Friday, 19 July 2013


A. Innate immunity includes defenses (physical, chemical, and cellular) that are poised to either prevent an infection or act rapidly to an infection. Innate defenses do not need prior exposure to an antigen to respond.

B. Anatomic and mechanical barriers to infection are designed to prevent infectious agents from accessing the body and include the skin, which is covered by protective layers of keratinized cells; mucus, which provides a mechanical and chemical barrier to infection; and chemical and molecular factors, such as surfactants, low pH, high salt, and acids. Some of these factors (low pH, high salt, surfactants, and acid) interfere directly with microbial life, whereas others recognize features of microbes that are common to some or all microbes (e.g., the enzyme lysozyme, which is found in tears, saliva, gastric secretions, and lysosomal granules of phagocytes, cleaves peptidoglycan of bacterial cell walls).
Defensins and cathelicidins are small cationic antimicrobial peptides that have direct antimicrobial activity, are found at mucosal surfaces, and are produced by many immune cells. Interferons, which interfere with viral replication, are released by host cells or immune cells in response to the presence of intracellular viruses. Biological factors such as normal flora bacteria (especially on the skin and gastrointestinal tract surfaces) provide a defense against infection by physically preventing access to the surfaces of the body, producing metabolites that create an inhospitable environment for pathogens, and consuming available nutrients.

C. Phagocytosis is the process by which microbes are engulfed and destroyed by immune cells, usually neutrophils or macrophages. Phagocytes can recognize some microbes directly (further discussed later).

D. The complement system consists of approximately 30 circulating and membrane-expressed proteins that serve as an effector system of both the innate and antibody-mediated adaptive immune responses. 

Most of the complement components are synthesized in an inactive form by the liver, and then activated, in a cascade manner, when needed. Complement activation occurs through three different pathways: alternative, classical, and lectin. Complement is responsible for increases in the inflammatory response, opsonization to enhance phagocytosis, lysis of cells, and immune complex clearance. Regardless of the mechanism of activation, all three pathways converge at C3, which is the most abundant complement protein in the blood.
1. Complement activation
a. The alternative pathway of complement activation is triggered by the carbohydrates, lipids, and proteins that are often found on foreign surfaces, particularly bacteria and fungi. The precipitating event involves spontaneous hydrolysis of complement C3 followed by C3b covalently binding to nearby surfaces. Other complement components then associate to continue the cascade of activation.
b. The classical pathway is initiated by the association of complement component C1 with immune complexes containing IgG or IgM. Alternatively, C1 can bind to several pentraxin proteins that are synthesized in response to infection, including pentraxin 3 (PTX3) and the acute-phase proteins—C-reactive protein (CRP) and serum amyloid P-component (SAP). Binding of C1 then activates other complement components to continue the cascade of activation.
c. The lectin pathway is activated when the mannose-binding lectin (MBL) binds to the carbohydrate moieties found on the surface of many bacteria, fungi, and parasites. Binding of MBL induces a conformational change such that MBL-associated proteins are active to continue the cascade of activation.

2. Defensive functions of complement. In the initial stages of the complement cascade, individual components are cleaved into fragments (typically designated by lowercase letters) that sequentially generate biologically active molecules. Because one active complement molecule can act on multiple subsequent complement molecules, initially small-initiating signals can be rapidly amplified.
a. Opsonins produced by complement, chiefly C3b, are covalently attached to the target surface. Phagocytic cells that have receptors for C3b include neutrophils and resident tissue macrophages.
b. Anaphylatoxins (potent activators of inflammation) are peptides (C3a and C5a) that exert their effects by binding to receptors present on a number of different cell types. Anaphylatoxins act as chemoattractants for phagocytes, stimulate vasodilation and smooth muscle contraction, and induce histamine release and oxidative burst in mast cells and neutrophils, respectively.
c. The membrane attack complex (MAC), formed by complement components C5b678 and polymerized subunits of C9, lyses target cells by forming a pore in the target cell membrane.

d. Complement activation through the classical pathway is an important feature of immune complex clearance. Small immune complexes, consisting of antigen–antibody (IgG or IgM) and C3b, are efficiently bound to the complement receptors present on erythrocytes and are then removed from the surface of the erythrocyte in the liver and spleen.
e. Regulatory proteins present on the membrane of the host cell (complement receptor 1, membrane co-factor protein(CD46), decay accelerating factor, and CD59) or as soluble proteins in the plasma (factor I and factor H) act at different steps of the complement cascade to prevent the inappropriate activation of complement on host cells and tissues.

E. The acute-phase response (APR) is a coordinated response to a number of triggers, including proinflammatory cytokines and bacterial LPS. During the APR, the hepatic production of a number of proteins is increased, including complement factors such as C3, MBL, and C-reactive protein; coagulation factors such as fibrinogen, plasminogen, and tissue plasminogen activator; transport and metal-binding proteins; and immunomodulatory agents such as granulocyte colony-stimulating factor and IL-1 receptor antagonist.

F. Inflammation is a collection of events that rapidly occurs following tissue injury or infection. There are several inflammatory pathways; many of the individual steps of inflammation are controlled by cytokines or other small regulatory molecules that are often referred to as inflammatory mediators.
The inflammatory response is largely protective, although in certain circumstances, such as hypersensitivity reactions and autoimmune diseases, inflammation can be the major mechanism of harm to the body. The hallmark signs of inflammation are pain, redness, swelling, and heat, most of which can be attributed to vasodilation of the local blood vessels, increased local vascular permeability (edema), and the inflammatory mediators that assist with leukocyte transmigration from the circulation to the tissue.

G. Phagocytic cells (neutrophils and monocytes/macrophages) are important cells of the innate immune defense system.
1. The phagocytes are recruited to sites of inflammation by adhesions that are expressed on local endothelial cells. The phagocytes then migrate to the site of the infection by following the concentration of inflammatory mediators.
2. Phagocytic cells can engulf bacteria, cellular debris, and other particulate matter via a number of recognition mechanisms. Neutrophils and macrophages also have a number of pattern recognition receptors (PRRs) that can bind directly to pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide, peptidoglycan, lipoteichoic acids, and mannans, which are widely expressed by microbial pathogens as repetitive motifs but are not present on host cells or tissues. Phagocytes also have receptors to bind to opsonins, such as antibody and complement.
3. Components that have been engulfed by a neutrophil or macrophage are initially contained within a membrane-bound vesicle, which then fuses with cytoplasmic granules containing defensins, lysozyme, lactoferrin, proteases, and other enzymes. The cell also acidifies the vesicle by actively pumping hydrogen ions into the interior. Phagocytes also synthesize a number of powerful oxidizing agents (superoxide anion, hydrogen peroxide, and hydroxyl radicals) via oxidative pathways (respiratory burst or oxidative burst).

H. Toll-like receptors (TLRs) are a family of pattern-recognition receptors of innate immunity that are present on many types of leukocytes, especially macrophages, dendritic cells, and neutrophils. Each type of TLR is specific for a different type of common pathogen component, such as lipopolysaccharide, teichoic acid, flagellin, and double-stranded RNA. TLRs share structural homology to each other and are membrane associated, being associated with either the outer membrane or internal membrane structures, depending on the PAMP that they recognize. Upon binding, TLRs induce phagocyte activation, enable the initiation of the adaptive immune response, and elicit the production of various cytokines for further immune function.

Comprehensive Pharmacy Review
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