Humoral immune response.pdf

Humoral immune response Adaptive George Nadăș, Professor of Immunology, [email protected] Humoral immune response Antibodydependent Antibodies – when? Antibody-mediated elimination of antigens antibodies are the Titer only defense mechanism used to combat microbes in 1,1 the Teceptors lumens of mu...

Humoral immune response Adaptive George Nadăș, Professor of Immunology, [email protected] Humoral immune response Antibodydependent Antibodies – when? Antibody-mediated elimination of antigens antibodies are the Titer only defense mechanism used to combat microbes in 1,1 the Teceptors lumens of mucosal organs and in newborn the fetus and a Humoral immune response Neutralization of Microbes and Microbial Toxins Antibodies against microbes and microbial toxins block the binding microbes and cellular receptors of these toxins to Humoral immune response Leukocyte Fc Receptors + NK - ADCC FcγRI (CD64) receptor (IgG1 and IgG3) - macrophages and neutrophils + NK Fcδ (IgE) - eosinophils Receptors Fc Humoral immune response IgE- and eosinophil-mediated killing of helminths IgE Coatedin Humoral immune response Complement activation – classical pathway Gavinmoleculefloating 4attacheda Humoral immune response Antibodies – when? Exogenous Ag – destroyed by antibodies – produced by B cells Against bacteria - neutralization of toxins or enzymes - killing – complement – classical pathway - ADCC – Fcγ receptor (IgG) and Fcδ (IgE) Against viruses - virion – complement or phagocytosis Against parasites - Th2 – IgE + epsinophils Against tumors - not in solid cancers - lymphosarcomas - complement I B-cell antigen receptor TCRjusthave30,000 200-500,000 BCR’s - soluble 4 peptide chains - heavy chains - light chains + 8 m Lexcept - Igα (CD79a) - Igß (CD79b) forIga Eatface misshapen chainson light Angie Humoral immune response Immunoglobulin Structure variable constant 4 polypeptide chains Two identical heavy chains Two identical light chains Constant and variable regions in each chain Humoral immune response Immunoglobulin Structure P ans Heavy chains 400-500 amino acids divided in 4-5 domains 1 variable domain (VH) 3-4 constant domains (CH) Five types of HC: Determines the Ig class Domains Heavy chain CH1, CH2, CH3, VH Humoral immune response Immunoglobulin Structure Light chains 220 amino acids in 2 domains 1 variable domain (VL) 1 constant domain (CL) Two types of LC: Κ (kappa) or λ (lambda) Neverboth Functionally identical Light chain CL, VL Humoral immune response Immunoglobulin Structure Fab - Fragment antigen binding Fc - Fragment crystallisable Tail crystalizable fragment Humoral immune response Immunoglobulin Structure sulfide i nterengina in firing Humoral immune response Antigen binding site Composed by the variable domains in light and heavy chains. Framework regions Complementarity determining regions (Hypervariable) madeofconstant variablefragments Humoral immune response CDRs Sequence variation in 6 to 10 amino acids in three regions of the variable domain Constant regions (Framework regions) in between CDRs epitope Humoral immune response Immunoglobulin Structure Humoral immune response BCR’s signal transducing component The BCR itself cannot signal directly to the cell Associates with glycoprotein heterodimers formed by pairing CD79a (Ig-α) with CD79b (Ig-β) Humoral immune response Hydrophobicmembrane structures Humoral immune response Antibodies Largest Soluble BCRs Divided in 5 classes (type of HC) IgG - γHeavy chain IgM - µ Heavy chain IgA – α Heavy chain IgE - ε Heavy chain IgD - δ Heavy chain ¼ SITdfoIyfEigto pp Humoral immune response IgG know the role in differentresponses γHeavy chain - 4 domains 180 kDa molecular weight Very mobile (Hinge region) mostimportantrole Abilitytomovefrombloodstream in propereventsof inflammation Difficultforlargemolecules Small size → tissues The most abundant in serum tissue Humoral immune response IgG Typicalfeatures Neutralization of microbes and toxins Opsonization of antigens asingleonecannottriggeractivationatleast2arerequired Activation of the classical pathway of complement Antibody-dependent cellular cytotoxicity (NK cells) Neonatal immunity transferedviaplacenta colostrum bornimportantwhen theyare bynew infection Absorbed to susseptable Humoral immune response IgM µ Heavy chain - 5 domains in each subunit 5-6 subunits per molecule 900 kDa molecular weight High (polymeric form) Humoral immune response IgM Second highest concentration in serum Major Ig of the primary immune responsein Responcesagainstproteinantigens