Phagocytes Phagocytes In 1903 Almroyh Wright demonstrated that the effIn 1903 Almroyh Wright demonstrated that the eff

ector function of phagocytes is triggered by immunector function of phagocytes is triggered by immunoglobulins.oglobulins.

It was replaced that the clearance function of phagIt was replaced that the clearance function of phagocytic cells was emphasized in the definition of the ocytic cells was emphasized in the definition of the reticuloendothelial system by Metchnikovian, and treticuloendothelial system by Metchnikovian, and they act primarily by engulfing and digesting bacterhey act primarily by engulfing and digesting bacteriaia 、、 cellular debriscellular debris 、、 and other particulate matter.and other particulate matter.

Phagocytic cells were divided into mononuclear pPhagocytic cells were divided into mononuclear phagocytes and neutrophil polymorphs. hagocytes and neutrophil polymorphs.

Macrophages Macrophages (Mononuclear phagocytes) (Mononuclear phagocytes)

Macrophages are released fMacrophages are released from bone marrow as immatrom bone marrow as immature monocytes and mature ure monocytes and mature in various tissue locations in various tissue locations where they reside for weekwhere they reside for weeks or yearss or years ，， and given diffand given different names in different tiserent names in different tissues.sues.

MonocytesMonocytes ：：– Large cells (12-20 um in diameter) wiLarge cells (12-20 um in diameter) wi

th kidney-shaped nuclei, loose nuclear th kidney-shaped nuclei, loose nuclear chromatin, and fairly abundant cytoplchromatin, and fairly abundant cytoplasmasm 。。

– There are cytoplasmic lysosomesThere are cytoplasmic lysosomes ，，which are azurophilic lysosomal granwhich are azurophilic lysosomal granules and contain lysozymeules and contain lysozyme 、、 myelopmyeloperoxidaseeroxidase 、、 and acid hydrolases.and acid hydrolases.

– They account for only 1-6% of all nucThey account for only 1-6% of all nucleated blood cells.leated blood cells.

– After releasedAfter released ，， they circulate for onlthey circulate for only about one day before setting into a py about one day before setting into a permanent site of residence in a tissue, termanent site of residence in a tissue, then called macrophages or histiocytes.hen called macrophages or histiocytes.

Macrophages Macrophages (Mononuclear phagocytes) (Mononuclear phagocytes)

Macrophages belong to a single lineage kMacrophages belong to a single lineage known as the mononuclear phagocyte systenown as the mononuclear phagocyte system.m.

They accumulate slowly at sites of infectiThey accumulate slowly at sites of infection, respond to a variety of stimuli and haon, respond to a variety of stimuli and have considerable potential for synthesis, seve considerable potential for synthesis, secretion and regeneration.cretion and regeneration.

They contain azurophilic lysosomal granuThey contain azurophilic lysosomal granules, also possess a non-specific esterase ales, also possess a non-specific esterase and produce various neutral proteases (sucnd produce various neutral proteases (such as collagenase, elastase, and plasminogeh as collagenase, elastase, and plasminogen activator). n activator).

Macrophages Macrophages (Mononuclear phagocytes)(Mononuclear phagocytes)

Macrophages are able to control tMacrophages are able to control the actions of lymphocytes in at lehe actions of lymphocytes in at least two major waysast two major ways ：：– Activated marcophages secrete poteActivated marcophages secrete pote

nt immunoregulatory peptides that cnt immunoregulatory peptides that control lymphocyte polification, diffeontrol lymphocyte polification, differentiation, and effector functionrentiation, and effector function 。。

– Activated marcophages are among tActivated marcophages are among the most important types of antigen-he most important types of antigen-presenting cellspresenting cells 。。

Macrophages Macrophages (Mononuclear phagocytes)(Mononuclear phagocytes)

Neutrophils Neutrophils (Neutrophil polymorphs) (Neutrophil polymorphs)

Neutrophils are polymorphonNeutrophils are polymorphonuclear, which are known as seuclear, which are known as segmented neutrophils (segs) or gmented neutrophils (segs) or polymorphonuclear leukocytepolymorphonuclear leukocytes (polys or PMNs).s (polys or PMNs).

