Adaptive Immunity PDF

Antigen-Specific Immun Responses  ◦ There are two types of adaptive immune responses, called humoral immunity and cell-mediated immunity, that are mediated by different components of the immune system and function to eliminate different types of microbes  ◦ A protein or carbonhydrate that...

Antigen-Specific Immun Responses  ◦ There are two types of adaptive immune responses, called humoral immunity and cell-mediated immunity, that are mediated by different components of the immune system and function to eliminate different types of microbes  ◦ A protein or carbonhydrate that is recognized and sufficient to initiate an immune response is called an immunogen ◦ An antigen is a molecule that is recognized by specific antibody or TCR on T cell, and generate a specific response as a foreign structure ◦ An epitope (antigenic determinant) is the actual molecular structure that interacts with a single antibody molecule or TCR  ◦ A protein or carbonhydrate that is recognized and sufficient to initiate an immune response is called an immunogen ◦ Immunogens may contain more than one antigen ◦ Not all molecules are immunogens, but all Antigens are immunogen ◦ In general, proteins are the best immunogens, carbonhydrates are weaker immunogens, and lipids and nucleic acids are poor immunogens  ◦ An epitope (antigenic determinant) is the actual molecular structure that interacts with a single antibody molecule or TCR ◦ Within a protein, an epitope may be formed by a specific sequence ‘ linear epitope’ or a three-dimensional structure ‘ conformational epitope’ ◦ The TCR recognize only linear epitopes ◦ Antigens and immunogens usually contain several epitopes, each capable of binding to a different antibody molecule or TCR Linear Conformational Epitope Epitope  ◦ Haptens (incomplete immunogens) are often too small to immunize (i.e., initiate a response) an individual but can be recognized by antibody ◦ Haptens can be made immunogenic by attachment to a carrier molecule, such as a protein given antigenic structure  ◦ Adjuvants usually prolong the presence of antigen in the tissue, promote uptake of the immunugen or activate DCs, macrophages, and lymphocytes ◦ Some adjuvants mimic the activators (e.g., microbial ligands for Toll-like receptors) present in a natural immunization ◦ During artificial immunization (e.g., vaccines), an adjuvant is used to enhance the response to antigen, however they are not antigens  ◦ Toleance’s meaning unresponsiveness of immun mechanisms ◦ During growth of the fetus, the body develops central immune tolerance toward self-antigens and any foreign antigens that may be introduced before maturation of the immune system ◦ Later in life, peripheral tolerance develops to other proteins to prevent uncontrolled or autoimmune responses ◦ For examle, our immune response is tolerant of the food we eat; alternatively, eating steak would induce antimuscle response ◦ Foreign ◦ Size ◦ Chemical and structural complexity ◦ Genetic constitution (MHC Segregation) ◦ Dosage, route, and timing of antigen ◦ The antigens include the following: 1. Foreignness: Generally, molecules recognized as ‘self’ are not immunugenic; for immunogenicity to occur, molecules must be recognized as ‘nonself’ 2. Size: The most potent immunogens are usually large proteins. In most cases molecules with a molecular weight less than 10.000 are weakly immunogenic, and very small ones (e.g, aminoacids) are nonimmunogenic. Certain small molecules (eg, haptens) become immunogenic only when linked to carrier protein  3. Chemical and structural complexity: A certain amount of chemical complexity is required. For example, aminoacid homopolymers are less immunogenic than heteropolymers containing two or three different amino acids 4. Genetic constitution of the host: Two strains of the same species of animal may respond differently to the same antigen because of a different composition of genes involved in the immune response (eg, different MHC alleles)  5. Dosage, route, and timing of antigen administration: Since the degree of the immune response depends on the amount of antigen given, the immune response can be optimized by carefully defining the dosage ( including number of doses), route of administration, (Oral, inhalation or parenteral) and timing of administration ( including intervals between doses)  ◦ The type of immun response initiated by an immunogen depends on its molecular structure ◦ T-independent antigens, these molecucules have a large, repetitive structure that is sufficient to activate B - cells directly to make antibody without the participation of T - cell help ; for example bacterial polysaccharides ( capsule), peptidoglycan, or flagellin ◦ In these cases, the response is limited to production of IgM antibody and fails to stimulate an anamnestic (booster) response ◦ T-dependent antigens are proteins ◦ They generate all five classes immunuglobulins and can elicit memory and an anamnestic (secondary-booster) response  ◦ The major histocompatibility complex (MHC) was first detected as genetic locus encoding the glycoprotein molcules (transplantation antigens) responsible for the rapid rejection of tissue grafts transplanted between genetically nonidentical individual ◦ It is now known that MHC molecules bind peptide antigens and present them to T cell ◦ Thus, these Tx