Immune System: Part I PDF

The Immune System http://www.sci-news.com/biology/article00943.html  Innate & Adaptive Immune Responses Largely non-specific First line of defense: Barriers Second line of defense: Internal Defenses Responses can initiate within minutes THE TWO BRANCH...

The Immune System http://www.sci-news.com/biology/article00943.html  Innate & Adaptive Immune Responses Largely non-specific First line of defense: Barriers Second line of defense: Internal Defenses Responses can initiate within minutes THE TWO BRANCHES OF THE IMMUNE SYSTEM ACT BOTH INDEPENDENTLY AND COOPERATIVELY Mounts attacks against specific foreign substances Collectively acts as third line of defense Responses take considerably more time to develop  Innate & Adaptive Immune Responses The immune system is a functional system as opposed to an organ system lymphoid organs immune cells functional molecules Innate and adaptive responses are intertwined both systems release and recognize the same/similar molecules innate responses, although ‘non-specific’ actually have specific pathways to target foreign substances proteins released by innate immune components alert the adaptive system of the presence of foreign substances A functional immune system can protect against microorganisms (bacteria, fungi, parasites) **also viruses cancer cells transplanted organs/grafts  Surface Barriers: First Line of Defense (Innate) First Line of Defense: Skin & Mucosa and associated components/secretions: Keratin in the epidermis is resistant to most weak acids and bases, bacterial enzymes, toxins Cilia in upper respiratory tract sweep potential pathogens/irritants towards the mouth Mucus membranes line all body cavities that open to the exterior: digestive, respiratory, urinary, reproductive Acid mantle of skin, vaginal, and stomach secretions inhibit bacterial growth Lysozyme of saliva, respiratory mucus, lacrimal fluid is anti-microbial Enzymes of the stomach digest proteins and kill micro-organisms Mucin can trap microorganisms in thick mucus, or can wash them away in thin watery mucus (ex: saliva) Defensins: broad-spectrum antimicrobial peptides are produced when surface barriers are breached and disrupt microbial membranes Components of sweat (ex: dermicidin) are toxic to bacteria https://immunesystem-sac.weebly.com/ Cells & Chemicals: Second Line of Defense (Innate) Phagocytes Cells that engulf and destroy particulate matter and pathogens via cytoplasmic extensions Professional phagocytes: neutrophils, dendritic cells, macrophages, mast cells Neutrophils are the most plentiful leukocyte Can also pierce a pathogen’s membrane via defensins Macrophages and dendritic cells derive from monocytes patrol the body in tissue spaces can become resident within specific tissues/organs Non-professional phagocytes: epithelial and endothelial cells, fibroblasts Phagocytosis: ‘Cell Eating’ In order for a phagocyte to ingest a pathogen, it must adhere to that pathogen recognition of the carbohydrate molecules on pathogen surface: carb ‘bar code’ detection of opsonins molecules that coat, or opsonize, a target provide a way to tag pathogens for destruction complement proteins or antibodies (Abs) Some pathogens can escape degradation by phagolysosome acidic conditions AND can thrive/multiply various parasites Mycobacterium species Respiratory burst Involve mainly macrophages Additional killing mechanisms: release of destructive free radicals (superoxide) production of oxidizing chemicals (peroxide) reactive oxygen and nitrogen species increasing the acidity (lowering pH) within the phagolysosome, which can activate other anti-pathogen enzymes Hematopoietic Cell Production Natural Killer (NK) Cells Circulate via the blood and lymph Non-specific Lyse and kill cancer cells and virus-infected cells before the adaptive immune system is activated Identify neoplastic and virus-harboring cells by detecting abnormalities in cell protein expression ex: down-regulation or lack of MHC molecules Non-phagocytic: kill by making direct contact with target cells induce apoptosis (programmed cell death) secrete chemicals that enhance inflammatory response Add image of killing  Inflammation Complex biological processes that are part of the body’s response to harm Inflammatory response is triggered by tissue injury physical trauma intense heat irritating chemicals infection by bacteria, fungi, viruses Several benefits to inflammation prevents the spread of damaging agents to adjacent tissues disposes of cell debris