Humoral Immune Response Activation of B Lymphocytes and Production of Antibodies
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Antibodies. Part of the adaptive immune response functions to neutralize and eliminate extracellular microbes and microbial toxinsMore useful against polysaccharide and lipids and these types of toxins
Humoral Immune Response Activation of B Lymphocytes and Prod...

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1. Chapter 7 Humoral Immune Response Activation of B Lymphocytes and Production of Antibodies

2. Antibodies Part of the adaptive immune response functions to neutralize and eliminate extracellular microbes and microbial toxins More useful against polysaccharide and lipids and these types of toxins ? B cells respond to many Ag types Na?ve B cells recognize Ag but can?t make Ab until activation allows differentiation to Ab secreting plasma cells

3. Phases and Types of HIR Na?ve B-cells have 2 classes of membrane bound Ab ? IgM and IgD act as receptor for Ag Activation of Ag specific cells leads to clonal expansion Go from 1 to 4000 Ab secreting cells Differentiation into effector cells called plasma cells secreted Ab is same specificity of as na?ve membrane bound receptor but during differentiation can cause Ab with different heavy chain and effector function ? heavy chain class (isotype) switching can handle different types of microbes Repeated exposure to causes Ab with increasing affinity to Ag ? affinity maturation improved capacity to bind and neutralize Ag

4. Recognition and Activation

5. T-Cell Dependence?? Ab response to different Ag may depend on the requirement of T-cell help or not B-cells recognize many Ags ? protein, polysaccharide, lipid and small chemicals Protein Ag makes poor or no Ab response when T-cells are absent = T-dependent Ab response T-helper cells play role in activation and powerful inducer of isotype switching Polysaccharidde, lipid and non-protein Ag stimulate Ab production without T helper cells = T independent Ab response little to no heavy chain switching or affinity maturation

6. B-Cell Subsets Respond Differently Protein and non-protein Ag result in different responses Majority are follicular B-cells (follicles of lymph organs) make the majority of T-dependent, class-switched ans high-affinity Ab to protein Ag also long-lived plasma cells Marginal zone B-cells (marginal zone of spleen white pulp) respond to blood bourne-polysaccharide Ag B-1 B-cells respond to non-protein Ag in mucosa and peritoneum Marginal zone and B-1 B-cells have Ag receptors of limited diversity and mainly IgM response

7. Responses Ab responses differ qualitatively and quantitatively 1? response is the first time exposed small amounts of Ab produced 2? response is the subsequent exposure more Ab produced if to a protein, see isotype switching and affinity maturation increase in TH cells with repeated stimulation Ag recognition ACTIVATES B-lymphocytes

8. Must be able to tell the difference between 1? and 2? responses

9. Stimulation of B-Cells by Ag Initiated when Ag-specific B-cells in lymphoid follicles of the spleen, LN and mucosal lymphoid tissues recognize Ag Ag of microbes in tissues or blood are transported and concentrated in B-cell rich follicles by possible method of: macrophages in subcapsular sinus may capture Ag and display to B-cells in adjacent follicles use BCR to recognize Ag in native conformation ? triggers pathway for signal transduction require additional signals from innate system Ag without processing ? NATIVE CONFORMATION

10. Ag-Induced Signaling in B-Cells Membrane Ig receptors cluster (bind and move together) and trigger biochemical signals that are transduced by receptor-associated signal molecules similar to T-cells activation must cross-link 2 or more receptors for signal transduction ? 2 or more Ag in an aggregate or repeating epitopes of one Ag molecule ? binds adjacent Ig molecules Polysaccharide, lipid and other non-protein Ag have multiple identical epitopes in each molecule (bind numerous Ig receptors on B-cell) transduced by receptor-associated proteins

11. Signals Receptor IgM and IgD ? highly variable with short cytoplasmic domains recognize Ag but do not transduce signals IgM and IgD are non-covalently linked to Ig? and Ig? to make the B-cell receptor (BCR) complex Ig? and Ig? contain conserved immunoreceptor tyrosine-based activation motifs (ITAM) ? seen in other activation receptors 2 or more Ag receptors cluster, Tyr in ITAM of Ig? and Ig? are phosphorylated by kinase associated with BCR complex Tyr-PO4 is the docking sites for adaptor protein which gets phosphorylated and recruits a number of signal molecules Signal cascade not as well understood as T-cells but essentially similar ? activates trnscription factor that turn on genes whose proteins involved in B-cell proliferation and differentiation

