BIO 580 - Medical Microbiology - Unit One Part B - Host ...



Objectives:1. understand how the appropriate lymphocytes are selected and activated and amplified2. understand how immune cells “talk” with each other via cytokines3. compare and contrast activation and response of T and B lymphocytes 4. compare and contrast the activation and response of Th1, Th2, and TC5. understand the interactions between nonspecific and specific host defenses6. understand how the specific immune response focuses the nonspecific response7. understand the power of the secondary (anamnestic) immune responseB. Specific Defenses = adaptive = acquired3rd line of defense – only one with antigenic memoryfeedback into the nonspecific defenses – enhance the effectiveness of the non-specific defensesSpecific immune system has to:recognizeactivaterespond1. Overviewa. RecognitionA specific interaction between an antigen and a receptorAnti genAntigens incl:***proteins (incl. proteins + carbos or lipids) (T and B)***complex polysaccharides (B only)***nucleic acids (B only)Full activation of the specific defenses involves several different types of immune cells working in concert:non-specific cells (antigen-presenting cells)specific cells (lymphocytes)Antigen-Presenting Cell (APC)Specialized cells that present antigenic determinants in a way that can be more easily recognized by lymphocyte RMost significant: dendritic cells (tissues) > macrophages > B cells2 main types of LymphocytesT lymphocytes (T cells)B lymphocytes (B cellsLymphocyte receptors (R)constant region – transmembrane variable region – interacts with antigenic determinantAntigenic determinant (= epitope) - small region of the antigenlinear or conformationalsmall in sizeGeneral Overview of Antigen Presentation - DiagramPresentation of antigenic determinant by an APC to a lymphocyte occurs in draining lymph nodes (surfaces, tissues) or spleen (blood)Initiates a chain of events that transforms a small, resting, na?ve lymphocyte into a highly active, functional lymphocyte.1945005670560b. Activation - of lymphocytes with complementary receptor1. receive and secrete cytokines2. undergo proliferation = clonal expansion1104 – 105 - occurs in lymphoid organs3. differentiate into functional sub-typeseffector – fight this timememory – reserves, to be deployed in the futurec. Response – of activated effector sub-typesactivated (= primed) effector T lymphocytes either:1. kill2. coordinate and regulateactivated effector B lymphocytes (called plasma cells)secrete antibodies2. Add in specificsT Lymphocytes2 categories of T cells by surface marker called Cluster Determinant1. CD4 - 2 functional types1) T helper cells = TH - regulate the immune system by activating other immune cellsa) Subset Th1 – secrete ?-IFN – respond to intracellular pathogens - boost macrophages, NK, mature TC; inhibit Th2b) Subset Th2 – secrete IL-4 – respond to extracellular pathogens - stimulate B cells to proliferate and differentiate; inhibit Th12) T regulatory cells (=Tregs) - regulate the immune system by the response2. CD8 =T cytotoxic cells =TC - attack & kill cells infected w/ intracellular pathogensa. Antigen Recognition by Na?ve Resting T lymphocytes*T cell receptor interacts with microbial (foreign) antigen + self antigenSelf antigens – Major Histocompatibility Complex (MHC) proteins2 classes of MHC Class I - on the surface of all nucleated host cellsClass II – on the surface of APCTHR - recog. foreign antigen complexed w/ Class II MHC + co-stimulatory interactions (depend on who the APC is)TCR - recog. foreign antigen complexed w/ Class I MHC + co-stimulatory interactionsb. Activation of T lymphocytes3871722196596Activation signal - cytokines, esp. IL from APC ex. IL-1 from macrophage↑ IL-2R and secrete/receive IL-2 proliferationDifferentiation into effector and memory cellsc. Response of Effector T LymphocytesEach category of effector T cell has a unique response:regulating the immune response = immunoregulationenhance response - THSubset Th1 - secretes ?-IFN - activates macrophages to kill their intracellular pathogens; activates NK, TC (down regulates Th2)Subset Th2 – secretes IL-4 – stimulates B cell proliferation (down regulates Th1)suppress response - Tregsdirect cell killing = cytotoxicity – TCIntegration via Lymphocyte Recognition, Activation, and Response - DiagramB Lymphocytesa. Antigen Recognition by B LymphocytesReceptor interacts with foreign antigen alone – does not need to see an MHC marker.b. Activation of B LymphocytesIL-4 from subset Th2 (also IL-2)Clonal expansion (= proliferation)Differentiation into effector (= plasma) and memory cellsc. Response of Effector B lymphocytes (=Plasma Cells)Secrete Antibody (Ab) at the rate of 1,000 molecules/min.Antibody Structure - DiagramActions