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1、clonal diversification of lymphocytes review of last lecturebone marrow thymuswhenever immature pre-t cells recognize self-antigens, they are programmed to auto-destruct in the thymuswhereasmature t cells proliferate when they contact antigens98% pre-t cells die in the thymusbone marrow when immatur

2、e pre-b cells recognize self-antigens then they auto-destruct in the bone marrowclones of mature b cells proliferate when contacting antigentoleranceto self substances treatments for autoimmune diseases - wipe out the mature b cells / reboot some exceptions sjgrens syndrome antigen123one clone of b

3、cells (b lymphocytes) by definition will only bind to one type of antigenic determinante.g., either to outside determinant#1 or to #2 or to #3 b cell clone #2 b cell clone #1 mature b cells antigen123fc regionfab region b cell clone #2 b cell clone #1 plasma cell clone #1 plasma cell clone #2 multi-

4、clonal antibodiesafter proliferating, many antigen stimulated b cells differentiate into plasma cellsmulticlonal stimulation activation of specific clones of b cellspolyclonal activation (non-specific activation of all b cell clones in the area by i.e., endotoxic lps)poly-carbohydrateantigen - repea

5、ting antigenic determinants b cellprotein antigen no repeating antigenic determinantsrequires t cell helpigm igg igahelp comes via soluble substances produced by stimulated helper t cellsb celligmcross-links no cross-links are possiblehelper t cells cytotoxic t cellscd 4 positivecd 8 positivet lymph

6、ocytes t cellsth tchelper t cells help b cells and cytotoxic t cells helper t cell clones t cells have t cell receptors on their surfacenot antibodies antigeneven if they do interact, no stimulation of the helper t cell- the antigenic determinants are hidden within the antigen (are not yet processed

7、), and need to be associated with a mhc 2 productbind in some cases via surface antibody (sometimes passively absorbed) or via complement deposited on the antigen then phagocytize the antigen (see the lecture handout).followed by digestion of the antigen that must occur without infecting the cell. n

8、ote ab and complement neutralize the antigen.antigen presenting cells do not have t cell receptorsantigen presenting cellsall types of antigen presenting cells (apc) continually produce major histocompatibility complex class ii products(mhc class 2 products)that are produced inside the cell move to

9、the surface then and stay on the cell surfacethese mhc 2 products are only on cells which digest and then present the digested fragments of the antigens to helper t cellstypes of antigen presenting cells:macrophages and macrophage-like cellsdendritic cells(and pre-dendritic cells)b cells (b lymphocy

10、tes)types of antigen presenting cells:macrophages and dendritic cellshave fc-receptors and complement receptors. thus these types of apc also can become armed with low levels of polyclonal ab-ag complexes via the ab that may be weakly fitting (very weak affinity) at the beginning of the infectionb c

11、ells (b lymphocytes)- monoclonal abantigen presenting cell must bind and digest the antigenantigenlow levels of ab to many substancestoll-like recptorsantigencomplement receptorsmajor histocompatibility complex (mhc)class 2 moleculegroove for an internal antigenic fragment (exposed after antigen was

12、 fragmented by host cell proteases)plasma membraneantigen presenting celle.g., macrophagemajor histocompatibility complex mhc class 2 molecule groove for anantigenic fragment ( fragmented by host cell proteases )plasma membraneantigen presenting celldigested fragments of the antigen then associate w

13、ith mhc class 2 products. antigenic determinants are now presented to helper t cells.helpert cellwith a correctt cell receptor cd4+ antigen presenting cell (apc)t cell receptorcd4apc binds to antigens and phagocytizes them. then digests them and associates them with mhc 2 products.helpert cellwith a

14、 correctt cell receptor cd4+ antigen presenting cell (apc)apc binds to antigens and phagocytizes them. then digests them and associates them with mhc 2 products.interleukins liberated. molecules that stimulate/help any type of t cells and any b cells that have contacted their antigenic determinantsm

15、ajor histocompatibility complex products mhcalso termed hla human leukocyte antigensclass 2 products interact with cd4 on helper t cellsafter the t cell receptor binds to the antigenic fragment within the appropriate mhc product, then cells are close enough together so thatmajor histocompatibility c

16、omplex (products) type 1(mhc class 1) class 1 products are always being produced on virtually all host cells.major histocompatibility complex (mhc)class 1 productgroove plasma membranebeta 2 microglobulinsynthesized viral fragments in the infected host cell virally infected host cellseries of differ

17、entsmall synthesized viral fragments- become associated with mhc 1 products being produced by the host cell synthesized viral fragments virally infected host cellseries of differentsmall synthesized viral fragments these associate with mhc 1 productsa bud or pocket of intact virus particlesready to

18、leave the host cellbefore it dies, the virally infected cell becomes a viral factorydrawing of the mhc 1major histocompatibility complex (mhc) class 1 molecular complexnote the groove plasma membraneoutside surfacenormal host cellgroove for small synthesizedviral fragmentone major histocompatibility

