Immunity PDF

Immune Non specific Specific system: (innate) (acquired) NONSPECIFIC MECHANISMS (general barriers to infection) LAYERS OF DEFENSE: SKIN MUCOUS MEMBRANE INTERACTING MECHANISMS SECOND LINE OF DEFENSE PHAGOCYTOSIS ANTIMICROBIAL PROTEINS...

Immune Non specific Specific system: (innate) (acquired) NONSPECIFIC MECHANISMS (general barriers to infection) LAYERS OF DEFENSE: SKIN MUCOUS MEMBRANE INTERACTING MECHANISMS SECOND LINE OF DEFENSE PHAGOCYTOSIS ANTIMICROBIAL PROTEINS THE INFLAMMATORY RESPONSE ◘ It can’t normally be penetrated by bacteria or viruses ◘ Cuts or abrasions can allow potentially harmful bacteria or viruses to enter the body. MUCOUS MEMBRANE SURFACE FLUID AND ENZYMES SALIVA: bathes the oral mucosa 1. Salivary Peroxidase System 2. Hydrogen peroxide - Continuously secreted in low PERSONAL SHIELDS concentration by bacteria, neutrophils and other host cells 3. Lactoferrin 4. Lysozyme: an enzyme that digest the cell walls of many bacteria and destroys many microbes entering the upper respiratory system and the openings Bars entry of harmful microbes around the eyes. Also counters pathogens with chemical defenses GINGIVAL CREVICULAR FLUID : Gingival epithelium has 3 functions: Washing non-adherent bacteria and their products out of the gingival sulcus 1. Epithelial cells are tightly attached to each other. Decrease diffusion of plaque products into the tissues 2. Keratinization to resist trauma. Carries into the gingival sulcus a constant supply of 3. Presence of permeability barriers - Inflammatory mediators - Protease inhibitors - Host defence agents such as complement and antibody IMMUNE CELLS  The most important antimicrobial proteins in the blood and tissues are interferons and the complement system. INTERFERONS: proteins secreted by virus-infected cells that inhibit neighboring cells from making new viruses COMPLEMENT PROTEINS: involved in nonspecific and specific defense Initiation of inflammation Opsonization Can lyse a cell target by combining with antibodies Disposal of cell debris A local inflammatory response is triggered by tissue damage. Injured cells release histamine, a chemical signal that dilates blood vessels and increases capillary permeability allowing large numbers of phagocytic white blood cells to enter the interstitial fluid.  Molecular markers Molecular markers on cell surfaces function in self/nonself recognition SELF-TOLERANCE: develops as T and B lymphocytes bearing antigen receptors mature in the thymus and bone marrow, and continues to develop even as the cells migrate to lymphoid tissues. Any lymphocytes with receptors for molecules present in the body are destroyed or are made nonfunctional This leaves only lymphocytes that are reactive against foreign molecules MAJOR HISTOCOMPATIBILITY COMPLEX (MHC): a biochemical fingerprint unique to each individual 2 TYPES OF MHC: CLASS I MHC: LOCATED ON ALL NUCLEATED CELLS (ALMOST EVERY CELL IN THE BODY) CLASS II MHC: RESTRICTED TO A FEW SPECIALIZED CELL TYPES OF THE BODY’S DEFENSE SYSTEM (MACROPHAGES, B CELLS, AND ACTIVATED T CELLS)  Internal defense mechanisms that are nonspecific depend mainly on PHAGOCYTOSIS: * PHAGOCYTOSIS is the ingestion of invading particles by certain types of white blood cells * Neutrophils comprise about 60% to 70% of all white blood cells Attracted by chemical signals, neutrophils can leave the blood and enter infected tissue by amoeboid movement. Once there they can DESTROY the microbes!!! (this migration of a chemical attractant is called chemotaxis) **Neutrophils tend to self-destruct as they destroy foreign invaders so they’re average life is only about a few days. Neutrophils are like SUICIDE BOMBERS! Monocytes (only make up about 5% of the WBC) strengthen phagocytic defense Monocytes mature into MACROPHAGES MACROPHAGES: The largest phagocytic cells Macrophages are amoeboid cells that move through tissue fibers and engulf and digest cellular debris and pathogens by phagocytosis They also stimulate lymphocytes and other immune cells to respond to pathogens A majority of macrophages are stationed at strategic points where microbial invasion is likely to occur (LIKE A BLOCKADE) Fixed macrophages are especially numerous in the lymph nodes and in the spleen, which are key organs of the lymphatic system.  