Tdependen Reduced in Indary More efficient than IgG at complement activation Rarely enter tissue fluids Becauseitstoobigtobeplacentaorcolostrumtransfer IgGwouldbehigh Humoral immune response IgA Secratory Found in mucousmembranes respiratorytract α Heavy chain - 4 domains in each subunit gotepethelium protecti Usually secreted as a dimer (360 kDa) main joining en usuallynotstrong fordimersuses ishaspolymericimmu receptor a feetons Humoral immune response IgA Does not active the classical complement pathway Mucosal immunity Neutralization of microbes and toxins FYI FYI Humoral immune response IgA Secreted by mucosal plasma cells Binds to receptors (pIgR) on the interior intestinal enterocytes Passed in vesicles to the cell surface In the intestinal lumen, the pIgR is cleaved Secretory component Humoral immune response IgA Humoral immune response IgE ε Heavy chain - 5 domains Presents a hinge region 190kDa molecular weight Low concentrations in serum Halflife2 3days short Humoral immune response IgE IgE it triggers the release of inflammatory molecules from the mast cells Mediates type I hypersensitivity reactions Responsible in part for immunity to parasitic worms Shortest half-life of all immunoglobulins (2 to 3 days) Lowest cells releasedfromplasma fromtheclassesthat are Humoral immune response IgD 100000more potent δ Heavy chain - 4 domains cells than dendritic Presents a hinge region 170kDa molecular weight IgD is mainly found attached to B cells Humoral immune response IgD Found in horses, cattle, sheep, pigs, dogs, rodents, and primates Not detected in rabbits or cats Does not have a clear role In humans, IgD binds to basophils → IL-4, IL-1, cathelicidins, and B cell activator factor Humoral immune response Ig isotype distribution in the organism Humoral immune response Immunoglobulin variants Isotypes Classes and subclasses Result of gene duplication Allotypes ifp.es iif AllIgawouiabebiueAnIgawooidbepinu I Variations in immunoglobulin amino acid sequences Ig of one individual may differ from those of another individual of the same species Idiotypes Variations in the amino acid sequences within the variable domains on light and heavy chains first Humoral immune response Immunoglobulin Humoral immune response Humoral immune response Costimulation of B cells Helper T cells – presented with antigen by an APC B cell – APC and receive costimulation from the same T cell Ag presentation by B cells B cells can activate Th cells with 1/1000 of the antigen concentration required activate macrophages Th2 cytokines (IL-4, IL-5, IL-6 and IL-13) to Humoral immune response CD40/CD40L (CD154) co-stimulation Humoral immune response Th cell co-stimulation Humoral immune response CD40/CD40L (CD154) co-stimulation CD40-CD154 (CD40L) upregulates expression of IL-4 and IL-5 receptors on B-cells Signals from CD40 synergize with IL-4 and IL-5 receptors cell development and Ig class switching Humoral immune response Cytokine secretion by Th2 cells IL-6 Needed for final Growth and differentiation of B cells differentiation of B cell into Expression of MHC II plasma cells Induces Ig class switching IL-6 + IL-5 ↑IgA production IL-6 + IL-1 ↑ IgM production IL-5 B cell → plasma cells IL-13 ↑IgM and IgG production Similar to IL-4 IL-5 + IL-4 ↑ IgE Required for optimal production production of IgE Selectively ↑IgA production IL-4 Humoral immune response B cell activation and antibody production The activation of B cells proliferation and their eventual differentiation into antibody-secreting plasma cells and memory cells Humoral immune response B cell activation and antibody production Humoral immune responses are initiated by specific B cell recognition of antigen in secondary lymphoid organs Antigen binds to membrane immunoglobulin M (IgM) and IgD on mature, naive B cells, generating signals required for their proliferation and differentiation into plasma cells Humoral immune response B cell activation and antibody production The antibody that is secreted by the plasma cell has essentially the same specificity as the original antibody that served as the antigen receptor on the surface of the naive B cell. A single B cell may, within a week, give rise to as many as 5000 antibodysecreting cells, each of which can secrete about 2000 antibody molecules every second. This cell expansion and the remarkable rate of antibody secretion are needed to keep pace with rapidly dividing microbes Humoral immune response T-dependent and T-independent antibody responses Most responses to protein antigens require T