They mature, are stored in boThey mature, are stored in bone marrow, are released rapidne marrow, are released rapidly into circulation in response ly into circulation in response to various stimuli, 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.

They are end-cell (They are end-cell ( 即即 terminally diterminally differentiated)fferentiated) ，在其轉移進入組織，在其轉移進入組織前，在循環系統僅停留數小時，前，在循環系統僅停留數小時，進入組織後也僅能存活進入組織後也僅能存活 1-21-2 天。天。

依依 neutrophil granulesneutrophil granules 可將其分為可將其分為兩類：兩類： azurophilic granules (azurophilic granules ( 除含除含lysozymelysozyme 、、 myeloperoxidasemyeloperoxidase 、、 aand acid hydrolasesnd acid hydrolases 外，尚有外，尚有 defendefensinssins 、、 serprocidinsserprocidins 等具抗菌性的等具抗菌性的陽離子性蛋白陽離子性蛋白 )) 及及 specific granulespecific granules (s ( 含含 lactoferrinlactoferrin 、、 lysozymelysozyme 、、 hihistaminase and transcobalamin II)staminase and transcobalamin II)

Neutrophils Neutrophils (Neutrophil polymorphs)(Neutrophil polymorphs)

Common features of phagocytes Common features of phagocytes responsesresponses 不論何種吞噬細胞，均經由不論何種吞噬細胞，均經由 chemotaxischemotaxis 、、 target recognitiontarget recognition 、、

ingestioningestion 、、 killing and degradationkilling and degradation 等四步驟進行吞噬並達到等四步驟進行吞噬並達到消滅外來細胞。消滅外來細胞。

Chemotaxis Chemotaxis

受傷組織會釋出一些生化物質受傷組織會釋出一些生化物質 (( 稱為稱為 chemotactic factors)chemotactic factors) ，利用，利用這些物質濃度關係吸引吞噬細胞迅速靠近。這些物質濃度關係吸引吞噬細胞迅速靠近。

對對 neutrophilsneutrophils 而言，而言， chemotactic factorschemotactic factors 可分為可分為 endogenous (host-endogenous (host-derived molecules)derived molecules) 及及 exogenous (derived by foreign cell metabolisexogenous (derived by foreign cell metabolism)m) ，且，且 neutrophilsneutrophils 細胞表面具有細胞表面具有 chemotactic factorschemotactic factors 的受器。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 Target Recognition 利用細胞表面受器與外來細胞表面之特殊醣基 利用細胞表面受器與外來細胞表面之特殊醣基 (specific sugar (specific sugar

residues, such as mannoseresidues, such as mannose 、、 glycanglycan 、、 or lipopolysaccharide)or lipopolysaccharide)接合而認識外來細胞。接合而認識外來細胞。

Target recognition is greatly enhanced when specific antibody of Target recognition is greatly enhanced when specific antibody of class IgG and/or C3b becomes fixed to the target surface (class IgG and/or C3b becomes fixed to the target surface ( 即會即會受到抗體或補體的調理作用受到抗體或補體的調理作用 )) 。。

NeutrophilsNeutrophils 及及 macrophagesmacrophages 均具有均具有 IgG1IgG1 及及 IgG3 Fc fragmentIgG3 Fc fragment 、、C3bC3b 、、 iC3b specific receptorsiC3b specific receptors ；； neutrophilsneutrophils 具有具有 IgA Fc fragmIgA Fc fragment lower affinity receptorent lower affinity receptor 。 。

Ingestion Ingestion Plasma membrane gradually envelops the ingested particle and Plasma membrane gradually envelops the ingested particle and

buds off the surface membrane internally to form the phagosombuds off the surface membrane internally to form the phagosomee 。。

Three major pathways for bringing extracellular materials into cThree major pathways for bringing extracellular materials into cellell ：：– Pinocytosis (cell drinking)Pinocytosis (cell drinking) ：： formation of minute surface vesicles filled formation of minute surface vesicles filled

with unmodified extracellular fluidwith unmodified extracellular fluid 。。– Receptor-mediated endocytosisReceptor-mediated endocytosis ：： to be triggered by the binding of a solto be triggered by the binding of a sol

uble ligand to one or more specific surface receptorsuble ligand to one or more specific surface receptors ；； the resulting polthe resulting polymerization of clathrin protein on the cytoplasmic aspect of the plasma ymerization of clathrin protein on the cytoplasmic aspect of the plasma membrane leads to invagination of the receptor and formation of a coatemembrane leads to invagination of the receptor and formation of a coated pitd pit 。。

