in host cells. Penicillin is notable in that it can induce all four types of hypersensitivity with various clinical manifestation. 38 39  Overview of the DTH response. (a) In the sensitization phase after initial contact with antigen (e.g., peptides derived from intracellular bacteria), TH cells proliferate and differentiate into TH1 cells. (b) In the effector phase after subsequent exposure of sensitized TH1 cells to antigen, the TH1 cells secrete a variety of cytokines and chemokines. These factors attract and activate macrophages and other non-specific inflammatory cells. Activated macrophages are more effective in presenting antigen, thus perpetuating the DTH response, and function as the primary effector cells in this reaction. 40 Type IV Sensitization phase and Effector phase of DTH  Examples of cell mediated reactions (Type IV) 1. Contact dermatitis: Many contact-dermatitis reactions, including the responses to formaldehyde, trinitrophenol, nickel, turpentine, and active agents in various cosmetics and hair dyes, poison oak, and poison ivy, are mediated by TH1 cells. Most of these substances are small molecules that can complex with skin proteins This complex is internalized by antigen-presenting cells in the skin (e.g., Langerhans cells), then processed and presented together with class II MHC molecules, causing activation of sensitized TH1 cells. Within 4-8 hrs. of the second exposure, the reaction starts and usually maximum at 48 hours 42 Type IV – contact dermatitis  A prolonged DTH response can lead to formation of a granuloma, a nodule- like mass. Lytic enzymes released from activated macrophages in a granuloma can cause extensive tissue damage.  2. Tuberculin Hypersensitivity The presence of a DTH reaction can be measured experimentally by injecting antigen intradermally into an animal / human and observing whether a characteristic skin lesion develops days later at the injection site. Tuberculin is an extract from the cell wall of Mycobacterium tuberculosis, purified protein derivative (PPD) test OR Mantoux test. That is used in skin testing in animals and humans to identify a tuberculosis infection. Development of a red, slightly swollen, firm lesion at the site of injection between 48 and 72 hours later indicates previous exposure. A positive skin-test reaction indicates that the individual has a population of sensitized Th 1 cells specific for the test antigen. 46 Tolerance and Autoimmunity Chapter 20 1  Horror Autotoxicus: Failure of host’s humoral and cellular immune systems to distinguish self from non-self. They result in an inappropriate response of the immune system against self-components termed autoimmunity Autoimmunity Can result in tissue and organ damage, can be fatal 2  Tolerance A number of mechanisms exist to protect individual from self- reactive lymphocytes. Central tolerance – A primary mechanism deletes T or B clones before maturity if they have receptors that recognize self-antigens with great affinity Peripheral tolerance – kills lymphocytes in secondary lymphoid tissue Also, life span of lymphocytes regulated by apoptosis 3 4 5  Peripheral Tolerance May be induced by Treg cells Unique group of CD4+ T cells Recognize self-antigens on immune system cells and seem to be able to suppress immune system Induce cell death in some immune cells Some antigens can produce tolerance and are called tolerogens rather than immunogens Factors promoting tolerance rather than stimulation of the immune system by a given antigen include: High doses of antigen Persistence of antigen in host Absence of adjuvants Low levels of co-stimulators Apoptotic cell death, called clonal anergy (Unresponsiveness to antigenic stimulus) Some self antigens are ignored by the immune system, this form of unresponsiveness is called clonal ignorance. 7   Auto Immunity Auto or Self antigens  Antigens present in ones own cells  Altered by the action of bacteria, viruses, chemicals or drugs as a non-self Auto antibody  Altered cell (Auto Ag) - elicits the productions of Antibody Auto Immunity (misnomer, alternative= auto allergy)  Immune response of auto Ab against self Ag  Humoral or cell mediated immune response against the constitute’s of the body’s own tissues.  There are more than 80 different kinds of diseases caused by autoimmunity. 9  Autoimmune Diseases Autoimmune diseases are a group of disorders in which tissue injury is caused by humoral (by auto-antibodies) or cell mediated immune response (by auto-reactive T cells) to self antigens.  Normally, the immune system does not attack the self -cells. However, there is a large group of autoimmune diseases in which the immune system does attack self-cells  The attack can be directed either against a very specific tissue or to a large no. of tissues  Once started, autoimmune diseases are hard to stop 10  Causes of Autoimmune Diseases 1. Release of Sequestered Antigens Any tissue antigens that are sequestered from the circulation, and are therefore not seen by the developing T cells in the thymus, will not induce self-tolerance. E.g. some Ag sperms after a vasectomy can induce auto-antibody formation in some men. lens protein after eye damage 2. Inappropriate Expression of Class II MHC Molecules Can Sensitize Autoreactive T Cells. E.g. insulin-dependent diabetes mellitus (IDDM). The pancreatic beta cells express high levels of both class I and class II MHC molecules. Graves’ disease have been shown to express class II MHC molecules on the membranes of thyroid acinar cells. 11 3. Polyclonal B-Cell Activation. A number of viruses and bacteria can induce nonspecific polyclonal B-cell activation. E.g. Gram-negative bacteria, cytomegalovirus, and Epstein-Barr virus (EBV). Inducing the proliferation of numerous clones of B cells that express IgM. 4. Genetic factors. Among all the genes that are associated with autoimmunity, the strongest associations are HLA genes, especially class II HLA genes. E.g. rheumatoid arthritis (DR4), IDDM (DR3, DR4, or DR3/DR4) Ankylosing spondylitis (B27) 12  Classification of Autoimmune Diseases Broadly classified into 3 groups 1. Haemolytic autoimmune diseases 2. Localized autoimmune diseases 3. Systemic autoimmune diseases 13 14  Classification of Autoimmune Diseases 1. Haemolytic autoimmune diseases Clinical disorder due to destructions of blood components. Auto Ab are formed against one’s own RBCs, Platelets or Leucocytes. E.g. Haemolytic anaemia, Leucopenia, Thrombocytopenia, etc. 15  Autoimmune Haemolytic anemia Lysis of RBC is due to the production of autoantibodies against the RBC-antigens. RBC half life= 120 days, Haemolytic anaemia