Introduction The innate immune system provides the first line of defense against pathogens It consists of multiple lines of defense including physical barriers such as mucous membranes soluble proteins such as complement specialized cells such as neutrophils The innate immune system is broadly effective but not adaptive because all components are germline encoded (not subject to recombination) components recognize conserved molecular patterns The innate immune system interacts with the adaptive immune system in important ways such as activation of the adaptive immune system by antigen presenting cells serving as effectors of the adaptive immune system Innate Immune Activation The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) PAMPs are structures that are conserved among large pathogen classes including lipopolysaccharides (LPS) in gram-negative bacteria lipoteichoic acids in gram-positive bacteria double stranded RNA in some viruses PAMPs are not present on mammalian cells ensuring that innate immune components do not damage the host detection of PAMPs indicates that pathogens are nearby PAMPs are detected by diverse pattern recognition receptors (PRRs) that are present in all innate immune cells trigger the acute inflammatory response upon being activated The Acute Inflammatory Reponse The acute inflammatory response is triggered when pathogens have breached the physical barriers of the body PAMPs are released and bind to local PRRs The acute inflammatory response consists of a release of soluble proteins into the bloodstream an early (< 5 hours) mobilization of neutrophils a late (> 5 hours) recruitment of macrophages The soluble protein response is known as the acute phase reaction stimulated by interleukin-6 release The protein components of the acute phase reaction consist of C-reactive protein which fixes complement and facilitates phagocytosis ferritin which binds and sequesters iron fibrinogen which promotes endothelial repair hepcidin which decreases iron absorption and iron release serum amyloid A which can accumulate during chronic inflammation Neutrophils are recruited in a coordinated fashion After arrival, neutrophils perform a variety of actions including generation of reactive oxygen species recruitment of macrophages for phagocytosis and antigen presentation Neutrophil Recruitment Neutrophil recruitment is a key part of the innate immune response because they phagocytose and damage pathogens recruit additional immune cells create a proinflammatory environment Neutrophil recruitment is a tightly coordinated process Steps Involved in Neutrophil Recruitment Stage Purpose Mediators Magination Dilates blood vessels around areas of damage Allows blood to flow slowly in potentially infected areas Nitric oxide Other vasoactive substrances Rolling Loose attachment of neutrophils to vessel walls Concentrates neutrophils near the endothelial cells of areas that have been previously damaged Selectins Glycoproteins Adhesion Tight attachment of neutrophils to the epithelium Stops the movement of neutrophils and primes them for further activity LFA integrins ICAM proteins Extravasation Diapedesis of neutrophils across vessel wall Localization of neutrophils to region of damage Integrins Pseudopodia Chemotaxis Extravascular attraction of neutrophils to pathogens Migration of neutrophils to sites of highest pathogen concentration IL-8 C5a Leukotriene B4 5-HETE Formyl-methionyl peptides Effector Mechanisms Three key effector mechanisms used by the innate immune system include opsonization of pathogens phagocytosis of pathogens generation of reactive oxygen species Opsonization is the process by which effector mechanisms are enhanced by coating pathogens with C3b and other opsonins recognition of opsonins by specific receptors on macrophages and neutrophils Phagocytosis is the process by which pathogens can be degraded and includes formation of pseudopodia around pathogenic material envelopment of the material by a phagosome fusion of the phagosome to endsomal and lysosomal compartments digestion of the material by degradative enzymes Reactive oxygen species are toxic metabolites that are used to damage pathogenic structures tightly controlled by inactivating enzymes Enzymes Involved in Reactive Oxygen Species Metabolism Activators Function Inhibitors Function NADPH oxidase Transform oxygen into superoxide radicals Glutathione peroxidase Inactivation of hydrogen peroxide into water by oxidizing glutathione Superoxide dismutase Transform superoxide radicals into hydrogen peroxide Glutathione reductase Reduction of glutathione to original state by oxidizing NADPH to NADP+ Myeloperoxidase Transformation of hydrogen peroxide into hypochlorite (bleach) Final toxic compound used to damage pathogens G6PD Reduction of NADP+ to original state via the hexose monophosphate shunt