IMMUNOLOGY

IMMUNOLOGY

Immunity to microbeInfection procces involved sequence interaction between the microbe andthe host : - entry of microbe - invasion & colonization - evasion from the host immunity- tissue injury or fuctional impair- ment Immunity to microbe1. Mediated by both natural and acquired immunity2. Stimulate distinct lyphocyt response and effector mechanism3. Influenced by their ability to evade or resist 4. Tissue injury & disase may be caused by the host response to mirobe and its product Extracelluler bacteria

- Replicating outside host cells :- gram-positive pus-forming (Sta- phylococcus & Streptococcus)- gram-hegative cocci (meningo- coccus & gonococcus)- gram-negative bacilli (eanteric)- gram positive bacilli (Clostridium)

Extracelluler bacteria cause disease by

1. Induce inflamation wich result in tissue destruction

2. Produce toxins, wich have diverse pathologic effect : a. endotoxin ( bacterial cell wall) b. exotoxin (actively secreted)Natural immunity to extracellulerbacteria-Phagocytosis by neutrophil , monocyt and tissue macrophages-Activation complement system in the absent of antibody-Inflamation MBacreial LPSCytokineChemokineor.vas. endoth.Adhesion neutrophil

monocytsMigration &local accula-tiom of inflam-matory cells

Activatinofinflam.cellBacterialeliminationSpecific imm. resp.to extracelluler bact.- Polysaccharides capsules & cell walls (as T-independent -antigent) directly stimulate B cells antibody- Respons of CD4+T cells to bacterial pro- teins in association with Class II MHC- Antibody & T cells perform several function that serve to eliminate bacteriabacteriaAPCHLA-IICD4+VariouscytokinesIFNTNFAntibodyresponseNacrophageactivation-->phagocytosis and Bacterialkilling

inflammationImmune evasion by extracelluler bact.- Mechanism utilized by bacteria to evade spedific immunity- Produce surface atigent that favor tissue invasion and colonization

Immune Evasion by Extacelluler bacteria - N.gonorrhoeaeAntigenic variation - E. coli - S.typhimurium

Inhibition of Compl. - Many bacteriaactivation

Resistence to phago- - Pneumococcuscytosis

Scavenging of reactive - Catalase positiveoxygen intermediates staphylococcus

Immune resp. to intracelluler bacteria- Mycobacteria- Listeria monocytogenes- Legionella pneumophila- Survive and replicate within host cells- Resistent to degradation in macropha- ges- Tend to cause chronic infection that may last yearsNatural immunity to intracelluler bacteria- Phagocytosis quite ineffective in controlling coloniza- tion and spread of this microorganism- Activate NK cells --> IFN- --> activate macrophage --> promote killing of phagocytosed bacteria- NK cells provide an early defense again this microbe

Specific immune responseto intracelluler bactera- CMI ( cell-mediated-immunity) 1. Killing of phagocytosed microbe as result of macrophage activation by T cells derived cytokines ( IFN-) 2. Lysis of infected cells by CD+ CTLsIFN-RestingmacrophaqgePhagocytosedicrobeCD4+Klling ofphagocytosedmicrobeRestingmacrophaqgePhagocytosedicrobeCD8Lysis of macrophageand dead of bacteriaImmune Evasion by intracellulerbacteriaInhibition of phagolysosom - M.tuberculosisFormation - Legionella pneumophilla

Scavenging of reactive oxygen - M. lepraeIntermediates (phenolic glycolipid)

Disruption of phagosome - Listeria monocytogenesmembrane, escpae into (hemolysin protein)cytoplasm Natural immunity to virus1. Viral infection directly stimulate the production of Interferon (IFN) --> inhibit viral replication2. NK cells lyse virally infected cells IFN can also enhance ability of NK cell to lyse infected target cells3. Complement activation and phagocy- tosis serve eliminate extracelluler viruses & from the circulation Specific immune response to virus- Is mediated by combination of humoral and celluler immune mechanism- Neutralizing and opsoning antibodies- The principal specific immunity to virus is lysis cells cells by CD8 CTLsImmune Evasion by VirusesAntigenic variation : - Influenza, rhinovirus, HIV Inhibition of Antigen processing - inhibition of proteasome activity : - EBV, human CMV

- block in TAP transport - HSV

- block MHC synthesis - Adenovirus, CMV

- removal of MHC I from ER - CMV Phagocytic Cells1. Professional phagocytes :- PMN leukocytes- Monocytes- Macrophages2. Paraprofessional-Dendritic cells (DC) have selective phagocyte activity3. Non professional :- fibroblast & ephithelial cells Macrophage function1. Detection of microbial invasion Opsonic and nonopsonic receptor for microbe and their product2. Restriction of microbial spread Phagocytosis Granuloma formation Intracelluler killing3. Recruitment of immune cells Cytokines & inflamatory mediators4. Accessory cells in lymphocyte activ.-Ag processing & and presentation-Costimulatory molecules : ligand forCD40 L, CD28 and CTLA4 (T cells)-Cytokines5. Effector cells in CMI-Increase phagocytosis-Increase intracelluler killing-Clearence of apoptotic cells6. Participation in humoral immunityProperties of Macrophages1. Membrane receptor-Scavenger receptor-C receptor-Fc- eceptor-Macrosialine-Cytokines receptor -CD14 (LPS receptor)2. Production of cytokines-IL-1- TNF - IL-12- IL-10- IL-4- FGF3. Antigent processing and presentation4. Produce enzymes- colagenase- elastase- lysozymes - lysosomal enzymes5. Production of bioactive lipid and small radical- Prostaglandin- Platelet activatig factor- reactive oxygen & nitrogen interme- diate. Phagocytosis1. Microbial recognition - PRRs (pattern recognition reseptor a. membrane bound b. free in plasma - Recognize wide variety of microbial molecules - As reeptors for binding & entry of many intraclluler pathogens2. Microbial uptake- actin polymerization- engulfment and internalization 3. Phagosomal maturtion- depolymerization of actin- fussion with endosome- final step : fussion with lysosome ---> phagolysosome generating low pH and containig degradative hy- lases 4. Microbial killing Accomplished by :- low pH of phagosom- limitation of nutrien (iron)- generation of reactive oxygen and nitrogen intermediates- Nramp-1 : removal of iron and di- valen cation from phagosom- phox ---> reactive oxygen intermed.- inos ----> reactive nitrogen intermed. Phox : phagocyte NADPH oxydase O2NADPHNADPH+O2-O2 -+H2OH2O2 + OH*H2O2 MPOCl-HOCl- + OH*antibacterialphoxLPSIL-1TNFIFN-INOSDeaminasioxydativeL-argininNO+H2O2peroxynitritNO+Thiol groupsnitrosothiol5. Production of soluble mediator- signal & recruit other cells to the side of infect.. Stimulate adaptive immune resp.6. Antigen presentation- Histocompatibility molecule(HLA)- HLA-I --> CD8 cells- HLA-II --> CD4 cellsa- Costimulatory molecules AgMHLA-IICD4Th1Th2BCGF, BCPF, BCDFBPAbCD8HLA-IIL-1IL-4 , IL-12NKIFN-IL-2ADCCREgolgi CD 4lysosomphagolysosomPhoxInosNram-1phagosom microbeproteasomTAPREgolgiCD 8viralAg-HLATCRCD28B7-1CD40LCD40APCT cellsCTLA4B7-2