cell help, so these antigens are called Tdependent. The term helper T lymphocyte came from the realization that T cells stimulate, or help, B lymphocytes to produce antibodies In T-dependent responses, some activated B cells begin to produce antibodies other than IgM; this process is called heavy chain isotype (class) switching Humoral immune response T-dependent antibody responses As the response develops, activated B cells produce antibodies that bind to antigens with increasing affinity, and these B cells progressively dominate the response; this process is called affinity maturation In addition to isotype switching and affinity maturation, helper T cells stimulate the production of long-lived plasma cells and the generation of memory B cells Humoral immune response T-independent antibody responses Multivalent antigens with repeating determinants, such as polysaccharides, can activate B cells without T cell help These antigens are called T-independent. T-independent responses are rapid but relatively simple, consisting mostly of low-affinity IgM antibodies, whereas Tdependent responses are slower to develop but result in more durable, high-affinity antibodies that are typically of the IgG, IgA, or IgE isotypes Humoral immune response Primary and secondary antibody responses to protein antigens differ qualitatively and quantitatively Primary responses result from the activation of previously unstimulated naive B cells, whereas secondary responses are due to the stimulation of expanded clones of memory B cells Humoral immune response Primary and secondary antibody responses to protein antigens differ qualitatively and quantitatively Secondary response Primary response Humoral immune response Primary and secondary antibody responses to protein antigens differ qualitatively and quantitatively Humoral immune response Distinct subsets of B cells respond preferentially to different types of antigens Follicular B cells (B2 cells) in secondary (peripheral) lymphoid organs make mostly antibody responses to protein antigens, and these B cell responses require collaboration with helper T cells Marginal zone B cells in the spleen (and other lymphoid tissues) and B-1 cells in mucosal tissues and the peritoneum recognize multivalent antigens, such as bloodborne polysaccharides, and mount primarily T-independent antibody responses Antigen Recognition Antigen Capture and Delivery to B Cells Antigens that elicit antibody responses may vary in size and composition (they may be small, soluble, large, or particulate) and may be free or bound to antibodies The major pathways of antigen delivery for different types antigens include the following: of Antigen Recognition Antigen Capture and Delivery to B Cells 1. Most antigens from tissue sites are transported to lymph nodes by afferent lymphatic vessels that drain into the subcapsular sinus of the nodes. Soluble antigens, generally smaller than 70 kD, may then reach the B cell zone through conduits that extend between the subcapsular sinus and the underlying follicles 2. Subcapsular sinus macrophages capture large microbes and antigenantibody complexes and deliver these to follicles. Antigen Recognition Antigen Capture and Delivery to B Cells 3. Antigens in immune complexes entering the spleen may bind to complement receptors (in particular, the complement receptor type 2 [CR2, CD21]) on marginal zone B cells, and these cells can transfer the immune complex– containing antigens to follicular B cells. 4. Polysaccharide antigens can be captured by macrophages in the marginal zone of splenic lymphoid follicles and displayed or transferred to B cells in this area. Always presented undegraded, intact, not processed by APC’s Antigen Recognition Activation of B Cells by Antigens and Other Signals The B cell receptor (BCR) complex of mature B cells is composed of membrane Ig molecules that bind antigens and associated Igα and Igβ proteins that deliver signals for B cell activation The BCR complex plays two key roles in B cell responses. First, binding of antigen to the receptor delivers biochemical signals to the B cells that initiate activation Second, the BCR internalizes the bound antigen into endosomal vesicles, and if the antigen is a protein, it is processed into peptides that may be presented by class II MHC molecules on the B cell surface for recognition by helper T cells Antigen Recognition Activation of B Cells by Antigens and Other Signals B cell activation is facilitated by the CR2 coreceptor on B cells, which recognizes complement fragments