12. B-Cell Activation Syk is similar to ZAP-70

13. Complement and B-Cell Activation B-cells express receptor for a complement protein which provides signals to activate B-cells when bound to ligand Complement is activated by microbes and Ab attached to microbes ? functions as effector mechanism of host defense (Chapter 8)

14. Complement Activation of B-Cells Microbe has C3d (cleavage product of C3) coating the surface B-cells has type 2 complement receptor (CR2 or CD21) and it binds to C3d B-cells recognize microbe Ag by the Ig receptor and also recognizes C3d on CR2 receptors C3d acts as the 2nd signal for B-cell activation CR2 enhances Ag-dependent activation of B-cells Ag recognition is 1st step and C3d-CR2 binding is the 2nd signal

15. Activation Microbes themselves or innate immune response to microbes provide signals in addition to Ag recognition to activate lymphocytes or microbial products attaching to TLR on B-cell C3d is similar to co-stimulators in T-cell activation

16. Consequences of Ag-Mediated B-Cell Activation Initiate B-cell proliferated and differentiation and prepare B cells to interact with TH cells if protein Ag B-cell enters cell cycle and proliferates ? clonal expansion Produces more IgM and secrete IgM ? early phase immune response induced

17. Early Phase is Greatest Response is greatest for polysaccharide and T-independent Ag multivalent cross-links many Ag-receptors activates C? strongly Proteins can?t do the 1st 2 so make weak response without TH response lack multiple, identical epitopes

18. Additional Steps At least 3 other changes to the B-cell to enhance ability to interact with TH cells ? acting as APC increase the expression of B7 costimulator molecule (2nd signal for T-cells), may amplify helper T-cell response and expression of cytokine receptors ? cytokine mediators of TH cell functions decrease the expression of chemokine receptors ? chemokines keep B-cell in follicles, without chemokines they can migrate out of follicle to where TH cells are concentrated

19. Function of T-Helper Cells Required for strong response to protein Ag B-cell and T-cell must recognize protein Ag and come together to stimulate B-cell proliferation and differentiation in the lymphoid tissue takes 3-7 days for Ab response

20. Activation and Migration Activated helper T-cells (effector cells) interact with Ag-stimulated B-cells at edge of follicles in lymphoid tissue

21. TH and B-Cell Interaction Na?ve CD4+ T-cell is stimulated to proliferate and differentiate into cytokine secreting effector cell Ag recognition and co-stimulation microbial Ag and protein Ag with adjuvants that cause expression of co-stimulators on APC extracellular microbes and vesicular microbes on MHC II in T-cell rich zones in LN depending on Ag ? become TH1, TH2 or TH17 subset portion of cells move out of LN to look for Ag T-cells move out of LN to circulation ? remove microbes CMI some T-cells migrate to the edge of lymphoid follicles while B-cells are moving outward; dependent on changes in chemokine receptors on activated lymphocytes and the chemokines are also expressed to bind receptors

22. Ag Presentation by B-Cells B-cells bind protein Ag (extracellular) by specific receptors and endocytose them ? process in endosome vesicles and display on MHC II for recognition by helper T-cells Membrane bound Ig can bind Ag with high affinity (low Ag concentration); very efficiently endocytosed and processed to be peptide on MHC II = act as APC specific recognition of Ag by Ig on the surface B-cells have ability to display multiple Ag for T-cell recognition ? B and T cells can recognize different epitopes of same Ag interactions remains Ag specific Ag-activated B-cells also express co-stimulators such as B7 to stimulate T-cells that recognize Ag on B-cells cannot activate na?ve T-cells

23. B- and T-Cell Interaction

24. TH-Cell Mediated Activation TH-cell recognize Ag on APC B-cell and activate it by expressing CD40L and secreting cytokines ? similar to T-cell activation of macrophages in CMI CD40L binds CD40 on B-cell ? sends signals for B-cell expansion and for synthesis and secretion of Ab Cytokines made in the T-cell bind to the B-cell and enhance proliferation and Ig production CD40L:CD40 interaction insures that B-cells are activated only when they come in contact with T-cell Helper T- cell signals trigger heavy chain switching and affinity maturation ? as seen in T-dependent protein Ag recognition