and pathogens alerts the adaptive immune system sets the stage for repair Four cardinal signs redness heat swelling pain **impaired function** is considered a fifth cardinal sign  Inflammatory Chemical Release Inflammatory process begins with a chemical alarm released by injured tissues and/or immune cells Macrophages use Toll-like receptors (TLRs) to recognize molecules associated with potential infection 10 types of human TLRs activated TLRs precipitate release of cytokines Additional chemicals (kinins, prostaglandins, complement proteins) further drive inflammatory response Vasodilation & Increased Vascular Permeability Inflammatory chemicals increase permeability of capillaries exudate (fluid containing clotting factors and Abs) enters tissue spaces exudate movement leads to swelling (edema) and pain some bacterial toxins may also contribute to pain edema has numerous benefits fluid influx into tissue spaces help mobilize foreign material to lymph nodes delivers complement and clotting factors clotting factors play important role in scaffolding for tissue repair mesh isolates bacteria from spreading to adjacent tissues **Streptococcus species have evolved enzymes that break down clot, facilitating invasion of surrounding tissues** Phagocyte Mobilization Begins soon after initiation of inflammatory response neutrophils are first cell type to infiltrate macrophages arrive next monocytes leave blood, enter the damaged area/tissue within 12 hrs develop large quantities of lysosomes and become macrophage complement protein cascade may initiate lymphocytes and antibodies (adaptive immune response) arrive Four steps in phagocytes mobilization leukocytosis margination diapedesis chemotaxis  Phagocyte Mobilization: Four Steps Leukocytosis: increase in leukocytes Injured cells release ‘leukocytosis-inducing factors’ neutrophils move into the area first Margination: neutrophils cling to inner walls of capillaries inflamed endothelial cells up-regulate expression of cell adhesion molecules (CAMs) cells that encounter CAMs slow and roll along the endothelia Diapedesis: continued chemical signaling prompts cells to flatten and squeeze between endothelial cells and extravasate Chemotaxis: movement along an increasing gradient of https://www.youtube.com/watch?v=LB9FYAo7SJU chemical signals https://www.youtube.com/watch?v=I_xh-bkiv_c inflammatory chemicals act as homing devices https://www.youtube.com/watch?v=HPdl-tBYXHY https://www.youtube.com/watch?v=ZUUfdP87Ssg https://www.youtube.com/watch?v=ZUUfdP87Ssg  Antimicrobial Proteins Enhance innate immune defenses direct attack on microorganisms hindering ability to reproduce Two most important: Interferons Complement System Interferons (IFNs) Mechanism to protect healthy cells from viral infection: block virus invasion Named because they ‘interfere’ with viral replication block protein synthesis degrade viral RNA Not virus-specific responses, so IFNs produced against one virus may protect against other viruses as well Two classifications: Type I IFNs: IFN-alpha, IFN-beta primarily have anti-viral effects activate NK cells Type II IFN: IFN-gamma secreted by lymphocytes activates macrophages Play a role in fighting cancer, as macrophages and NK cells can act against cancer cells Therapeutically used to treat hepatitis C, genital warts (cause by HPV), multiple sclerosis, and hairy cell leukemia (excess B cells)  Complement System 20+ plasma proteins that circulate in inactive states mechanism for destroying foreign substances: lysis and killing of bacteria coating with complement: opsonization non-specific ‘complements’ or enhances both the innate and adaptive immune defenses All 3 pathways converge at C3 C3 -> C3a and C3b C3 cleavage leads to enhanced inflammation promotion of phagocytosis cell lysis via Membrane Attack Complex (MAC) protein complex is assembled to form a pore in target cell membrane compromise membrane integrity -> cell lysis  Fever abnormally high body temperature systemic response to invading microorganisms release of pyrogens act on hypothalamus to ‘reset’ physiological thermostat benefits of fever liver and spleen sequester iron and zinc, making them less available for bacterial growth increased temperature drives up cellular metabolic rate, speeding up repair processes Adaptive Immune Response SPECIFIC defense system Response is systemic: immunity is not restricted to the initial infection site Memory is formed: if re-challenged/re-infected by the same pathogen/substance, the immune