Page 100 Complete Your CE Test Online - Click Here The following definitions provide a brief overview and function of these terms (Delves, 2017; Neviere, 2017; Jaffer, Wade, & Gourlay, 2010). ● ● Phagocytic cells ingest and destroy microbial components. Phagocytic cells include neutrophils present in blood and tissues, monocytes in blood, and macrophages in tissues. ● ● Natural killer cells are responsible for destroying tumor cells and cells infected with viruses. ● ● Leukocytes include neutrophils, eosinophils, basophils, monocytes, and macrophages. Leukocytes are the cells present in the inflammatory response. ● ● Polymorphonuclear neutrophils (PMNs) are the main cellular participants in the acute inflammatory process. Neutrophils are the first responders to the site of injury or infection. They are stored in the bone marrow, circulate via blood, and accumulate at the site of injury or infection. ● ● Complement system is a protein cascade that helps clear pathogens from the host. ● ● Cytokines are small proteins that are chemical mediators that recruit immune cells to the site of infection or injury. Cytokines are key in the proinflammation and anti-inflammation response of the body and play a pivotal role in the development of sepsis. ● ● Chemokines are small molecules that direct the movement of leukocytes. Inflammatory chemokines are produced in response to bacterial toxins and inflammatory cytokines. Our innate immune response is known as the first line of defense against an invading organism and is an immediate response by our body. Upon the initial invasion of the harmful organism, blood vessels dilate and the injured tissue or site of infectious agent is flooded with fluid, coagulation factors, cytokines, chemokines, platelets, and inflammatory cells that include white blood cells (also known as leukocytes), such as neutrophils, monocytes, macrophages, eosinophils, and basophils. The increase of blood flow to the injured area is responsible for the heat and redness associated with the acute inflammatory response. Increased vascular permeability is responsible for localized edema. White blood cells – such as macrophages in the tissues, neutrophils in the blood and tissues, and monocytes in the bloodstream – recognize the invader and bind to it. There are three different ways this recognition and binding may occur (Neviere, 2017): 1. Pattern recognition receptors (PRRs): PRRs are located on the surface of immune cells and may recognize the invader by the molecular pattern of the pathogen. PRRs are responsible for alerting the immune cells of the body that there is an invading organism. To use an army analogy, PRRs are like the watchmen who are on the lookout for an approaching enemy army. They notice the enemy army by their uniform and call the troops (the immune cells) to fight the invaders. Following are the three families of PRRs: ○ ○ Toll-like receptors (TLRs). ○ ○ Nucleotide-oligomerization domain (NOD). ○ ○ Retinoic acid-inducible gene (RIG-1). 2. PRRs can also recognize danger signals or patterns associated with a given invader that is released during the inflammation process. 3. The triggering receptor on myeloid cells (monocytes, macrophages, and granulocytes, collectively) can recognize and bind to microbial components. In general, when the immune cells (the troops) are recruited to local tissues and bind to infectious agents for phagocytosis, the binding process activates inflammatory cytokines (Kawamoto & Minato, 2004; Neviere, 2017). More specifically, immune cells bind to the invader, and Toll-like receptors (TLRs) activate the nuclear factor (NF-kb) within the monocyte, which then leads to the production of proinflammatory cytokines known as tumor necrosis factor (TNF-a) and interleukin 1 (IL-1) (LaRosa, 2010). TNF-a and IL-1 also activate the coagulation cascade (explained below) and cause the production of prostaglandins, leukotrienes, platelet-activating factor, and phospholipase A2 (LaRosa, 2010). The function of cytokines is to regulate the inflammatory response, including the coagulation cascade, and trigger more inflammatory immune cells (leukocytes) to go to the location of infection (Shulte, Bernhagen, & Bucala, 2013). Chemokines, molecules that direct the movement of the immune cells to the site of injury or invasion, help out in a process known as chemotaxis. Normally, anti-inflammatory cytokines are activated in the immune response. Their purpose is to regulate and suppress the immune system to prevent an exaggerated inflammatory response (Neviere, 2017). Anti-inflammatory cytokines and regulatory proteins of the complement system work together to stop the inflammatory process when the threat to the host is no longer present (Markiewski, DeAngelis, & Lambris, 2008). There is a definitive endpoint in the normal immune system response when the invader is phagocytosed and neutralized and debris is cleared. In sepsis, this endpoint is not realized, and the response spreads. Acquired immunity Acquired immunity (also known as adaptive immunity) relies on previous exposure to an invader. Acquired immunity includes white blood cells, such as lymphocytes, T cells and B cells. They make up between 20% and 40% of the white blood count and are important in fighting off infection (Foxx, 2016). The acquired immune system is activated if the innate response has not entirely rid the body of infection – both types of immunity work simultaneously to rid the body of infection. The acquired immune system has a specific plan to fight off the invading organism through experience of previous exposure. If the infection remains localized and the invading organism has been entirely neutralized through innate and acquired immune function, tissue is repaired, healing is complete, homeostasis resumes, and the body is rid of infection. Complement system The complement system is an important defense mechanism in fighting off infections and is activated during the innate immune response. Proteins are released that help with the destruction of microorganisms and help control the inflammatory reaction. These proteins act as a bridge between the innate and adaptive immune response (Markiewski et al., 2008). Regulatory complement proteins work to halt the inflammatory process after the successful removal of the invading organism or resolution of injured tissue (Markiewski et al., 2008). Coagulation cascade During the normal immune system response, inflammatory cytokines (specifically IL-1 and TNFa), in response to injury or invasion, trigger the release of tissue factors. This begins the coagulation cascade. This leads to the production of thrombin and fibrin and eventually to the formation of clots that help keep invading organisms localized. Bradykinin, a peptide, is a key component of the coagulation cascade that also causes increased vascular permeability and vasodilation. It is responsible for the inflammatory-mediated pain response that occurs during the process of acute inflammation and contributes to hypotension secondary to vasodilation. The following key points further describe the process. Key points ● ● Two types of immunity respond to an invader, innate immunity that we are born with and acquired or adaptive immunity that develops after exposure to an invader. ● ● Upon invasion from an organism, blood vessels dilate, and the site of invasion is flooded with coagulation factors, cytokines, chemokines, platelets, and inflammatory cells (white blood cells, such as neutrophils, macrophages, monocytes, eosinophils, and basophils). ● ● White blood cells – such as neutrophils, macrophages, and monocytes – recognize the invader and bind to it, causing the release of inflammatory cytokines. Elevated white blood counts indicate the presence of organisms that may lead to sepsis.