醫(yī)學(xué)免疫學(xué)課件：B lymphocytes and humoral immune response

1、B lymphocytes and humoral immune responseThe B-cell receptor complex is made up of cell-surface immunoglobulin with one each of the invariant signaling proteins Ig and Ig The complete B-cell receptor is thought to be a complex of six chains: two identical light chainstwo identical heavy chainsone as

2、sociated heterodimer of Ig and Ig, each of which has one ITAM (immunoreceptor tyrosine-based activation motifs ) essential for the ability of the B-cell receptor to signal.TCR SignalingThe logic of B-cell receptor signaling is similar to that of T-cell receptor signaling, but some of the signaling c

3、omponents are specific to B cellsThe B-cell receptor is composed of antigen-specific chains associated with ITAM-containing signaling chains Ig and Ig.In B cells, three protein tyrosine kinases of the Src family-Fyn, Blk, and Lyn are responsible for phosphorylation of the ITAMs.B cells do not expres

4、s ZAP-70; instead, Syk, containing two SH2 domains, is recruited to the phosphorylated ITAM.Because there are at least two receptor complexes in each cluster, Syk molecules become bound in close proximity and can activate each other by transphosphorylation, thus initiating further signaling. B-cell

5、antigen receptor signaling is modulated by a co-receptor complex of at least three cell-surface molecules, CD19, CD21, and CD81.The B-cell equivalent to the co-receptors CD4 and CD8 is a complex of cell surface proteins-CD19, CD21, and CD81-which is known as the B-cell co-receptor.CD21 is a receptor

6、 for the C3dg fragment of complement. This means that antigens such as bacterial pathogens on which C3dg is bound can cross-link the B-cell receptor with the CD21:CD19:CD81 complex. This induces phosphorylation of the cytoplasmic tail of CD19 by B-cell receptor-associated tyrosine kinases, which in

7、turn leads to the binding of Src-family kinases, the augmentation of signaling through the B-cell receptor itself, and the recruitment of PI3-kinase.Summary of the intracellular signaling pathways initiated by cross-linking of B-cell receptors by antigenHumoral Immune responseThe course of an infect

8、ion can be divided into several distinct phasesThe humoral immune response is mediated by antibodies secreted by plasma cellsTD antigen and TI antigenProtein antigens Signal 1 is delivered through its antigen receptor (BCR). Signal 2 is delivered by a helper T cell that recognizes degraded fragments

9、 of the antigen as peptides bound to MHC class II molecules on the B-cell surface (center panel); the interaction between CD40 ligand (CD40L, also called CD154) on the T cell and CD40 on the B cell contributes an essential part of this second signal.TI antigenSome microbial constituents, such as bac

10、terial polysaccharides.Signal 1 is delivered through its antigen receptor (BCR). Signal 2 is delivered along with the antigen itself, through Toll-like receptors that recognize antigen-associated TLR ligands, such as bacterial lipopolysaccharide (LPS) or bacterial DNA.Helper T cells stimulate the pr

11、oliferation and then thedifferentiation of antigen-binding B cells.Linked recognition: B cells and helper T cells must recognize epitopes of the same molecular complex in order to interactHelper T cells stimulate B cells through binding of CD40 and directed cytokine secretionOpsonized antigens are c

12、aptured and preserved by subcapsular sinus macrophagesMacrophages residing in the lymph node subcapsular sinus (SCS) express complement receptors 1 (CR1) and CR2Antigen-binding B cells meet T cells at the border between the T-cell area and a B-cell follicle in secondary lymphoid tissueFollicular den

13、dritic cell (FDC) is a nonphagocytic cell of nonhematopoietic origin.Antigens derived from microorganisms are transported to lymph nodes via the lymph, and to the spleen via the blood.Both T cells and B cells proliferate in the primary focus for several days, and this constitutes the first phase of

14、the primary humoral immune response.Plasma cells secrete antibody at a high rate but can no longerrespond to antigen or helper T cellsThe second phase of a primary B-cell immune response occurs when activated B cells migrate into follicles and proliferate to form germinal centersActivated B cells fo

15、rm germinal centers in lymphoid folliclesThe structure of a germinal centerThe germinal center is a specialized microenvironment in which B-cell proliferation, somatic hypermutation, class switching and selection for strength of antigen binding all occur.Closely packed centroblasts, which express CX

16、CR4 and CXCR5, form the so-called dark zone of the germinal center; the less densely packed light zone contains centrocytes, which express only CXCR5. Cells in the dark zone produce CXCL12, which attracts the CXCR4-expressing centroblasts. B cells undergo several important modifications in the germi

17、nal center that produce a more effective antibody response.Germinal centers are sites of intense cell proliferation and cell deathGerminal center B cells undergo V-region somatic hypermutation, and cells with mutations that improve affinity for antigen are selectedClass switching in thymus-dependent