19、 complex (mhc) class 1 product associates with one of the many viral fragments synthesized within the host cell. then the mhc-1 + viral fragment travels to the surface. other mhc class 1 products associate with other synthesized viral fragments.groove containing one small synthesizedviral fragmentvi

20、rally infected host cellsynthesizedviral fragmentsmhc-1 +plasma membranegroove for small synthesizedviral fragmentplasma membraneinfected host cellsynthesizedviral fragmentsmhc-1 +other mhc class 1 products associate with other synthesized viral fragments.synthesized viral fragments bind the mhc 1 m

21、olecule,while inside the virally infected cell, then move to the cell surface. virally infected host cellto review:cytotoxic t cell is stimulated (only) when encountering the complex of the specific antigenic fragment (recognized by its t- cell receptor) and the mhc class 1 productcytotoxic t cell v

22、irally infected host cellseries of differentsmall synthesized viral fragments associatedwith mhc-1 onthe infected cells surface cytotoxict cellwith a correctt cell receptor cd8+ virally infected host cellt cell receptorcd8 virally infected host cellcytotoxict cellwith a correctt cell receptor cd8+ f

23、rom another clonea cytotoxict cellwith another correctt cell receptor cd8+ virally infected cell is terminated via direct damage and via signals to self-destructprevious pop quiz question 1:you recently saw a patient with severe inflammatory periodontal disease. over twenty different specific b lymp

24、hocyte clones were detected in the tissues immediately surrounding the infected periodontal pockets. after several days the b cells in this area were again tested and several of the b cells clones had a higher affinity (or better fit) for the same antigens.how do specific b cell clones recognize ant

25、igens? and why did the fit (affinity) become higher for selected clones?question 2:pregnant ladies are advised not to receive x-rays because rapidly dividing cells are very susceptible to dna damage.describe fetal t cell clonal development. what would be the possible consequences of x-rays on fetal

26、t cell clonal development? previous take-home open-book examination from dr. boackle along with t cells, monocytes/macrophages, and high numbers of pmns (polymorphonuclear leukocytes), a curiously elevated number of b lymphocytes and plasma cells are observed in the inflamed tissues in periodontal d

27、isease. what specific and non-specific mechanisms might be responsible for the observed numbers of stimulated b cells in these periodontal tissues? what are toll-like receptors and what are their possible roles in periodontal disease, especially in face of the infection with gram-negative bacteria?

28、p primary and secondary signals are needed for the proper stimulation and function of specific t cells (t lymphocyte clones) and of specific b cells (b lymphocyte clones) that are present in the periodontal tissues. indeed, specific immune responses to periodontal organisms certainly occur. describe

29、 how those lymphocytes first arrived in the inflamed periodontal tissues, then describe in detail the respective primary and secondary signals that stimulate the activation and proliferation of specific t cells (t lymphocyte clones) and of specific b cells (b lymphocyte clones)-be sure to discuss an

30、tigen presentation. fully explain the reasons that each signal or contact is needed for proliferation of these specific lymphocytes. th2th1th17tregdefense against parasitic worms, allergy, asthmadefense against intracellular pathogensdefense against extracellular bacteria, autoimmunity, cancerimmuno

31、suppressionundifferentiated t helper cellproduceupon antigenic stimulation, nave cd4+ t cells (undifferentiated t helper cells) undergo proliferation and differentiate into cytokine-producing t helper (t(h) effector cells. t(h)2 cells produce il-4, il-5, and il-13 cytokines, and mediate immunity aga

32、inst extracellular pathogens and allergic reactions; whereas t(h)1 cells secrete effector cytokine ifn-gamma and regulate cell-mediated immunity. directly quoted from pappu bp, dong c. curr protoc immunol. 2007 nov;chapter 6:unit 6.25. quoted fromth2th1th17tregdefense against parasitic worms, allerg

33、y, asthmadefense against intracellular pathogensdefense against extracellular bacteria, autoimmunity, cancerimmunosuppressionundifferentiated t helper cellproducerecent studies have identified a novel t(h) subset, called t(h)17, th(il-17), or inflammatory t(h) (thi) cells, characterized by the produ

34、ction of a proinflammatory cytokine, il-17, and regulating inflammatory responses. thus th17 cells may play a role in the pathogenesis of rheumatoid arthritis. simvastatin (a statin) induces ifn-gamma, il-4, and il-27 production in monocytes, which together inhibited il-17 transcription and secretio

35、n in cd4(+) t cells. could statins represent a promising therapeutic approach for multiple sclerosis and other chronic inflammatory diseases? zhang et al 2008 j. immunol.;180:6988-96.quoted fromth2th1th17tregdefense against parasitic worms, allergy, asthmadefense against intracellular pathogensdefen

36、se against extracellular bacteria, autoimmunity, cancerimmunosuppressionundifferentiated t helper cellproducetreg play a critical role in the maintenance of peripheral tolerance to self-proteins. however tregs may also facilitate early protective responses to local viral infections by somehow allowi

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