25. Isotype Switching Heavy class chain is switched to a different isotype to broaden functional capabilities Helper T-cell help with the switch from IgM/IgD to another isotype allows humoral immune response to adapt in order to combat microbe optimally IgG is used to opsonize microbes and extracellular viruses ? phagocytosed by neutrophils and macrophages; usually IgG1 and IgG3 classes bind the Fc receptor on the phagocyte with high affinity and specificity for ? heavy chain IgE is used to fight helminths by recruiting eosinophils which recognize the ? heavy chain by way of Fc receptor

26. Effector Functions of Ab

27. Reasons for Switching Need to make a response that can remove various microbes ? needs to be more than IgM and IgD Class switching is mediated by CD40L:CD40 mediated signals ? different cytokines involved cytokines influences which heavy chain class an individual B-cell and progeny will switch to No CD40L or CD40 ? B-cells secrete only IgM

28. X-Linked Hyper IgM Syndrome Inactivating mutations in CD40L gene on the X-chromosome ? no functioning forms of CD40L Mostly IgM Ab produced due to the defective heavy chain switching Also defective CMI because of the effect on T-cell activation (use of CD40L)

29. Class Switching (Switch Recombination) Process is well understood In IgM B-cells the VDJ region of variable portion is adjacent to C? gene splice mRNA of VDJ RNA to C?RNA = make ? heavy chain Cytokines and CD40 signals stimulate transcription thru a C gene segment to make something other than IgM ? 5? end intron has conserved sequence that is the switch region activation causes 3? switch region of C? to link to 5? switch region of downstream constant region and delete entire intron, removing the ? gene RNA switch region is not present for C? gene enzyme Activation-Induced Deaminase (AID) plays a role in switch recombination

30. Switching VDJ region in contact with C regions downstream ? Ab may have new heavy chain but the specificity in the variable region is the same as IgM VDJ region stays the same (where Ab specificity resides)

31. Cytokine Impact INF? complements both B-cells and phagocytes INF? makes opsonizing Ab (from TH1 cells) promotes phagocytosis ? also INF? is phagocyte activating bacteria and viruses stimulate the formation of TH1 cells (secretes INF?) IgE class switching is ruled by IL-4 (TH2 cytokine) and eosinophil activation by IL-5 (also from TH2 cells) Nature of helper cell activity guides the Ab response optimized for the microbe helper T-cells may act as ?master controller? of the immune response Also influenced by site of immune response mucosal epithelium has IgA ? B cells and unknown cytokine to switch to IgA

32. Affinity Maturation Affinity of Ab produced to protein Ag increases with prolonged or repeated exposures to that Ag Ab binding to microbe or Ag increases if infection is persistent or recurrent due to point mutations in the V region ? Ag binding hypervariable region happens only in T-dependent protein Ag mutation rate 1:1000 nucleotides ? somatic hypermutation

33. Mutation Accumulation

34. Helper Cells Are Critical Affinity maturation occurs in germinal center of lymphoid follicles ? Somatic Hypermutation of Ig genes in dividing B-cells ? followed by selection of high affinity B-cells by Ag displayed by follicular dendritic cells As response goes on, increase in the level of Ab and decrease in the Ag so B-cells with high affinity Ab receptors will bind Ag on the FDC and therefore survive apoptosis B cells are selected to survive must bind Ag at lower and lower Ag concentration germinal center B-cells die unless rescued by Ag-recognition Ag:Ab complex can activate complement

35. Affinity Maturation

36. Where?? Occurs in different parts of lymphoid tissue Mature na?ve B-cell recognize Ag and move to peripheral edge of the follicle where it encounters the T helper cell and start to secrete Ab Plasma cells move away from B-cell rich regions continue to secrete Ab even when Ag is gone Fraction of cells after heavy class switching (occurs outside of follicle) will become memory cells and wander until contact the Ag again

37. T-Independent Ab Response Needs no T-cell help Polysaccharides, lipids and non-protein molecules no T-cell recognition / no MHC response happens because these Ag are multi-valent (have multiple identical epitopes) and can activate B-cell Two types of Ab differ

38. Ab Feedback Most B-cells will die by apoptosis except for memory and small number of plasma cells Removal comes from the B-cell having a Fc receptor, Fc?RII that will bind Fc part of Ab and receptor mediated signaling terminates the humoral immune response when sufficient IgG present


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