that are covalently atached to the antigen or are part of immune complexes containing the antigen (A) Microbial products engage Toll-like receptors (TLRs) on B cells, which also enhances B cell activation (B) Helper T Cell–Dependent Antibody Responses to Protein Antigens The Sequence of Events During T Cell– Dependent Antibody Responses A Immune responses are initiated by the recognition of antigens by B cells and CD4 + T cells. The activated lymphocytes migrate toward one another and interact at the interface of T and B cell zones. B The initial T-dependent B cell proliferation and differentiation result in the formation of an extrafollicular focus, in which B cells proliferate, can undergo isotype switching, and differentiate into plasma cells (mostly shortlived) Helper T Cell–Dependent Antibody Responses to Protein Antigens The Sequence of Events During T Cell– Dependent Antibody Responses Protein antigens are independently recognized by specific B and T lymphocytes in secondary lymphoid organs, and the two activated cell types interact with each other to initiate humoral immune responses Naive CD4 + T cells are activated in the T cell zones by antigen presented by DCs The activated helper T cells and activated B cells migrate toward one another and interact at the edges of the follicles, where the initial antibody response develops. Some of the activated T and B cells migrate into follicles to form germinal centers, where more specialized antibody responses are induced. Helper T Cell–Dependent Antibody Responses to Protein Antigens Antigen presentation on B cells to helper T cells Protein antigens recognized by membrane immunoglobulin are endocytosed and processed, and peptide fragments are presented in association with class II major histocompatibility complex (MHC) molecules. Helper T cells recognize MHC-peptide complexes on the B cells and then stimulate B cell responses. Helper T Cell–Dependent Antibody Responses to Protein Antigens Role of CD40L:CD40 Interaction in T-Dependent B Cell Activation Upon activation, helper T cells express CD40 ligand (CD40L), which engages its receptor, CD40, on antigen-stimulated B cells and induces B cell proliferation and differentiation, initially in extrafollicular foci and later in germinal centers CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily Helper T Cell–Dependent Antibody Responses to Protein Antigens Extrafollicular B-cell activation B cell activation in the extrafollicular focus results in an early antibody response to protein antigens and sets up the subsequent germinal center reaction Extrafollicular foci of T-dependent B cell activation generate low-affinity antibodies that can circulate and limit the spread of an infection. Each such focus may produce 100 to 200 antibody-secreting plasma cells In the spleen, extrafollicular foci develop in the outer portions of the T cell–rich periarteriolar lymphoid sheath (PALS) or between the T cell zone and the red pulp, and these collections of cells are also called PALS foci. Similar Tdependent foci are observed in the medullary cords of lymph nodes. Helper T Cell–Dependent Antibody Responses to Protein Antigens T Follicular Helper (Tfh) Cells Within 4 to 7 days after antigen exposure, activated antigen-specific B cells outside the follicle induce some previously activated T cells to differentiate into T cells, which express high levels of the chemokine receptor CXCR5 and play critical roles in germinal center formation and function Differentiation of T cells from naive CD4 + T cells requires two steps: initial activation by antigen-presenting DCs and subsequent activation by B cells The choice between a Th1, Th2, or Th17 fate on the one hand or a T fate on the other depends partly on the strength of the initial interaction between peptide–class II MHC complexes on DCs and the T cell receptor (TCR) on naive CD4 + T cells Helper T Cell–Dependent Antibody Responses to Protein Antigens The Germinal Center Reaction The characteristic events of helper T cell–dependent antibody responses, including affinity maturation, generation of long-lived plasma cells and memory B cells, and continuing isotype switching, occur in organized structures called germinal centers that are created within lymphoid follicles during T-dependent immune responses The complex process of B cell differentiation and selection of cells with the highest affinity antigen receptors that occurs in these sites is called the germinal center reaction Helper T Cell–Dependent Antibody Responses to Protein Antigens