I. Basophils!- Characteristics: rare, don't divide, lobed nucleus obscured by basophilic granules!- Have 2 types of granule: azurophilic (lysosomes) and specific granules (contain: heparin, histamine, heparan sulfate, leukotrines)!- Membrane bound Fc receptors that bind circulating IgE!- Function: related to mast cells, bind specific antigen to IgE on Fc receptor --> degraulation of basophils --> bronchial constriction and edema!- Antihistamines inhibits their and mast cells effects II. Eosinophils - Characteristics: less rare than basophils, don't divide, visible bi-lobed nucleus, cytoplasm crammed w/granules!- Azurophilic granules - specific eosinophilic granules: elliptical, contain crystalloid body surrounded by less dense matrix, contain: !- MBP, EPO= cytotoxic effect of parasites!- EDN= neutralizes worms!- arylsulfatase= neutr. leukotrines!- histaminase= neutr. histamines!- collagenase= cells can migrate thru CT!- Functions: !- Major role in host defense against parasites (abundant in GI), punch holes in worms!- Moderate bad effects of inflammatory vasoactive agents!- Phagocytose and eliminate antigen-antibody complexes!III. Neutrophils, Polymorphonuclear neutrophilic leukocytes, Polys, PMNs:!- Characteristics:!- most numerous, polymorphic nucleus w/2-5 lobes, Barr body= condensed X chrom of females!- cytoplasm smooth, colorless/pink, roun, motile cell, may have pseudopods, small golgi, few mitochondria!- many small faint granules:!1) azurophilic granules (lysosomes), contain:!- hydrolases, proteases, lipases, phospholipases, glucosidases, nucleases!- M6P groups on their N-linked oligosaccs for targeting from golgi --> lysosomes (muts in this pathway lead to disease)!- myeloperoxidase--> highyl reactive/toxic super oxides!- defensins: small anti-microbial peptides!2) Specific granules (smallest and most numerous), contain various hydrolases!- type IV collagenase!- lysozyme: breaks down bacterial cell walls!- phospholipase!- compliment activators!3) tertiary granules contian:!- metaloproteinases (gelatinase and collagenase) facilitate migration thru CT!- phosphatases!- Extravasation= how they leave the blood stream= passage thru blood vessles involving cell surface adhesion molecules !1) Margination: tethering and rolling med. by neutrophil selectins and endothelial cell selectin-receptors !2) Adhesion involves neutrophil surface integrins (activated by endothelial cytokine signals) and endothelial integrin receptors!3) Immunoglobin superfamily (cell adhesion molecules) engage w/endothelial receptors--> neutrophils become firmly attached!4) Diapedesis: neutrophil migrates across the vessel wall w/assistancce from mast cells (open endothelial intercellular junctions), extend pseudoposide and pass thru endothelium !- Chemotaxis: how they find/sense the presence of a foreign body!- Neutraphil surface receptors bind chemical signals made by Rho-family GTPases in resonse to infection/inflammation!- Binding --> signaling cascade --> acts to steer the machinery of locomotion!- How do they move to their target?!- Branched polymerization of an actin network at leading edge of the cell and depoly of this network behind the leading edge!- ex. Listeria bacterial motility!1) Actin monomers present in large pool and unable to assemble, each bound to profilin!2) Profilin binds to actin monoers, prevents assembly!3) WASp has domains for binding signaling molecules that are released by binding of external ligans to membrane receptors!- Gets activated, binds/stimualtes Arp2/3!4) Arp2/3 bind side of existing actin filaments and to pointed end of a forming actin fil., nucleates actin assembly at site near pm, negates effects of profilin, cross-links fils growing next to eacch other!5) Capping protein limits elongation at barb ends of actin fils!6) Filaments age at trailing edge --> filament actin ATP hydrolyzed --> actin-ADP!7) ADF/cofilin severs/depolymerizes older actin-ADP fils, release actin-ADP monomers!8) Profilin recycles actin-ADP monomers by catalyzing nucleotide exchange to form actin-ATP!!!!!- Phagocytosis= how neutrophils destroy their foreign target!1) Attachment of particle (ex. virus) to neutrophil outside!- Neutrophil cell surface receptors recog. foreign body ligands!- facilated by opsonins/opsonization (ex. antibody, complement) --> bind to ligands --> make them more "tasty" to phagocytes !2) Two types of engulfment!- Both pathways involve attached of ligand to receptor --> signaling cascade involving tyrosine phosphorylation and Rho-fam GTPases!- Receptor-mediated endocytosis (ex. of viruses)!- Clathin, AP2, and dynamin form an endocytic vesicle!- Phagocytosis of larger bodies (ex. bacteria)!- Attachment of larger particles --> signaling molecules trigger polymerization/reorg. of actin network (same as cell loco) --> pm forced to surround particle --> more host receptors bind to foreign ligands --> zipper pm to foreign body!---> Fusion of pm --> engulfment of particle in a phagosome!- actin network disassembles so phagosomes hooks onto MTs and motors way into cyto to lysosomes !3) Fusion w/lysosomes -->formation of phagolysosome!- Fusion and fission removes pm proteins, replaces them w/proteins for fusing w/lysosomes!- In phagolysosome: foreign body exposed to defensins, toxic oxidants, pH lowered from 7-->4 --> denatures foreign matter and activates lysosomes hydrolase!- Degradation products are recycled!- In massive infection: neutrophils secrete interleukins --> syn. of prostaglandins --> act on hypothalamus --> fever = component of inflammation!4) Undegraded materieal forms a residual body= lipfuscin in old cell (ex. neuron cell bodies)!5) All neutrophils die forming pus!!IV: Granulopoiesis!- all 3 granulocytes develop following similar scheme with sim. names for diff. stages!!!!!- Myeloblast - 1%, can't really see by normal LM, not clear whether 1 gives rise to all 3 grans (granulocytes) of if special 1 for each gran type!- large, big euchrom. nucleus w/nucleoli, pale blue cyto w/mitochondria and a few azurophilic grans!- mitotically active, making promyelocytes - Promyelocyte - 4%, can see!- large, nucleus w/euchrom and heterochrom,!- Numerous azurophilic granules (primary lysosomes), all of which are made at this stage!- Mitotically active, making myelocytes - Myelocyte - Specific granules are 1st produced!, thus you can distinguish the 3 types of grans!- basophilic series: .5%!- eosinophil: 4%!- neutrophil: 63%!- specific grans contained the active compounds
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