Principle of Immune Response PDF

## Principle of Immune Response ### Main Task: The main task of the immune system is to **Recognize, Attack** and **Memorize**. - **Recognize:** - PAMPs (from pathogens) & DAMPs (from injured cells) - PRR, TLR - APC - **Attack:** - Signaling: - Cytokines - Comple...

## Principle of Immune Response ### Main Task: The main task of the immune system is to **Recognize, Attack** and **Memorize**. - **Recognize:** - PAMPs (from pathogens) & DAMPs (from injured cells) - PRR, TLR - APC - **Attack:** - Signaling: - Cytokines - Complement - MHC - **Memorize:** - Reaction: - Opsonization - Phagocytosis - Inflammation - etc. ## Principle of Innate and Adaptive Immunity ### Innate Immunity - Pathogen Associated Molecular Patterns (proteins, carbohydrates, lipids, nucleic acids) - PRRs - MΦ (Macrophage) - DC (Dendritic Cell) - Pathogen phagocytosis and elimination - **Fast acting** - **Generally recognize antigen** - **Easy to manipulate** ### Adaptive Immunity - Ag presentation - Co-stimulatory molecules - Naïve T-cell - CTL (Cytotoxic T lymphocyte) - Treg (Regulatory T Cell) - Th1 (T helper 1 cell) - Th2 (T helper 2 cell) - Th17 (T helper 17 cell) - B cell - Antibody production - Cytokines/Chemokines - **Delayed response, need introduction** - **Antigen-specific** - **Memory cells** ## Professional antigen-presenting cells | Cell type | Location in lymph node | Antigen uptake | MHC expression | Co-stimulator delivery | Antigen presented | Location | |---|---|---|---|---|---|---| | Dendritic cell | T-cell areas | +++ Macropinocytosis and phagocytosis by tissue dendritic cells, Viral infection | Low on tissue dendritic cells, High on dendritic cells in lymphoid tissues | Constitutive by mature, nonphagocytic lymphoid dendritic cells | Viral antigens, Peptides, Allergens | Ubiquitous throughout the body | | Macrophage | N/A | +++ Phagocytosis | Inducible by bacteria and cytokines | Inducible | Particulate antigens, Intracellular and extracellular pathogens | Lymphoid tissue, Connective tissue, Body cavities | | B cell | Follicle | +++ Antigen-specific receptor (Ig) | Constitutive, Increase on activation | Inducible | Soluble antigens, Toxins, Viruses | Lymphoid tissue, Peripheral blood | ## Activation of Cellular Immune Response - Antigen-specific T-cell activation requires three distinct signals: - **Signal 1**: antigen-specific signaling mediated by T-cell receptor (TCR) engagement of pathogenic peptides presented by major histocompatibility complex (MHC) molecules. - **Signal 2**: costimulatory signaling. Mainly mediated by the interaction of CD28 with one of the B7 molecules (CD80 and CD86). - **Signal 3**: polarizing signaling mediated by various cytokine milieus produced by dendritic cells. ## Signal 1: Major histocompatibility complex - **Infected cell:** - Antigen fragment - Class I MHC molecule - T cell receptor - 1: Antigen associates with MHC molecule - 2: T cell recognizes combination - **(a) Cytotoxic T cell** - **Microbe:** - 1 - Antigen-presenting cell - Antigen fragment - Class II MHC molecule - T cell receptor - 2 - **(b) Helper T cell** - The function of MHC molecules is to bind peptide fragments derived from pathogens and display them on the cell surface for recognition by the appropriate T cells. ## MHC Class 1 vs MHC Class 2 | MHC Class 1 | MHC Class 2 | |---|---| | One membrane-spanning α chain (heavy chain) produced by MHC genes, and one β chain (light chain or β2-microglobulin) produced by the β2-microglobulin gene. | Two membrane-spanning chains, α and β, of similar size and both produced by MHC genes. | | Present in all nucleated cells | Only present on specialised APC | | Present endogenous antigens that originate from the cytoplasm. | Present exogenous antigens that originate extracellularly from foreign bodies such as bacteria. | | Present antigen to cytotoxic T cell lymphocytes (CD8+ T cells) | Present antigen to helper T cell lymphocytes; (CD4+ T cells) | | Presentation of foreign-intracellular antigens or altered self-antigens; targets cell for destruction | Presentation of foreign extracellular antigens; induces antibody production, and attracts immune cells to area of