Companion Notes to WE#6; Weichhart et al; Immunity 2008 The innate immune system; is an important subsystem of the overall immune response system that comprises the cells and mechanisms that defend the host from infection by other organisms. The cells of the innate system recognize and respond to pathogens in a generic way, but, unlike the adaptive immune system, the system does not confer long-lasting or protective immunity to the host. Innate immune systems provide immediate defense against infection, and are found in all classes of plant and animal life. The major functions of the vertebrate innate immune system include: • Recruiting immune cells to sites of infection, through the production of chemical factors, including specialized chemical mediators, called cytokines • Activation of the complement cascade to identify bacteria, activate cells, and promote clearance of antibody complexes or dead cells • Identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialized white blood cells • Activation of the adaptive immune system through a process known as antigen presentation Acting as a physical and chemical barrier to infectious agents. Prolonged inflammation, Chronic inflammation, a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. It is useful to differentiate between inflammation and infections, as there are many pathological situations where inflammation is not driven by microbial invasion - for example, atherosclerosis, type III hypersensitivity, trauma, and ischaemia. There are also pathological situations where microbial invasion does not result in classic inflammatory response—for example, parasitosis, which leads to an eosinophilia. Antigen-presenting cell (APC) is a cell that displays antigen complexed with major histocompatibility complexes (MHCs) on their surfaces; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). These cells process antigens and present them to T-cells. Almost all cell types can serve as some form of APC, and APCs are found in a large variety of tissue types. Professional antigen-presenting cells, including macrophages, B cells, and dendritic cells, specialize in presenting foreign antigen to T helper cells, while other cell types can present antigen originating inside the cell to cytotoxic T cells. In addition to the MHC family of proteins, Antigen presentation relies on other specialized signaling molecules on the surfaces of both APC’s and T cells. The APC’s are vital for an effective adaptive immune response, as the functioning of both cytotoxic and helper T cells are dependent on APCs. Antigen presentation allows for the extreme specificity of adaptive immunity and can contribute to immune responses against both intracellular and extracellular pathogens. It is also involved in defense against tumors. Dendritic cells (DCs) are one of the APC’s of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and the adaptive immune systems. 1 DC are present in those tissues that are in contact with the external environment, such as the skin and the inner lining of the nose, lungs, stomach and intestines. They can also be found in an immature state in the blood. Once activated, they migrate to the lymph nodes where they interact with T cells and B cells to initiate and shape the adaptive immune response. Macrophages engulfs and digests cellular debris, foreign substances, microbes, cancer cells, and anything else that does not have the types of proteins specific of healthy body cells on its surface in a process called phagocytosis. These large phagocytes are found in essentially all tissues, where they patrol for potential pathogens by amoeboid movement. Besides phagocytosis, they play a critical role in nonspecific defense (innate immunity) and also help initiate specific defense mechanisms (adaptive immunity) by recruiting other immune cells such as lymphocytes. They are important APC’s to T cells. In humans, dysfunctional macrophages cause severe diseases such as chronic granulomatous disease that result in frequent infections. Beyond increasing inflammation and stimulating the immune system, macrophages also play an important anti-inflammatory role and can decrease immune reactions through the release of cytokines. Macrophages that encourage inflammation are called M1 macrophages, whereas those that decrease inflammation and encourage tissue repair are called M2 macrophages. This difference is reflected in their metabolism; M1 macrophages have the unique ability to metabolize arginine to the "killer" molecule NO, whereas M2 macrophages have the unique ability to metabolize arginine to the "repair" molecule ornithine. They can be identified by their expression of specific of proteins such as CD14, CD40, CD11b, CD64, F4/80 (mice)/EMR1 (human), lysozyme M, MAC-1/MAC-3 and CD68. Monocytes are a type of leukocytes. They are the largest of all leukocytes and are precursors to macrophages, dendritic cells and foam cells. They are part of the innate immune system of vertebrates including all mammals, birds, reptiles, and fish. They are amoeboid in shape, having agranulated cytoplasm. Monocytes have unilobar nuclei, which, makes them one of the types of mononuclear leukocytes (containing azurophil granules). The archetypal idea of the nucleus is that it is bean-shaped or kidney-shaped, although the most important distinction is that it is not deeply furcated into lobes, as occurs in polymorphonuclear leukocytes. Monocytes constitute 2% to 10% of all leukocytes in the human body. They play multiple roles in immune function. Such roles include: (1) replenishing resident macrophages under normal states, and (2) in response to inflammation signals, monocytes can move quickly (approx. 8–12 hours) to sites of infection in the tissues and divide/differentiate into macrophages and dendritic cells to elicit an immune response. Half of them are stored in the spleen and change into macrophages after entering into the tissue spaces, and in endothelium can transform into foam cells. Neutrophil (PMN) granulocytes are the most abundant type of granulocytes and the most abundant (40% to 75%) type of white blood cells in most mammals. They form an essential part of the innate immune system. Functionality varies in different animals. They are formed from stem cells in the bone marrow. They are short-lived and highly motile, or mobile, as they can enter parts of tissue where other cells/molecules wouldn't be able to enter otherwise. Neutrophils may be subdivided into segmented neutrophils and banded neutrophils (or bands). They form part of the polymorphonuclear cell family (PMNs) together with basophils and eosinophils. The name neutrophil derives from staining characteristics on hematoxylin and eosin (H&E) 2 histological or cytological preparations. Whereas basophilic white blood cells stain dark blue and eosinophilic white blood cells stain bright red, neutrophils stain a neutral pink. Normally, neutrophils contain a nucleus divided into 2–5 lobes. Neutrophils are a type of phagocyte and are normally found in the bloodstream. During the beginning (acute) phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation. They migrate through the blood vessels, then through interstitial tissue, following chemical signals such as Interleukin-8 (IL-8), C5a, fMLP and Leukotriene B4 in a process called chemotaxis. Neutrophils are recruited to the site of injury within minutes following trauma, and are the hallmark of acute inflammation; however, due to some pathogens being indigestible, they can be unable to resolve certain infections without the assistance of other types of immune cell. Neutrophils undergo a process called chemotaxis, which allows them to migrate toward sites of infection or inflammation. Cell surface receptors allow neutrophils to detect chemical gradients of molecules such as interleukin-8 (IL-8), interferon gamma (IFN-γ), C3a, C5a, and Leukotriene B4, which these cells use to direct the path of their migration. Neutrophils have a variety of specific receptors, including ones for complement, cytokines like interleukins and IFN-γ, chemokines, lectins, and other proteins. They also express receptors to detect and adhere to endothelium and Fc receptors for opsonin. 3 T helper cells (Th cells) are a type of T cell that play an important role in the immune system, particularly in the adaptive immune system. They help the activity of other immune cells by releasing T cell cytokines. These cells help suppress or regulate immune responses. They are essential in B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages. + + Th cells express the surface protein CD4 and are referred to as CD4 T cells. Such CD4 T cells are generally treated as having a pre-defined role as helper T cells within the immune system. For example, when an APC expresses an antigen on MHC class II, a CD4+ cell will aid those cells through a combination of cell to cell