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PHM226 II WHITE CELLS CHEMICAL WARFARE lecture outline

2. Blood Cells. Type of cellRed blood cells (erythrocytes)White blood cells (leukocytes) polymorphonuclear/granular leukocytesNeutrophils (50 ? 60%)Eosinophils (1 ? 4%)Basophils (0.5 ? 2%) mononuclear leukocytesLymphocytes (20 ? 40%)Monocytes (2 ? 9%)(? mac

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PHM226 II WHITE CELLS CHEMICAL WARFARE lecture outline

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    5. Inflammation or infection MPO(myeloperoxidase), HOCl(hypochlorite), SOD (superoxide dismutase). HOCl + red cell GSH = GSH cyclic sulfonamide (biomarker for HOCl formation in vivo that reflects inflammation (oxidant formed by neutrophils)) 5

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    14. NADPH oxidase family: tissue location J.Biol.Chem 283,16961-16965(2008) NOX1 colon>prostate,uterus,breast,macrophage? NOX2 phagocyte H2O2 for MPO >> hepatocyte,B lymphocyte, cardiomyocytes,endothelial cells NOX3 inner ear,fetal NOX4 kidney,blood vessels,cardiomyocytes,endoth. NOX5 lymphoid tissue,testis Duox1 & 2 (dual oxidase) makes thyroxine hormone and H2O2 for thyroid peroxidase TPO >lung,GI 14

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    16. 16 Rheumatoid Arthritis Therapy

    17. 17 Anti-Inflammation therapy ROS Scavenger Therapy SOD, selenomethionine/Vit E, 5-aminosalicylate, penicillamine:Cu (cuprimine) Macrophage inhibitor therapy: Gold thiomalate or auranofin or zinc or copper salicylate Prostaglandin Synthetase Inhibitors:-(NSAIDS) COX-1 many cells e.g.aspirin,ibuprofen, but GI bleeding,kidney COX-2 inflammatory cells e.g. VIOXX (withdrawn), CELEBREX but cardiovascular problems. “Biologics” antibodies that inhibit inflammatory cytokines e.g.TNF-a Diet: decrease arachidonate intake (meat), increase omega 3 fatty acids (fish) decreases bad prostaglandins, decrease Fe intake References: Semin. Arthritis Rheum. 27: 366-70 (1998). Autoimmunity Reviews 7,1-7(2007) Anti-inflammatory Biologics

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    23. Tumor Necrosis Factor (TNFa) as the primary trigger for inflammatory response ?Macrophages,monocytes,lymphocytes,keratinocyte TNFa incr in chronic inflammatory diseases: rheumatism,arthritis,encephalitis,tumors Rheumatoid arthritis , psoriasis,Crohn’s disease Proinflammatory > antiinflammatory cytokines Drug therapy: NSAIDs, GC glucocorticoids,DMARDs disease modifying antirheumatic drugs Biologic therapy: Enbrel (TNF receptor fusion),antibodies humira or remicade 23

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    26. Macrophage killing mechanism Macrophages endocytose & present antigens to T cells as foreign substances Exocytose (via specific receptors) IgC and C3 coated bacteria Produce H2O2 to kill mycobacteria Produce cytokines PDGF,PAF,TNFa & ß, IL1 convert arginine to NO Prevents foam cell formation by endocytosis of oxid. LDL by macrophage oxid LDL & fusion with lysosomes and digestion by cathepsins & Plipases. 26

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    31. T lymphocytes formed in b.m.& mature in thymus 1) T helper cells help B cells mature into plasma cells. CD4+T cells express CD4 protein on their surface 2)19% Cytotoxic T cells destroy viral infective & tumor cells 3)Memory Tcells CD4+(lost in AIDs) or CD8+(cytotoxic) subset of antigen T cells that persist long after infection. 4) Regulatory T cells (suppressor T cells) 5)Natural killer (NK) largest T cell.Interferons cause cytotoxic granule release 6) Antigen-presenting cell (APC) 31

    32. B cells bursa of fabricius(birds) Plasma cells are large B cells exposed to antigens and produce antibodies that bind to microbes. In tissues not plasma. Contain rough e.r. & cell rapid apoptosis (short life) Memory B cells formed from activ.B cells(long life) 23% B-1 cells IgM>IgG in peritoneal & pleural cavities B-2 cells 32

    33. Treatment Immunosuppressants and anti-inflammatories B cell depleting agents like rituximab Anti-cytokine therapies like tocilizumab No truly effective therapies exist

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