infection | ## Signal 2: Co-stimulatory signaling - **A**: - APC - B7 CD28 - T cell - Signal 2 - Activation - Signal 1 - MHC/Ag - TCR - **Cytokine production** - **T-cell proliferation** - **B**: - APC - CD28 - T cell - Induction of anergy - Signal 1 - MHC/Ag - TCR - **No cytokine production** - **No cell division** - **Becomes anergic** - **Undergoes apoptosis** ## Signal 3: Cytokines - **Cytokines** are a large group of proteins, peptides or glycoproteins that are secreted by specific cells of the immune system. - **Cytokines** are a category of signaling molecules that mediate and regulate immunity, inflammation and hematopoiesis → **COMMUNICATION** - **Cytokine producing-cells:** Macrophage, T cells, B cells, Mast cells, Endothelial cells, Fibroblast - **Role of cytokines:** - **Direct:** 1. More than one effect on different cell types (pleiotropi) 2. Autoregulation (autocrine function) 3. Effect on nearby cells (paracrine function) - **Indirect:** 1. Induce the expression of receptors for other cytokines or work together with other cytokines to stimulate cells (synergism) 2. Prevent the expression of receptors or the production of cytokines (antagonism) - Sitokin plays a role in many immune responses, such as the activation of T cells, B cells, monocytes, macrophages, induction of cytotoxicity and inflammation. Some cytokines also have anti-neoplastic effects and effects on hematopoiesis. - **Synergy**: Two or more cytokines have a synergistic effect. - **Antagonism**: The ability of one cytokine to inhibit the action of another cytokine. - **Redundancy**: Multiple cytokines have the same or overlapping effects. - **Pleiotropism**: The ability of one cytokine to cause the multiplication of different types of target cells. ## Functions of cytokines - **Activation** of immune cells (Eg: IL-1, IL-8, IFN-γ) - **Inhibition** of immune cells activation (Eg: IL-10, TGF-β) - **Recruitment** of immune cells (IL-2, IL-12) - **Cytotoxic** (Eg: TNFα, IL-2, IFN-γ) - **Repair** (Eg: TGF-β) ## Complement System - The **complement system** is a part of the innate immune system that enhances (complements) the ability of antibodies and phagocytic cells. - **End results**: - Clear microbes and damaged cells - Promote inflammation - Attack pathogen's cell membrane. - **Consists** of a number of small proteins that are synthesized by the liver, and circulate in the blood as inactive precursors. - **Trigger** → cleavage by specific proteases → **cytokine release** → **activation** - **11 proteins are mostly involved**: B, C1-9, and D - **Enzyme precursors** ### Schematic overview of the complement cascade | Pathway | Description | |---|---| | Classical Pathway | Antigen-antibody complexes | | MB-Lectin Pathway | Lectin binding to pathogen surfaces | | Alternative Pathway | Pathogen surfaces | - **Complement activation** - **Recruitment** of inflammatory cells - **Opsonization** of pathogens - **Killing** of pathogens ### Functions of Complement System - **1. Membrane Attack Complex:** Direct destruction of microbes (cell lysis) - **2. Opsonization:** Uses opsonins to tag foreign pathogens for elimination by phagocytes - **3. Chemotaxis:** C5a attracts neutrophils and macrophages to the antigen location. - **4. Mast Cell Activation:** C3a, C4a, C5a ### Complement System: Activation | Name | Description | |---|---| | Antigen-antibody reaction | C1q, Classical pathway, Ag-Ab complexes | | Mannose binding Lectin (MBL) | Neisseria, candida, salmonella, Lectin pathway, MBL, Lectin binds mannose on pathogens, MASPS, C4, C2, C3 convertase | | Bacterial endotoxin (mostly Gram - , yeast) | Alternative pathway, C3b, fB, fD, P, Pathogens, injured tissue | - C3aR - C3 convertase - CR1 - FcR - C3 - C3a - C3b (opsonization) - C5 convertase - C5 - C5b - C5a - C5aR - Inflammation - MAC (Membrane Attack Complex) - Cell lysis and activation ### Complement system: Functions - **1. Membrane Attack Complex**: direct destruction of microbes (cell lysis) - **2. Opsonization**: uses opsonins to tag foreign pathogens for elimination by phagocytes - **3. Chemotaxis**: C5a attract neutrophils and macrophage to antigen location - **4. Activation of Mast Cells**: C3a, C4a, C5a