Term
Professional Phagocytes
- (phagocytosis = ingestion of particles) |
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Definition
•Monocytes
–Blood borne pool of cells, can move to sites where needed
–Kill microbes; process and present antigen
•Not as mature or effective, in general, as macrophages
•Macrophages
–Resident in tissues
•Kupffer cells (liver)
•Alveolar macrophages (lung)
•Microglial cells (brain)
•Osteoclasts (bone)
–Kill microbes; process and present antigen
–Other roles in cellular homeostasis
•Repair damaged tissue
•Remodel bone
•Neutrophils
–Blood borne pool of cells, can move to sites where needed
–Kill microbes; do not present antigen
•Dendritic cells
–Primary function is antigen processing and presentation
–Also can make cytokines and chemokines
–Involved in innate immunity
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Term
The Strategy of Phagocytosis |
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Definition
•The anti-microbial strategy involving phagocytes could be described as a distributed defense (not centralized).
–Phagocytes are resident in some tissues/areas of the body (i.e. monocytes and neutrophils in the blood; macrophages and dendritic cells in organ tissue)
–Can quickly move into tissues as infection, trauma, or other stimuli attract them
–Inflammation/immune response begins
•This contrasts with the strategy for initiating acquired immune responses, which is centralized.
–Microbial antigens (either from lymph or ingested by dendritic cells accumulate in lymphoid tissues, e.g., lymph nodes)
–Lymphocytes travel through, and those specific for the antigen respond, and then initiate the appropriate immune response
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Term
The Process - Extravasation |
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Definition
•Monocytes, neutrophils, and other immune cells (within the blood) roll along the vascular endothelium under normal conditions
•Upon a signal, they stop, squeeze through the endothelium and enter organ tissue
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Term
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Definition
•Leukocytes moving on the endothelium or those cells in various organ tissues can move towards a site of infection by a process called diapedesis “crawling”
•This is a directed process in which the cells move towards a concentration of chemoattractants, such as chemokines (i.e. IL-8) or bacterial products such as N-formyl peptides
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Term
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Definition
•A variety of surface receptors on phagocytes bind to microbial components
•Mannose receptor, glucan receptor, scavenger receptor, toll-like receptors (TLR1-TLR11) and CD14 all bind directly to microbial components leading to production of inflammatory mediators and phagocytosis
•Others such as CD11b/CD18 (CR3) and FcR bind to coated bacterial products/bacteria
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Term
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Definition
• Professional phagocytes have complement receptors (CR1, CR2, CR3).
• For example, CR3, which is comprised of CD11b/CD18, enhances phagocytosis of complement-coated microbes.
•Phagocytic cells have receptors that bind to antibody-coated particles. In some cases (e.g., bacteria with capsules), binding and phagocytosis may be minimal without antibody, complement, or C-reactive protein to act as an opsonin.
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Term
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Definition
•An Opsonin is a molecule that acts as a bindingenhancer for the process of phagocytosis. |
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Term
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Definition
•A wide array of microbial components (e.g. LPS), as well as cytokines (e.g., interferon-g) activate macrophages (and other cells) to produce products that contribute to inflammation and/or to make phagocytes more effective microbe killers.
•Direct activation is often mediated through Pathogen Associated Molecular Pattern (PAMP) receptors (i.e. toll-like receptors).
–For example, LPS is recognized by TLR4/CD14 and double stranded RNA (product of many viruses) is recognized by TLR3.
–DNA microarray (gene chip) experiments indicate that hundreds of inflammation/microbicidal-related proteins are upregulated when these receptors bind ligand.
•Note: Pathogens can interfere with TLR-signaling to prevent inflammation.
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Term
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Definition
•After recognition of microbial components by receptors on the surface of the phagocyte, the microbe is ingested by means of membrane invagination to produce a phagosome.
•The phagosome fuses with a lysosome, which possesses low pH and degradative enzymes, to form a structure that is termed, a phagolysosome.
•This, in most cases, kills the microbe.
•Opsonization with antibody generally enhances the process of phagocytosis
•Some microbes (e.g., Salmonella, Listeria, Mycobacteria), however, can withstand the phagolysosome environment, interfere with phagolysosome fusion or escape from the phagolysosome environment.
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Term
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Definition
•Most bacteria are effectively retained in phagosomes and destroyed when these fuse with lysosomes.
•However, Listeria monocytogenes can escape into the cytoplasm in unactivated macrophages (left panel). However, activation by exposure to IFN-g prevents this escape (right two panels).
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Term
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Definition
•Anti-microbial agents are found in lysosomes of monocytes, neutrophils, and macrophages.
•Activity/release can be triggered by cytokines or phagocytosis (i.e. respiratory burst leading to generation of reactive oxygen species).
•The respiratory burst generates large quantities of toxic oxygen metabolites that are potent anti-microbial agents.
•They are also often lethal to the phagocyte and may damage surrounding tissues; they are secreted into the extracellular fluid, as well as into phagosomes.
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Term
Specifics of Phagocytes Killing |
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Definition
•Neutrophils generate reactive oxygen species at near maximum levels when initially triggered.
•Macrophage (and monocyte) production of reactive oxygen species can be increased substantially if the cells are exposed to certain T cell-derived cytokines, such as IFN-g. Thus, although some microbes can be initially controlled by the innate immune system, they often require factors released by the cell-mediated immune response for clearance.
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Term
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Definition
•Microbes are broken down by enzymes in the phagolysosome to basic constituents (amino acids, etc.) for reuse by the macrophage or excretion.
•Via this process, peptides are generated that associate with MHC class II proteins, which are then transported to the cell surface for presentation to T cells.
•Dendritic cells are the most effective antigen presenting cells.
•Macrophages (and monocytes) can also perform this function, but they may require activation by cytokines for optimal performance.
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Term
Role in Resistance to Microbes |
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Definition
•Defects in phagocytes or phagocyte function are associated with profound immune defects.
•Reveals the importance of these cells in the immune response in humans.
•The effector mechanisms induced by antibody (neutralization and opsonization) ultimately depend on phagocytes (except at mucosal surfaces where inhibition of microbial attachment is also critical [barrier function]).
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Term
Role in Resistance to Cancer |
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Definition
•Tumor cells per se do not activate macrophages sufficiently to cause them to become tumoricidal. However, macrophages that are activated by other means can be beneficial (or harmful) to the host.
•They can kill cancer cells (become tumoricidal) and/or produce angiogenic or anti-angiogenic factors, which promote/prevent tumor development.
•Thus, macrophages may or may not be important in normal immune surveillance for cancer, but they may be useful in immunotherapy, if properly modulated.
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Term
Role in Wound Healing/Bone Remodeling/Cellular Homeostasis |
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Definition
•Tissue macrophages are largely responsible for recognizing, clearing, and recycling damaged or old leukocytes and red blood cells (in the tissue).
•Macrophages are responsible for clearing apoptotic and dieing cells before their internal contents are released and cause an aberrant inflammatory or necrotic response.
•Macrophages are involved in peripheral tissue repair by clearing dead tissue and connective tissue components, as well as in bone remodeling (in the bone, macrophages are called osteoclasts), healing, and growth, through their degradation of regions of the bone so further growth can occur.
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