system can mount a faster, more potent response Cells that regulate adaptive responses must be primed by an initial exposure to a specific foreign substance Humoral Immunity (antibody-mediated immunity) circulate in the body’s fluids (humors) produced by lymphocytes primarily bind to extracellular targets Cellular Immunity (cell-mediated immunity) lymphocytes themselves defend the body targets are usually virus- or parasite-infected cells, cancer cells, grafted tissues killing by lymphocytes is either direct: lymphocytes act in a cytotoxic capacity indirect: secretion of chemicals that enhance activity of other cells  Antigens Antigen: any substance that can mobilize an immune response The specific feature or portion of the molecule that the immune system responds to is called an antigenic determinant or EPITOPE Antigens are generally large, complex molecules can be proteins, carbohydrates, lipids, nucleic acids can be natural or synthetic are considered non-self Small molecules (short peptides, many hormones) are generally not immunogenic Large molecules with many identical, repeating subunits are poorly immunogenic Antigens exist in two types: Complete antigens have: immunogenicity: can stimulate specific lymphocytes to proliferate reactivity: ability to react with activated lymphocytes and the antibodies they produce Incomplete antigens (haptens): must complex with some endogenous protein in order to be recognized as an antigen ex: penicillin, poison ivy  Self-Antigens: MHC Proteins MHC: Major histocompatibility complex glycoproteins on the surface of all cells (except mature erythrocytes) Alternative name (and also the name used for the genes that code for MHC): HLA-> human leukocyte antigens Millions of combinations of HLA genes are possible (VDJ gene rearrangement) basis of tissue rejection During development the immune system is programmed/educated to recognize antigens that are self vs non-self and to not attack self self-antigens are NOT foreign -> immune system should not attack T LYMPHOCYTES CAN ONLY RECOGNIZE/BIND TO ANTIGENS THAT ARE PRESENTED TO THEM IN THE CONTEXT OF MHC PROTEINS  Adaptive Immunity: Lymphocyte Development, Maturation & Activation Adaptive Immunity involves 3 cell populations for proper function B lymphocytes (B cells): produce antibodies- humoral immunity T lymphocytes (T cells): cellular response arm, non- antibody producing- cellular immunity APCs- antigen presenting cells that show/present/display antigens to the lymphocytes 1. Origin: All lymphocytes develop in red bone marrow from hematopoietic stem cells 1. T & B Cells: Lymphoid progenitor 2. APCs: myeloid progenitor  Adaptive Immunity: Lymphocyte Development, Maturation & Activation 2. Maturation: Immuno-competence: each lymphocyte becomes able to recognize its one specific antigen B cells: BCR (B Cell Receptor) T cells: TCR (T Cell Receptor) Self-tolerance: each lymphocyte should be unresponsive against self-antigens on MHC T cell maturation is better understood than B cell maturation and is known to be a 2-step process that spares about 2% of the cell populations Positive selection: only T cells that are able to recognize self-MHC proteins survive non-self antigen has to be presented in the context of an MHC molecule T cells that do not pass this step get eliminated via apoptosis Negative selection: ensure that T cells do not recognize self-antigen on MHC B cell maturation is likely similar  Adaptive Immunity: Lymphocyte Development, Maturation & Activation 3. Seeding secondary lymphoid organs and circulation B and T cells move from the primary (thymus and bone marrow) to the secondary lymphoid organs spleen lymph nodes T cells will spend significant time circulating from blood to lymph increases likelihood of encountering antigen ~65-85% of blood-borne lymphocytes  Adaptive Immunity: Lymphocyte Development, Maturation & Activation 4. Antigen Encounter and Lymphocyte Activation Naïve lymphocytes usually encounter antigen in lymph node or spleen When an antigen is recognized by a lymphocyte with its particular specific receptor, that cell undergoes further development: clonal selection 5. Proliferation and Differentiation Activated cell will proliferate and create a pool of clones all bearing the identical antigen-specific receptor Effector cells: will do the work of fighting infection Memory cells: generally long-lived cells that will respond rapidly to a secondary encounter with the same antigen B and T cells will circulate through the body on patrol