– PhagocytosisPhagocytosis ：： multiple surface receptors sequentially engage the surfamultiple surface receptors sequentially engage the surface of a target particlece of a target particle ，， usually >100 um in diameterusually >100 um in diameter 。。

• Phagosome fuses with lysosomal granules to form the phagolysosome 。

Killing and Degradation Killing and Degradation 吞噬細胞毒殺作用可藉由一些吞噬細胞毒殺作用可藉由一些 cytokinescytokines 的刺激，如的刺激，如 IFN-γIFN-γ 刺激刺激 TT

NF-αNF-α 的產生的產生 (( 可因細菌感染而經可因細菌感染而經 macrophagesmacrophages 產生產生 )) 。。 吞噬細胞藉由下列兩種機制，進行細吞噬細胞藉由下列兩種機制，進行細

胞攻擊作用：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 p

hagolysosome ，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(Hhydrogen peroxide(H22OO22)) 與與 superoxide superoxide anion(Oanion(O22

--)) 接觸反應產生接觸反應產生 hydroxyl radicahydroxyl radical(˙OH)l(˙OH) ，或，或 hydrogen peroxidehydrogen peroxide 與吞噬與吞噬細胞之細胞之 halide(Clhalide(Cl-- or I or I--)) 經過經過 myeloperoximyeloperoxidase(MPO)dase(MPO) 的催化形成的催化形成 hypohalide(OClhypohalide(OCl-- or OIor OI--)) 和水。和水。

hypohalide(OClhypohalide(OCl-- or OI or OI--)) 可進一步與可進一步與 hydrhydrogen peroxideogen peroxide 反應產生反應產生 singlet oxygensinglet oxygen 。。

氧化過程可提供吞噬細胞重要的氧化過程可提供吞噬細胞重要的 antimicrantimicrobial effectobial effect 。。

氧化過程會產生一些氧化過程會產生一些 toxic materialstoxic materials 也也會藉由一些酵素作用以降低其毒害，如：會藉由一些酵素作用以降低其毒害，如：– CatalaseCatalase ：大量出現於：大量出現於 peroxisomesperoxisomes 中，中，

可將可將 hydrogen peroxidehydrogen peroxide 轉成水及氧分子。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 ne

utrophils 及具有 nitric oxide synthetase(NOS) 的組織

– Oxygen-independent mechanismsOxygen-independent mechanisms» 於中性或鹼性環境下，當吞噬細胞形成於中性或鹼性環境下，當吞噬細胞形成 phagolysosomephagolysosome

時，一群時，一群 basic cationic proteinsbasic cationic proteins 會被活化對抗會被活化對抗 G(+)G(+) 及及 GG(-)(-) 細菌，如：細菌，如：

defensinsdefensins ：具：具 29-43 amino acids29-43 amino acids 的循環性的循環性 peptidepeptide ，可以插入，可以插入目標細胞膜中。目標細胞膜中。

serprocidinsserprocidins ：如：如 elastaseelastase 、、 cathepsin Gcathepsin G 、、 proteinase Gproteinase G 及及 azurazurocidinocidin 等；有些具等；有些具 serine esterasesserine esterases ，但它們的抗菌特性與其酵，但它們的抗菌特性與其酵素活性無關。素活性無關。

» 於酸性環境中，於酸性環境中， lysosomal enzymeslysosomal enzymes 變的活化，如：變的活化，如： lysozymelysozyme ：會水解：會水解 G(+)G(+) 細菌細胞壁的細菌細胞壁的 peptidoglycanpeptidoglycan 。。 acid hydrolasesacid hydrolases ：分解許多細菌組成分子。：分解許多細菌組成分子。 lactoferrinlactoferrin ：： has a bacteriostatic effect due to its ability to bind irhas a bacteriostatic effect due to its ability to bind ir

on strongly, thus making it unavailable to bacteriaon strongly, thus making it unavailable to bacteria 。 。

Killing and Degradation Killing and Degradation