The immune system recognizes foreign microbes, toxins or transplanted tissues It knows that they don’t belong It then develops an immune response to inactivate or destroy the specific type of invader HUMORAL IMMUNITY: based on circulation of antibodies in the blood and lymph, and defends against free viruses, bacteria, and other extracellular threats. CELL-MEDIATED IMMUNITY: reacts against transplanted tissue and cancer cells. Immunologic aspects of the microbial-host interaction  Innate factors such as complement, resident In leukocytes, and especially mast cells play an important role in signaling endothelium, thus initiating response inflammation. Acute inflammatory cells (i.e., neutrophils) protect local tissues by controlling the periodontal microbiota to within the gingival crevice and junctional epithelium. Chronic inflammatory cells, macrophages, and bacterial lymphocytes protect the entire host from within the subjacent connective tissues and do all that is necessary to prevent a local infection from becoming infection systemic and life threatening, including the sacrifice of local tissues. Innate Factors and Initiation of Inflammation The onset of inflammation involves the development of edema and erythema, which are signs of vascular changes. Complement activation in response to bacterial infection results in generation of the complement-derived anaphylatoxins C3a and C5a. Anaphylatoxins are substances that stimulate vascular changes indirectly by causing degranulation of the resident leukocytes, the mast cells. Degranulated mast cells increase within the gingival connective tissue as gingival inflammation increases. Mast cells form tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), interleukin-4 (IL-4), and interleukin-6 (IL-6); when stimulated, they induce transcription of proinflammatory cytokines such as IL-1, IL-6, Interferon-γ(IFN-γ), and others. In healthy individuals, complement levels in gingival crevicular fluid (GCF) are about 3% of that in serum. As periodontal inflammation increases, a concomitant increase in the levels of complement components occurs. The levels of complement components in GCF are more than adequate to support the recruitment of acute and chronic inflammatory cells, opsonization and neutralization of pathogens or pathogenic substances, and local regulation of connective tissue changes. Host bacterial interaction in periodontal diseases The stimulation of endothelial cells by C5a, IL-1β, TNF- α, and bacterial lipopolysaccharide (LPS) results in the expression of selectins on the luminal surface of the endothelial cells and release of chemokines from the endothelial cells. These processes are central in transendothelial migration of leukocytes which results in the movement of leukocytes into the local tissues. Interleukin-8 (IL-8) and intercellular adhesion molecule-1 (ICAM-1) production in the epithelial cells in response to periodontal bacteria provides a chemotactic signal for neutrophils (PMN). Neutrophils function to control the bacterial invasion by phagocytosis but also secrete matrix metalloproteinases (MMP-8), which may contribute to tissue destruction. Complement components also may contribute to efficient bacterial phagocytosis. TRANSENDOTHELIAL MIGRATION OF LEUKOCYTES Functions of Neutrophils - Migration and chemotaxis: - WBC normally travel along the center of the lumen of blood vessel, but in inflamed tissues the blood flow is slowed by fluid exudation and they adhere more readily to endothelial cells, the mechanism is called “rolling” and "margination”. - Neutrophils migrate across the endothelium by "diapedesis“ ❖ Two phases of leukocyte endothelium adherence. ▪ Selectin-dependent phase (mainly in rolling and margination) ▪ Integrin-dependent phase (mainly in diapedesis)  The interaction of bacterial antigens with peripheral dendritic cells leads to the generation of systemic antibody, whereas interaction with local B cells leads to production of local antibody. Antibody specific to many of the periodontal microorganisms is essential for phagocytosis. The production of interleukin-1β (IL-1 β), tumor necrosis factor alpha (TNF- α), and prostaglandin E2 (PGE2) in response to bacterial lipopolysaccharides (LPS) leads to bone resorption through osteoclast activation, proliferation, and differentiation. Controlling