What are the initial events in chronologic order resulting in an inflammatory response against a microbial pathogen
• Microbes breach the physical epithelial barrier. The innate immune system response begins with the epithelial secretion of alarmins (S100A and antimicrobial defensins).
• The complement pathway is activated by C3 and factor B binding to the microbial membrane (alternate pathway) and/or mannan-binding protein interacting with the microbe (lectin pathway). This results in the generation of the MAC and chemoattractants C3a and C5a that will recruit cells of the innate immune system.
• N -Formylmethionyl peptides from microbes activate neutrophils and macrophages, which in turn upregulate integrins for binding to the endothelium. These cells will produce chemoattractants to recruit additional immune cells, reactive oxygen intermediates to kill microbes, NETs to trap microbes, and cytokines to activate other components of the immune response.
• Local macrophages begin to phagocytize microbes and NETs.
• The presence of microbe PAMPs will trigger PRRs on epithelia and innate immune cells to signal cytokine (IL-1, IL-6, IL-8, TNFα) release.
• In response to cytokines (IL-1, TNFα) and other stimuli, LTs and PGs are synthesized. IL-1 and TNFα also upregulate endothelial cell adhesion molecules to facilitate the influx of neutrophils, monocytes, and lymphocytes into the invaded tissue.
• IL-6 stimulates the generation of acute phase proteins (CRP, fibrinogen, alpha-1-antitrypsin, alpha-2 macroglobulin, haptoglobin, serum amyloid A) by the liver. The acute phase response results in elevated erythrocyte sedimentation rate and CRP levels and a decrease in albumin.
• Complement activation products (C3a, C5a), IL-8, LTB 4 , and platelet-activating factor are chemoattractants for neutrophils and circulating monocytes. Monocytes enter inflammatory site and become macrophages.
• Neutrophils phagocytize microbes. Specific granules filled with degradative enzymes (lysozyme, collagenase, elastase) and azurophilic granules (lysosomes) destroy the phagocytized microbe. Neutrophils die at the inflammatory site, contributing to inflammation.
• Monocytes and macrophages become dominant effector cells 24 to 48 hours into inflammation.
• Inflammatory mediators released throughout this process contribute to cardinal signs of inflammation.
• PGE 2 : vasodilation (redness, warmth), increased vascular permeability (swelling), and increased pain sensitivity to bradykinin.
• Prostacyclin: vasodilation.
• Thromboxane A 2 : platelet activation.
• Platelet-activating factor: vasodilation, increased vascular permeability, platelet activation.
• Bradykinin: activates nerve fibers (pain).
• APCs (DCs) present antigen bound to MHC molecules to activate acquired (adaptive) immune system (T and B lymphocytes), occurring 3 to 5 days after microbial invasion.
