Human Defense Mechanisms.docx

Human Defense Mechanisms Inflammation can be specific (and is also called the immune response) or non-specific (also termed the inflammatory response). Inflammation can be innate (meaning natural or present at birth) or acquired (evolving over time after birth). We are all born with the same innate...

Human Defense Mechanisms Inflammation can be specific (and is also called the immune response) or non-specific (also termed the inflammatory response). Inflammation can be innate (meaning natural or present at birth) or acquired (evolving over time after birth). We are all born with the same innate abilities to protect ourselves, but each one of us will each vary in our ability to acquire immunity based on our individual experiences with exposure to pathogens and foreign antigens over our lifetime. We will all develop our own unique immune systems, tailored just for us. So, we have three types of defense mechanisms: Natural barriers (our first line of defense) include the epithelial layer of the skin and mucous membranes lining the gastrointestinal, genitourinary and respiratory tracts. These are called natural ‘physical’ barriers. These physical barriers can include mechanical and chemical types. Mechanical means of ridding the body of pathogens include sloughing, sneezing, coughing, vomiting, urinating and the cilial action of the respiratory tract. As well, low skin temperatures discourage the growth of bacteria. Chemical barriers include mucous, perspiration, saliva, tears, and earwax that trap and kill microorganisms. Some of these barriers contain enzymes, fatty and lactic acids and antimicrobial proteins that destroy bacteria. Similarly, our own normal bacterial flora are capable of producing chemicals to keep pathogens at bay. Inflammation (our second line of defense) is the primary focus of this module and will be discussed in more detail shortly. Immunity is considered our third line of defense and is an acquired, specific and adaptive ability. Over time, our immune system develops specific antibodies designed to target specific antigens and this defense mechanism has memory. This means that upon first exposure to an antigen, our immune system makes antibodies targeted toward that antigen. Then, upon subsequent exposure to that same antigen, those antibodies that ‘match’ the antigen will be called to action to fight off new infection. In your readings, you will also come across terms like ‘humoral’ and ‘cellular’ in reference to inflammation and immunity. These terms simply tell us where the inflammatory response originates. Humoral implies that the response comes from the blood or plasma components. Humoral response in inflammation involves complement factors while in immunity, it involves the formation and action of antibodies. The cellular response refers to a cell-derived process. In inflammation, the involved cells are neutrophils and macrophages and in the immune response, we are talking about lymphocytes. Goals of Inflammation The goals of inflammation include: •Movement of all the necessary blood and cellular components to the site of injury or insult •Delivery of nutrients and blood cells to eradicate the offender •Dilution, confinement and elimination of the offending agents •Stimulation and facilitation of components of the immune system •Promotion of healing with generation of new tissue How are these goals accomplished? There are three major events that occur pretty much simultaneously and include: The first is an increased metabolic rate. When called upon to fight injury or infection, cells step up their usual daily routines and increase production of the necessary items for battle. As a result, we increase our heat production, our oxygen and glucose consumption and our production of wastes. Secondly, we have dilation of blood vessels to help speed up delivery of the inflammatory components to the site of injury. And finally, we have an increased capillary permeability which allows for movement of white cells, (specifically neutrophils) proteins and nutrients out of the blood vessels and into the tissue where they can go to work. Cells Involved in Inflammation Before we examine the processes involved in inflammation, it would first be helpful to review the functions and roles of the cells involved in these processes. Normally, cells float within our blood vessels continuously and harmoniously. In response to inflammation though, each cell type springs into action to perform a very specific function. There are numerous biochemical mediators released from mast cells, plasma proteins and dying cells which trigger the production of ‘adhesion molecules’ on the surface of many cells. Adhesion molecules cause these cells to stick to, or ‘adhere’ to the endothelium. Let’s look at each of the cell types involved in the inflammatory response, beginning with the endothelium. Endothelial Cells: Endothelial cells line the walls of blood vessels and normally maintain very close contact with each other. The space between them is very tight, limiting the movement of cells and particles