Immunology. Richard Coico

Immunology - Richard Coico


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extravasation is a process that undergoes the following sequential steps: tethering, rolling, activation, adhesion, crawling, and transmigration, with each step relying on the function of a defined set of molecules.

Schematic illustration of leukocyte adhesion to endothelium leads to their adhesion, activation, and extravasation from the blood to tissue where they are needed to help destroy pathogens such as bacteria that initiate this response

      Collectively, these events manifest the triad of clinical signs of inflammation: pain, redness, and heat. These can be explained by increased blood flow, elevated cellular metabolism, vasodilation, release of soluble mediators, extravasation of fluids that move from the blood vessels to surrounding tissue, and cellular influx. Pain is caused by increased vascular diameter, which leads to increased blood flow, thereby causing heat and redness in the area. As discussed below, subsequent reduction in blood velocity and concomitant cytokine‐induced and kinin‐induced increased expression of adhesion molecules on the endothelial cells lining the blood vessel promote the binding of circulating leukocytes to the vessel. These events facilitate the attachment and entry of leukocytes into tissues and the recruitment of neutrophils and monocytes to the site of inflammation. Another major change in the local blood vessels is increased vascular permeability. This results from the separation of previously tightly joined endothelial cells lining the blood vessels leading to the exit of fluid and proteins from the blood and their accumulation in the tissue. These events account for the swelling (edema) associated with inflammation, which contributes significantly to the pain, and to the attendant redness and heat associated with the accumulation of cells to the site.

      Most of the cells involved in inflammatory responses are phagocytic cells, consisting mainly of the polymorphonuclear leukocytes that accumulate within 30–60 minutes, phagocytize the intruder or damaged tissue, and release their lysosomal enzymes in an attempt to destroy the intruder. If the cause of the inflammatory response persists beyond this point, within 4–6 hours the area harboring the invading microorganism or foreign substance will be infiltrated by macrophages and lymphocytes. The macrophages supplement the phagocytic activity of the polymorphonuclear cells, thus adding to the defense of the area. They also participate in the processing and presentation of antigens expressed by the invading pathogen or foreign substance to T cells, which then generate antigen‐specific responses. Activated T cells synthesize and release a variety of cytokines that proactively stimulate antigen‐specific B cells, thus facilitating antibody production. Within 5–7 days, antibodies produced by these B cells are detectable as serum antibodies and thus become part of the humoral immune defense arsenal.

      Localized Inflammatory Responses: Roles of Kinins and the Coagulation Pathway

      Activation of the kinins and the coagulation system also contributes to localized inflammatory responses. Once activated, the kinins have several important localized effects on cells and organ systems. Together with the locally released cytokines, they (1) act directly on local smooth muscle and cause muscle contraction; (2) act on axons to block nervous impulses, leading to distal muscle relaxation; and (3) act on vascular endothelial cells, causing them to contract and leading to increase in vascular permeability.

      Kinins are very potent nerve stimulators and are the molecules most responsible for pain (and itching) associated with inflammation. They are rapidly inactivated after their activation by proteases, which are generated during these localized responses.

      Following kinin‐induced damage to blood vessels, the coagulation pathway is activated. Plasma enzymes are activated in a cascading manner contributing to the inflammatory response by forming a physical barrier with platelets (clot or thrombus) that prevents microorganisms from entering the bloodstream. The simultaneous activation of kinins and the coagulation system during inflammatory responses thus produces inhospitable conditions for invading pathogens as well as new physical barriers to limit their ability to use the circulatory system to gain entry to distal tissues and organs.

      The Acute Phase Response

Schematic illustration of the acute phase response stimulated by cytokines produced by innate immune cells
Protein Immune system function
C‐reactive protein Binds to phosphocholine expressed on the surface of dead or dying cells and some types of bacteria Opsonin
Serum amyloid P component Opsonin
Serum amyloid A Recruitment of immune cells to inflammatory sites Induction of enzymes that degrade extracellular matrix
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