The Germinal Center Reaction The germinal center reaction consists of a number of sequential steps: 1. Initiation of the germinal center by T cells 2. Entry of B cells into the GC 3. B cell proliferation 4. Somatic mutations in Ig genes 5. B cell migration within the GC 6. Selection of high-affinity B cells 7. Repetitive mutation and selection 8. Differentiation into long-lived plasma cells 9. Memory B cell formation Helper T Cell–Dependent Antibody Responses to Protein Antigens Heavy Chain Isotype (Class) Switching In T-dependent responses, some of the progeny of activated IgM- and IgD-expressing B cells undergo heavy chain isotype (class) switching and produce antibodies with heavy chains of different classes, such as γ, α, and ε B cells change the isotypes of the antibodies they produce by changing the constant regions of the heavy chains, but the specificity of the antibodies remains unaltered Helper T Cell–Dependent Antibody Responses to Protein Antigens Heavy Chain Isotype (Class) Switching Isotype switching in response to different types of pathogens is regulated by cytokines produced by the helper T cells that are activated by these pathogens Switching from IgM to IgG is a prominent aspect of T-dependent antibody responses against many bacteria and viruses. IgG antibodies promote phagocytosis of opsonized microbes, activate complement , transferred - placenta -newborns The humoral response to many helminthic parasites is dominated by IgE antibodies, which participate in elimination of the helminths + hypersensitivity reactions B cells in mucosal tissues switch to IgA, which is the antibody class that is most efficiently transported through epithelia into mucosal secretions, where it prevents microbes from entering through the epithelia Helper T Cell–Dependent Antibody Responses to Protein Antigens CD40 signals CD40 signals work together with cytokines to induce isotype switching The molecular mechanism of isotype switching is a process called switch recombination, in which the Ig heavy chain DNA in B cells is cut and recombined The key enzyme required for isotype switching is AID (activation-induced (cytidine) deaminase) AID expression is induced in activated B cells mainly by CD40 signals from Tfh cells Helper T Cell–Dependent Antibody Responses to Protein Antigens Affinity Maturation: Somatic Mutation of Immunoglobulin Genes and Selection of High-Affinity B Cells Affinity maturation is the process that leads to increased affinity of antibodies for a particular antigen as a T-dependent humoral response progresses, and it is the result of somatic mutation of Ig genes followed by selective survival of the B cells that produce antibodies with the highest affinities. The process of affinity maturation generates antibodies with an increased ability to bind antigens and thus to more efficiently neutralize and eliminate microbes and their toxins Helper T Cell–Dependent Antibody Responses to Protein Antigens B Cell Differentiation Into AntibodySecreting Plasma Cells Plasma cells are morphologically distinct, terminally differentiated B cells commited to abundant antibody production They are generated after the activation of B cells through signals from the BCR, CD40, TLRs, and other receptors including cytokine receptors two types of plasma cells Short-lived plasma cells are generated during T-independent responses and early during T-dependent responses in extrafollicular B cell foci, described earlier. These cells are generally found in secondary lymphoid organs and in peripheral nonlymphoid tissues. Long-lived plasma cells are generated in Tdependent germinal center responses to protein antigens. Signals from the B cell antigen receptor and IL-21 cooperate in the generation of plasma cells and their precursors, called plasmablasts. Plasmablasts are the earliest cells in the lineage of antibodysecreting cells Helper T Cell–Dependent Antibody Responses to Protein Antigens B Cell Differentiation Into AntibodySecreting Plasma Cells Plasmablasts generated in germinal centers enter the circulation and home to the bone marrow, where they stop dividing and differentiate into long-lived plasma cells Typically 2 to 3 weeks after immunization with a T cell–dependent protein antigen, the bone marrow becomes a major site of antibody production Plasma cells in the bone marrow may continue to secrete antibodies for decades after the antigen is no longer present. These antibodies can provide immediate protection if the antigen is encountered later almost half the antibody in the blood of a