antigens are responsible for antigen recognition by the T cell  ◦ In humans, the MHC is a cluster of extensively studied genes located on chromosome 6. ◦ Among the many important genes in the human MHC, also known as HLA, are those that encode: ◦ MHC class I proteins ◦ MHC Class II proteins ◦ MHC Class III proteins  ◦ MHC class I proteins are encoded by the HLA-A, -B, and C genes ◦ These proteins are made up of two chains :a transmembrane glycoprotein and β2 – microglobulin Class I molecules are to be found almost all nucleated cells in the body ◦ Key exceptions are observed on cells in the retina and brain ◦ The class MHC I locus also includes genes encoding proteins involved in antigen processing (eg, transporters associated with antigen processing [TAPs]  ◦ The class MHC II proteins are encoded by the HLA-D region ◦ There are three main families: the DP-, DQ-, and DR- encoded molecules ◦ This locus retains control of immun responsiveness and different allelic forms of these genes confer striking differences in the ability to mount an immune response against a given antigen  ◦ HLA-D locus- enceded proteins are made up of two noncovalently associated transmembrane glycoproteins ◦ Unlike class I proteins, The class II MHC proteins have a restricted tissue distribution and are chiefly found on APCs as macrophages, dendritic cells, and B cells ◦ Their expression on other cells (eg, endothelial cells or epithelial cells) is induced by IFN-ϒ  ◦ Analysis of the function of cells with respect to interaction with MHC molecules reveals that peptide antigens associated with class I MHC molecules are, recognized by CD8-positive cytotoxic T lymphocytes, whereas MHC class II-associated peptide antigens are recognized by CD4-positive helper T cells ◦ MHC Class III locus encodes complement proteins and several cytokines  ◦ There are two separate properties of the MHC that make it difficult for pathogens to evade antigen presentation by MHC molecules: Polygenicity - containing several loci encoding proteins of identical function. So we have three antigen-presenting MHC class I and MHC class II genes. Polymorphism - having multiple alleles at each locus. Classical MHC class I and II molecules involved in T-cell activation via antigen presentation  ◦ Antigen processing and presentation are the means by which antigens become associated with self-MHC molecules for presentation to T cells with appropriate receptors ◦ Proteins from exogenous antigens, such as bacteria, are internalized via endocytic vesicles into APCs such as the various types of dendritic cells and macrophages  ◦ Then, they are exposed to cellular proteases in intracellular vesicles ◦ Peptides, approxymately 10-30 amino acid residues in length, are generated in endosomal vesicles ◦ The endosomal vesicles can then fuse with exocytic vesicles containing class II MHC molecules  ◦ Class I MHC–associated peptides are produced by the proteolytic degradation of cytosolic proteins, the transport of the generated peptides into the endoplasmic reticulum(ER), and their binding to newly synthesized class I molecules ◦ Most cytosolic protein antigens are synthesized within cells, and some are phagocytosed and transported into the cytosol ◦ The major mechanism for the generation of peptides from cytosolic protein antigens is proteolysis by the proteasome  ◦ The generation of class II MHC–associated peptides from endocytosed antigens involves the proteolytic degradation of internalized proteins in endocytic vesicles and the binding of peptides to class II MHC molecules in these vesicles ◦ Most class II–associated peptides are derived from protein antigens that are captured from the extracellular environment and internalized into endosomes by specialized APCs ◦ Internalized proteins are degraded enzymatically in late endosomes and lysosomes to generate peptides that are able to bind to the peptide-binding clefts of class II MHC molecules  ◦ Some dendritic cells have the ability to capture and to ingest virus-infected cells or tumor cells and present the viral or tumor antigens to naive CD8+ T lymphocytes  ◦ Several small populations of T cells are able to recognize nonprotein antigens without the involvement of class I or class II MHC molecules ◦ These populations are exceptions to the rule that T cells can see only MHC associated peptides ◦ The best defined of these populations are NKT cells and γδ T cells  ◦ NKT cells express markers that are characteristic of both natural killer (NK) cells and T lymphocytes and express αβ T cell receptors with very limited diversity ◦ NKT cells recognize lipids and glycolipids displayed by the class I–like “non-classical” MHC molecule called CD1 ◦ The NKT cells that recognize the lipid antigens may play a role in defense against microbes, especially mycobacteria (which are rich in lipid components)  ◦ γδ T cells are a small population of T cells that express antigen receptor proteins that are similar but not identical to those of CD4+ and CD8+ T cells ◦ γδ T cells recognize many different types of antigens, including some proteins and lipids, as well as small phosphorylated molecules and alkyl amines ◦ These antigens are not displayed by MHC molecules, and γδ cells are not MHC restricted. It is not known if a particular cell type or antigen display system is required for presenting antigen to these cells