across the vessel wall. In addition to this ‘traffic control’ function, endothelial cells also: Produce antiplatelet and antithrombotic agents to prevent formation of clots Produce both vasoconstrictors and vasodilators to regulate flow Regulate leukocyte extravasation through the use of adhesion molecules Regulate immune cell proliferation through secretion of colony-stimulating factors Participate in the repair process through angiogenesis and formation of an extracellular matrix Platelets: These cells are also referred to as thrombocytes and they circulate passively until activated by products of tissue degradation like collagen, thrombin, and platelet activating factor. Their primary role is one of hemostasis or the stemming of blood flow. Once activated, they produce potent inflammatory mediators which result in increased vascular permeability, chemotaxis, adhesive and proteolytic properties of the endothelium Neutrophils: These cells represent one type of granulocyte (so named because enzyme-containing lysosomal granules are found within their cytoplasm) and are considered the chief phagocytic leukocytes. We’ll talk more about phagocytosis a little later. Early in the inflammatory response (about 90 minutes to 6-12 hours post injury), these cells are attracted to the site of injury by chemotactic factors. On their surface are found a number of different ‘receptors’ each designed to recognize and interact with certain substances such as bacterial glycoproteins, microbes, cytokines, chemokines. Because of their lysosomal enzymes, they are called upon to destroy invaders and remove subsequent debris. Once they themselves die off, they become exudate, or pus. In the presence of inflammation, neutrophils are released from bone marrow and the neutrophil count will rise. They are relatively short-lived because they are incapable of division, and when they die off, they release macrophage chemotactic factor to attract macrophages to the site of injury. In the presence of severe inflammation, as demand for neutrophils increases, the bone marrow can’t quite keep up and releases immature neutrophils called ‘bands’. When the ‘band’ count is elevated on a CBC, we then know that the bone marrow is overworked and trying valiantly to keep up with an on-going inflammatory process. Monocytes/Macrophages: Like the neutrophils, monocytes are also leukocytes derived from bone marrow, but contain larger and fewer lysosomes than their counterparts. They too, express receptors that interact with a variety of substances. Typically, monocytes exit the circulation in response to inflammation and take up residence in various tissues as the more mature macrophage. Monocytes then, are considered to be an immature form of macrophage. Macrophages are named according to their tissue location- some examples include Kupffer cells in the liver, alveolar macrophages in the lung, microglia in the brain to name a few. Macrophages arrive at the site of inflammation a little later than the neutrophils (about 24-48 hours post injury). Eventually, they replace the neutrophils as they die off. Macrophages are often associated with chronic inflammation as they are somewhat sluggish. Monocytes/macrophages differ somewhat from neutrophils in other ways too. They produce very potent vasoactive mediators (prostaglandins, leukotrienes, platelet activating factor, inflammatory cytokines and growth factor) and they engulf more material than neutrophils. Their lifespan is 3-4x longer than neutrophils and they also interact with the immune system. Macrophages are responsive to lymphokines from T cells which enhance their efficacy and work with the immune system by processing and presenting antigens to the lymphocytes and by stimulating growth and differentiation of granulocytes and monocytes in the bone marrow and substances that promote wound healing. Eosinophils: Eosinophils are granulocytes with many lysosomes. They contain biochemical mediators of inflammation and are especially prominent in the allergic response and hypersensitivity disorders. As well, they are particularly good at tackling parasitic infections. Like their counterparts, eosinophils circulate in the blood until they are needed to respond to insult or injury. Then, they migrate to the tissues where they modulate release of inflammatory mediators and degrade vasoactive molecules, controlling the vascular effects of histamine and serotonin. Basophils: Basophils are very similar in function to eosinophils. They too, produce lipid mediators and cytokines to induce the inflammatory response. They too, are important in the allergic and hypersensitivity reactions. They also interact with the immune system in that they bind to IgE through receptors on their cell surface. This action triggers the release of histamine and vasoactive agents. Mast Cells: In just a few moments, we will be discussing the role and function of mast cells in great detail. Suffice it to say, they are considered the most important activators of the inflammatory response, by performing two functions: degranulation and synthesis of mediators.