18、 antibody responses requires expression of CD40 ligand by helper T cells and is directed by cytokinesDifferent cytokines induce switching to different antibody classesSurviving germinal center B cells differentiate into either plasma cells or memory cellsIn B cells, the transcription factors Pax5 an

19、d Bcl6 inhibit the expression of transcription factors required for plasma-cell differentiation, and Pax5 and Bcl6 are downregulated when the B cell starts differentiation. The transcription factor IRF4 then induces the expression of BLIMP-1, a transcriptional repressor that switches off genes requi

20、red for B-cell proliferation, class switching, and affinity maturation.B cells in which BLIMP-1 is induced become plasma cells; they cease proliferating, increase the synthesis and secretion of immunoglobulins, and change their cell-surface properties.Some plasma cells deriving from germinal centers

21、 in lymph nodes or spleen migrate to the bone marrow, where a subset lives for a long period, whereas others migrate to the medullary cords in lymph nodes or splenic red pulp.Other germinal center B cells differentiate into memory B cells. Memory B cells are long-lived descendants of cells that were

22、 once stimulated by antigen and had proliferated in the germinal center. They divide very slowly if at all; they express surface immunoglobulin but secrete no antibody, or do so only at a low rate.Some bacterial antigens do not require T-cell help to induce B-cell responsesMost protein antigens are

23、dependent on helper T cells.Some bacterial polysaccharides, polymeric proteins, and lipopolysaccharides are able to stimulate naive B cells in the absence of T-cell help. Such antigens are known as thymus-independent antigens (TI antigens).TI antigens: TI-1 and TI-2 TI-l antigens contain molecules t

24、hat cause the proliferation and differentiation of most B cells regardless of their antigen specificity; this is known as polyclonal activation. TI-l antigens are often called B-cell mitogens.LPS and bacterial DNA are TI -1 antigens.Naive murine B cells express most TLRs constitutively, but naive hu

25、man B cells do not express high levels of most TLRs until they receive stimulation through the B-cell receptor. Tl-1 antigens induce polyclonal B-cell responses at high concentrations and antigen-specific antibody responses at low concentrationsAt high concentration, the signal delivered by Tl-1 ant

26、igens is sufficient to induce proliferation and antibody secretion by B cells in the absence of specific antigen binding to surface immunoglobulin. Thus, all B cells respond. At low concentration, only B cells specific for the Tl-1 antigen bind enough of it to focus its B-cell activating properties

27、onto the B cell; this gives a specific antibody response to epitopes on the Tl-1 antigen.Such responses may be important in defense against several extracellular pathogens: they arise earlier than thymus-dependent responses because they do not require the previous priming and clonal expansion of hel

28、per T cells. However, TI -1 antigens are inefficient inducers of affinity maturation and memory B cells.Tl-2 antigensTl-2 antigens such as bacterial capsular polysaccharides contain highly repetitive structures.Tl-2 antigens have no intrinsic B-cell-stimulating activity. Whereas TI-l antigens can ac

29、tivate both immature and mature B cells, TI-2 antigens can activate only mature B cells;Immature B cells are inactivated by encounter with repetitive epitopes. Responses to several TI-2 antigens are made prominently by B-1 cells ( CD5 B cells) and marginal zone B cells,TI-2 antigens most probably ac

30、t by simultaneously cross-linking a critical number of B-cell receptors on the surface of antigen-specific mature B cellsExcessive cross-linking of B-cell receptors renders mature B cells unresponsive or anergic, just as it does immature B cells. Thus, the density of TI-2 antigen epitopes presented

31、to the B cell is critical. If it is too low, receptor cross-linking is insufficient to activate the cell; if too high, the B cell becomes anergic.As well as producing IgM, thymus-independent responses can include switching to certain other antibody classes, such as IgG3 in the mouse. This isprobably

32、 the result of help from dendritic cells, which provide secreted cytokines such as BAFF and membrane-bound signals to proliferating plasmablasts as they respond to TI antigensProperties of different classes of antigen that elicit antibody responsesThe distributions and functions of immunoglobulin cl

33、assesAntibodies of different classes operate in distinct places and have distinct effector functionsEach human immunoglobulin class has specialized functions and a unique distributionTransport proteins that bind to the Fc regions of antibodies carry particular isotypes across epithelial barriersDime

34、ric IgA binds specifically to a receptor called the polymeric immunoglobulin receptor (plgR). When the plgR has bound dimeric lgA, the complex is internalized and carried through the cytoplasm of the epithelial cell in a transport vesicle to its luminal surface. This process is called transcytosis.I

35、gG and IgM predominate in blood (shown here for simplicity by IgM and IgG in the heart), whereas IgG and monomeric IgA are the major antibodies in extracellular fluid within the body. Dimeric lgA predominates in secretions across epithelia, including breast milk. The fetus receives lgG from the moth