of Antibody Molecules – focus the non-specific1. direct – binding to antigen – interfere with receptor interaction – any microbe that uses specific attachment sites = neutralizing***2. indirect – linking a bacterium to a phagocyte = opsonization (followed by phagocytosis)OpsoninRate of PhagocytosisMicrobe+phagocytenone-/+C3b+CRP+AbC3b + Ab3. indirect - link many small antigens together = agglutination (followed by phagocytosis)4. indirect - complement activation - classical pathway (followed by either opsonization and phagocytosis or lysis)5. indirect - ADCC - antibody dependent cellular cytotoxicity2612390118745Activation of Classical Complement Cascade - DiagramC1C2C4C2bC2aC4bC4aC2a4bC3C3C3aC3b C3aC3bC5 C5aC5bC5b678 multiple C9 (MAC)Fill in:Triggers –Important molecules – Consequences - Timing – Complement activation enhances phagocytosis and inflammation and leads to cell lysis.Classes of Antibody MoleculesAntibody = Immunoglobulin (Ig) – proteins found in fluids in the body5 Classes:ClassStructure%LocationRolesIgGmonomer75-80serum, extra vascular spaces, crosses placentafix complementopsoninIgAmonomerdimer15-21serum, tears, saliva, mucus, colostrumneutralizingIgMpentamer6-7serum, 1st made by virgin B cells, 1st made by fetusfix complementagglutinatingIgDmonomer<1low levels in serumB cell surface? regulate clonal expansion?IgEmonomer0.01skinRT fluidbind to mast cells & basophilsFeedback into the non-specific defenses; esp. complement, phagocytosisFunction of Memory Lymphocytes – the reserves - stronger response on secondary exposure to antigenare more memory cells then there were naive cells at the beginning of the primary responsewere primed to antigen during primary response so are able to bind more strongly to APCmemory is usually long-lasting, yearsPrimary versus Secondary (= anamnestic) Response - DiagramMisc.Killer (K) cellsRely on antigen specific antibodies BUT interact with antibody in a nonspecific way, participate in the non-specific interior defenses:K cells include:NKmacrophageeosinophilAll K cells have receptors for Fc of antibody moleculesK cells bring about lysis of the antibody-coated cell in a process called antibody-dependent cellular cytotoxicity (ADCC); for pathogens that are too big to phagocytize.SUMMARIZE – Specific DefensesFill in tableCytokine or pro-inflammatory mediatorSecreted by:Acts on:Functions to:IL-1IL-2IL-4IL-23IFN ?IFN ?IFN ?TNFComplete:TH301828232131function – recognition – activation – response – Th1 - -- Th2 – TCfunction – recognition - activation – response – Tregfunction – recognition - activation – response – B Lymphocyterecognition – activation – response –SUMMARIZE – Specific DefensesList the Specific Interior Defenses important against Bacteria List the Specific Interior Defenses important against VirusesCONCEPT CHECK – Specific defensesConcept MapDraw a concept map that illustrates the connections between the specific and nonspecific immune responsesCONCEPT CHECK – Specific DefensesContinuation of the Case of SteveWhen Steve. awoke on the second morning, his condition was clearly deteriorating. The first thing he noticed was that the small area of redness and swelling had extended to include his entire hand, with the margin of redness now visible just above his wrist. Faint red streaks had appeared along the inner part of his arm and tender lumps were noticeable below his elbow and under his arm. His fever seemed higher than the night before, and he felt too weak to walk.Steve was too sick to travel, and his friends figured that it would take several days to return with medical help. They decided to stay in camp and let Steve rest. Over the next couple of days Steve and his friends were relieved to find him gradually improving. The red area did not advance past his forearm. Although the hand remained painful and swollen, he felt less tired and the fever was gone. Four days after the first presentation of inflammation, when he was a little better, they headed back and took Steve to the nearest emergency room.The doctor diagnosed a presumed bacterial infection and prescribed a broad-spectrum antibiotic that was likely to be effective against the unknown infecting bacterium. The medication was taken orally, and Steve was sent home. The redness and swelling of the hand subsided gradually over the next two weeks.1. What were the tender swellings that Steve noticed behind his elbow and under his arm and why were they swollen? 2. Steve began to improve within 4-5 days of initial infection. How could antibody have played a role in resolving Steve’s symptoms within this time frame?3. What functions did these antibodies play in the immune response to Steve’s bacterial infection? ................
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