Bacterial Invasion: Primary Role for Neutrophils Neutrophils are the first leukocytes to arrive at the site of inflammation and are the dominant cell type within the junctional epithelium and the gingival crevice. For neutrophils to control bacterial infections effectively, their functions, including, chemotaxis, transepithelial migration, opsonization, phagocytosis, and intraphagolysosomal killing, must be intact. Disorders of neutrophils are associated with invasive periodontal infection and aggressive periodontitis. Severe periodontal destruction involving both the primary dentition and the permanent dentition is evident in individuals with disorders affecting neutrophil chemotaxis and phagocytosis.  About 1% to 2% of all neutrophils migrate across the junctional epithelium daily. This transepithelial migration requires a chemotaxin gradient. The junctional epithelium expresses the chemotactic cytokine (chemokine) IL-8 and intercellular adhesion molecule-1 (ICAM-1).  P. gingivalis prevevts transepithelial migration of neutrophils and prevents epithelial cells from secreting IL-8 in response to bacterial challenge. P. gingivalis also has a potential virulence factor through production of periodontain, an α1-proteinase inhibitor of human neutrophil elastase. Opsonization refers to the coating of bacteria, with host proteins that facilitate phagocytosis. For example, a bacterial cell may be coated with complement components for which the neutrophil has receptors. Bacterial cells may be coated with specific antibody that fixes complement that is recognized by the neutrophil receptor. IgG isotype also facilitates phagocytosis directly by binding with the neutrophil Fc receptor and appears to be essential for phagocytosis of certain periodontal pathogens.  Patients with periodontitis exhibit very high serum titers of IgG to specific periodontal pathogens. Antigen-presenting cells (APCs) such as the peripheral dendritic cells (e.g., Langerhans cells, macrophages, B cells) are abundant within the gingival tissues and can transport antigen to regional lymph nodes, thus promoting the production of serum IgG antibody. Scaling and root planing stimulates antibody production against microorganisms such as P. g. and A. a. The antibody facilitate host clearance of periodontal pathogens. For example, the antibody is essential for opsonization and phagocytosis of A. a. and virulent strains of P. gingivalis. The antibody also neutralizes bacterial components important in colonization or host cell interactions. Antibody specific for P. gingivalis prevents recolonization of deep periodontal pockets in periodontitis patients. In LAP, the absence of a host antibody response contribute to disease progression.  Once the bacterial cell is bound to the neutrophil, ingestion (phagocytosis) results in entrapment of the bacterial cell into the phagosome. Bacteria within the phagosome and phagolysosome may be killed by oxidative or nonoxidative mechanisms. The gingival sulcus is characteized by a diminished level of oxygen, and the oxidation-reduction (redox) potential of the periodontal pocket is more reduced than the gingival sulcus. This is indicated by measurements of crevicular oxygen levels and redox potential and reflected by the growth of strictly anaerobic bacteria such as P. gingivalis and the oral spirochetes. The oxidative killing mechanisms of crevicular neutrophils may be intact in a healthy sulcus but impaired in the periodontal pocket. A shutdown of oxidative killing may be an important factor in the progression to periodontitis.  Nonoxidative mechanisms of killing involve phagosome- lysosome fusion, resulting in secretion of bactericidal substances such as lysozyme, cathepsin G, and α-defensins into the phagolysosome containing the ingested bacterium. Some periodontal pathogens evade phagocytic cells as a virulence mechanism. For example, the leukotoxin of A. a. kills phagocytes Specific antibodies to A. a. or antileukotoxin serum protects neutrophils from leukotoxin-mediated injury and enables phagocytosis to proceed.  Periodontal manifestations of disorders affecting neutrophil function. A and B, Clinical appearance of patients with cyclic neutropenia, a condition that involves reduction in the number of circulating neutrophils (blood neutrophil levels