Transcript Phagocytes
Phagocytes In 1903 Almroyh Wright demonstrated that the effector function of phagocytes is triggered by immunoglobulins. It was replaced that the clearance function of phagocytic cells was emphasized in the definition of the reticuloendothelial system by Metchnikovian, and they act primarily by engulfing and digesting bacteria、cellular debris、 and other particulate matter. Phagocytic cells were divided into mononuclear phagocytes and neutrophil polymorphs. Macrophages (Mononuclear phagocytes) Macrophages are released from bone marrow as immature monocytes and mature in various tissue locations where they reside for weeks or years，and given different names in different tissues. Macrophages (Mononuclear phagocytes) Monocytes： – Large cells (12-20 um in diameter) with kidney-shaped nuclei, loose nuclear chromatin, and fairly abundant cytoplasm。 – There are cytoplasmic lysosomes， which are azurophilic lysosomal granules and contain lysozyme、 myeloperoxidase、and acid hydrolases. – They account for only 1-6% of all nucleated blood cells. – After released，they circulate for only about one day before setting into a permanent site of residence in a tissue, then called macrophages or histiocytes. Macrophages (Mononuclear phagocytes) Macrophages belong to a single lineage known as the mononuclear phagocyte system. They accumulate slowly at sites of infection, respond to a variety of stimuli and have considerable potential for synthesis, secretion and regeneration. They contain azurophilic lysosomal granules, also possess a non-specific esterase and produce various neutral proteases (such as collagenase, elastase, and plasminogen activator). Macrophages (Mononuclear phagocytes) Macrophages are able to control the actions of lymphocytes in at least two major ways： – Activated marcophages secrete potent immunoregulatory peptides that control lymphocyte polification, differentiation, and effector function。 – Activated marcophages are among the most important types of antigenpresenting cells。 Neutrophils (Neutrophil polymorphs) Neutrophils are polymorphonuclear, which are known as segmented neutrophils (segs) or polymorphonuclear leukocytes (polys or PMNs). They mature, are stored in bone marrow, are released rapidly into circulation in response to various stimuli, and make up an army of more or less idetical circulating phagocytes that are poised to respond quickly and in vast numbers wherever tissue injury has occurred. Neutrophils (Neutrophil polymorphs) They are end-cell (即terminally differentiated)，在其轉移進入組 織前，在循環系統僅停留數小時， 進入組織後也僅能存活1-2天。 依neutrophil granules可將其分為 兩類：azurophilic granules (除含 lysozyme、myeloperoxidase、and acid hydrolases外，尚有defensins、 serprocidins等具抗菌性的陽離子 性蛋白)及specific granules (含 lactoferrin、lysozyme、 histaminase and transcobalamin II) Common features of phagocytes responses 不論何種吞噬細胞，均經由chemotaxis、target recognition、 ingestion、killing and degradation等四步驟進行吞噬並達到 消滅外來細胞。 Chemotaxis 受傷組織會釋出一些生化物質(稱為chemotactic factors)，利用這 些物質濃度關係吸引吞噬細胞迅速靠近。 對neutrophils而言，chemotactic factors可分為endogenous (hostderived molecules)及exogenous (derived by foreign cell metabolism)， 且neutrophils細胞表面具有chemotactic factors的受器。 • 對macrophages而言， 需經過活化增加其 metabolic rate、 molility及phagocytic activity，因此其細胞 表面亦具有許多受器 接受刺激活化。 Target Recognition 利用細胞表面受器與外來細胞表面之特殊醣基 (specific sugar residues, such as mannose、glycan、or lipopolysaccharide)接合 而認識外來細胞。 Target recognition is greatly enhanced when specific antibody of class IgG and/or C3b becomes fixed to the target surface (即會受 到抗體或補體的調理作用)。 Neutrophils及macrophages均具有IgG1及IgG3 Fc fragment、 C3b、iC3b specific receptors；neutrophils具有IgA Fc fragment lower affinity receptor。 Ingestion Plasma membrane gradually envelops the ingested particle and buds off the surface membrane internally to form the phagosome。 Three major pathways for bringing extracellular materials into cell： – Pinocytosis (cell drinking)：formation of minute surface vesicles filled with unmodified extracellular fluid。 – Receptor-mediated endocytosis：to be triggered by the binding of a soluble ligand to one or more specific surface receptors；the resulting polymerization of clathrin protein on the cytoplasmic aspect of the plasma membrane leads to invagination of the receptor and formation of a coated pit。 – Phagocytosis：multiple surface receptors sequentially engage the surface of a target particle，usually >100 um in diameter。 • Phagosome fuses with lysosomal granules to form the phagolysosome。 Killing and Degradation 吞噬細胞毒殺作用可藉由一些cytokines的刺激，如IFN-γ刺激TNFα的產生(可因細菌感染而經macrophages產生)。 吞噬細胞藉由下列兩種機制，進行細 胞攻擊作用： – Oxygen-dependent mechanisms： •利用膜上的oxidase將氧分子(O2)轉變成 superoxide anion(O2-)。 •使用到醣解作用時所產生的NADPH當作 氧分子被還原的能量來源。 •此反應步驟由細胞表面進行到細胞內的 phagolysosome，將superoxide anion(O2-)自 動轉變為hydrogen peroxide(H2O2)，並產生 singlet oxygen(1O2，反應性高，分子穩定 性差)或可藉由superoxide dismutase(SOD) 轉變為hydrogen peroxide(H2O2)，並產生 oxygen(O2)。 hydrogen peroxide(H2O2)與superoxide anion(O2-)接觸反應產生hydroxyl radical(˙OH)，或hydrogen peroxide與吞噬 細胞之halide(Cl- or I-)經過 myeloperoxidase(MPO)的催化形成 hypohalide(OCl- or OI-)和水。 hypohalide(OCl- or OI-)可進一步與hydrogen peroxide反應產生singlet oxygen。 氧化過程可提供吞噬細胞重要的 antimicrobial effect。 氧化過程會產生一些toxic materials也會藉 由一些酵素作用以降低其毒害，如： – Catalase：大量出現於peroxisomes中，可將 hydrogen peroxide轉成水及氧分子。 – Superoxide dismutase：將singlet oxygen hydrogen peroxide轉成hydrogen peroxide， hydrogen peroxide進而被glutathione peroxidase分解掉。 – Caeruloplasmin：extracellular antioxidant，與SOD具有相同角色，為acute phase proteins 之一，其合成受到IL-1的影響。 – Nitric oxide：cytotoxic compound for which oxygen is a substrate，由斯neutrophils及具有 nitric oxide synthetase(NOS)的組織 Killing and Degradation – Oxygen-independent mechanisms » 於中性或鹼性環境下，當吞噬細胞形成phagolysosome 時，一群basic cationic proteins會被活化對抗G(+)及G(-) 細菌，如： defensins：具29-43 amino acids的循環性peptide，可以插入目 標細胞膜中。 serprocidins：如elastase、cathepsin G、proteinase G及 azurocidin等；有些具serine esterases，但它們的抗菌特性與其 酵素活性無關。 » 於酸性環境中，lysosomal enzymes變的活化，如： lysozyme：會水解G(+)細菌細胞壁的peptidoglycan。 acid hydrolases：分解許多細菌組成分子。 lactoferrin：has a bacteriostatic effect due to its ability to bind iron strongly, thus making it unavailable to bacteria。