36、er by transplacental transport. lgE is found mainly associated with mast cells just beneath epithelial surfaces (especially of the respiratory tract, gastrointestinal tract, and skin). The brain is normally devoid of immunoglobulin. ?Immunoglobulin classes are selectively distributed in the bodyMany

37、 common diseases are caused by bacterial toxinsNeutralization of toxins by IgG antibodies protects cells from their damaging actionViral infection of cells can be blocked by neutralizing antibodiesAntibodies can block the adherence of bacteria to host cellsMany bacterial infections require an intera

38、ction between the bacterium and a cell-surface receptor. This is particularly true for infections of mucosal surfaces. The attachment process involves very specific molecular interactions between bacterial adhesins and their receptors on host cells; Antibodies against bacterial adhesins can block su

39、ch infectionsAntibody:antigen complexes activate the classical pathway of complement by binding to C1 qComplement receptors are important in the removal of immune complexes from the circulationCR1 on the erythrocyte surface has an important role in the clearance of immune complexes from the circulat

40、ion. Immune complexes bind to CR1 on erythrocytes, which transport them to the liver and spleen, where they are removed by macrophages expressing receptors for both Fc and bound complement components.Distinct receptors for the Fc region of the different immunoglobulin classes are expressed on differ

41、ent accessory cellsFc and complement receptors on phagocytes trigger theuptake and degradation of antibody-coated bacteriaThe most important Fc-bearing cells in humoral immune responses are the phagocytic cells of macrophages and neutrophils.Phagocyte activation can initiate an inflammatory response

42、 that causes tissue damage, and so Fe receptors on phagocytes must be able to distinguish antibody molecules bound to a pathogen from the much larger number of free antibody molecules that are not bound to anything.Bound antibody is distinguishable from free immunoglobulin by its state of aggregatio

43、nFree immunoglobulin molecules bind most Fc receptors with very low affinity and cannot crosslink Fc receptors. Antigen-bound immunoglobulin binds to Fc receptors with high avidity because several antibody molecules that are bound to the same surface bind to multiple Fc receptors on the surface of t

44、he accessory cell. This Fc receptor cross-linking sends a signal to activate the cell bearing it. With Fc receptors that have ITIMs, the result is inhibition.Antibody-coated target cells can be killed by NK cells in antibody-dependent cell-mediated cytotoxicity (ADCC)NK cells are large granular non-

45、T, non-B lymphoid cells that have FcyRIII (CD16) on their surface. When these cells encounter cells coated with IgG antibody, they rapidly kill the target cells. ADCC is only one way in which NK cells can contribute to host defense.Mast cells and basophils bind lgE antibody via the high-affinity fee

46、 receptorlgE antibody crosslinking on mast-cell surfaces leads to a rapid release of inflammatory mediators.The course of a typical acute infection that is cleared by anadaptive immune reactionDynamics of Adaptive ImmunityThe course of an infection can be divided into several distinct phasesProtecti

47、ve immunity consists of preformed immune reactants and immunological memoryThe first time a particular pathogen is encountered, pathogen-specific antibody and effector T cells are produced. After the infection has been cleared, their levels gradually decline. An early reinfection with the same patho

48、gen is rapidly cleared by these preformed immune reactants. There are few symptoms, but levels of immune reactants are found to increase temporarily (light blue peak). Reinfection years afterward leads to an immediate and rapid increase in pathogen-specific antibody and effector T cells as a result

49、of immunological memory, and disease symptoms are mild or inapparent.The generation of secondary antibody responses from memoryB cells is distinct from the generation of the primary antibody responseBoth the affinity and theamount of antibody increase with repeated immunizationSummaryThe humoral imm

50、une response to infection involves the production of antibody by plasma cells derived from B lymphocytes, the binding of this antibody to the pathogen, and the elimination of the pathogen by phagocytic cells and molecules of the humoral immune system. The production of antibody usually requires the

51、action of helper T cells specific for a peptide fragment of the antigen recognized by the B cell, a phenomenon called linked recognition. An activated B cell first moves to the T-zone-B-zone boundary in secondary lymphoid tissues, where it may encounter its cognate T cell and begin to proliferate. S

52、ome B cells become plasmablasts, and others will move to the germinal center, where somatic hypermutation and class switch recombination take place. B cells generated there that bind antigen most avidly are selected for survival and further differentiation, leading to affinity maturation of the anti

53、body response. Cytokines made by helper T cells direct class switching, leading to the production of antibody of various classes that can be distributed to various body compartments.IgM antibodies are produced early in an infection by conventional, or B-2, cells, and is also made in the absence of i

54、nfection by subsets of nonconventional B cells in particular locations (natural antibodies). IgM has a major role in protecting against infection in the bloodstream, whereas isotypes secreted later in an adaptive immune response, such as IgG, diffuse into the tissues.Antigens with highly repeating antigenic determinants and that c