healthy adult is produced by long-lived plasma cells. Secreted antibodies enter the circulation and mucosal secretions, but mature plasma cells do not recirculate Helper T Cell–Dependent Antibody Responses to Protein Antigens B Cell Differentiation Into AntibodySecreting Plasma Cells The differentiation of B cells into antibodysecreting plasma cells involves major structural alterations in components of the endoplasmic reticulum and secretory pathway and increased Ig production as well as a change in Ig heavy chains from the membrane to the secreted form. The cell enlarges dramatically, the endoplasmic reticulum and Golgi complex become prominent Morphology of plasma cells. A, Light micrograph of a plasma cell in tissue. B, Electron micrograph of a plasma cell Helper T Cell–Dependent Antibody Responses to Protein Antigens B Cell Differentiation Into AntibodySecreting Plasma Cells Ig production changes from the membrane form (characteristic of B cells) to the secreted form (in plasma cells) because of a change in the carboxy terminal of the Ig heavy chain protein transition from membrane to secreted Ig is caused by alternative RNA processing of the heavy chain messenger RNA (mRNA) Production of membrane and secreted μ chains in B lymphocytes. Alternative processing of a primary RNA transcript results in the formation of mRNA for the membrane or secreted form of the μ heavy chain Helper T Cell–Dependent Antibody Responses to Protein Antigens Generation of Memory B Cells Memory B cells are generated during the germinal center reaction and are capable of making rapid responses to subsequent introduction of antigen Because memory cells develop mainly in germinal centers, they are primarily generated during T-dependent immune responses Although the majority of memory B cells develop in germinal centers in a T-dependent manner, some IgM-expressing memory B cells are generated without T cell help and with little or no somatic hypermutation in a T-independent manner Memory cells survive for long periods, apparently without continuing antigenic stimulation, because they express high levels of the anti-apoptotic protein BCL-2 Antibody Responses T-dependent antibody response T-independent antigens Antibody Responses to TIndependent Antigens Many nonprotein antigens, such as polysaccharides, lipids, and nucleic acids, stimulate antibody production in the absence of helper T cells, and these antigens and the responses they elicit are termed thymus independent (TI) These antibody responses differ in several respects from responses to T cell–dependent protein antigens The antibodies produced in the absence of T cell help are generally of low affinity (IgM), with limited isotype switching to some IgG subtypes and also to IgA Antibody Responses to TIndependent Antigens Subsets of B Cells That Respond to T-Independent Antigens The marginal zone and B-1 subsets of B cells are especially important for antibody responses to TI antigens Marginal zone B cells are a distinct population of B cells that mainly respond to polysaccharides After activation, these cells differentiate into short-lived plasma cells that produce mainly IgM B-1 cells represent another lineage of B cells that responds readily to TI antigens mainly in the peritoneum and in mucosal sites Antibody Responses to TIndependent Antigens Mechanisms of T-Independent Antibody Responses The most important TI antigens, polysaccharides, glycolipids, and nucleic acids, cannot be processed and presented in association with MHC molecules, and therefore they cannot be recognized by CD4 + helper T cells Most TI antigens are multivalent, being composed of repeated identical antigenic epitopes many polysaccharides activate the complement system by the alternative or lectin pathway, generating C3d, which binds to the antigen and is recognized by CR2, thus augmenting B cell activation Antibody Responses to TIndependent Antigens Protection Mediated by TIndependent Antibodies practical significance of TI antigens is that many bacterial cell wall polysaccharides belong to this category, and humoral immunity is the major mechanism of host defense against infections by such encapsulated bacteria (pneumococcus, meningococcus, and Haemophilus) - congenital or acquired deficiencies? T-independent antigens also contribute to the generation of natural antibodies, which are present in the circulation of normal individuals and are apparently produced without overt exposure to pathogens Antibody Feedback Antibody Feedback: Regulation of Humoral Immune Responses By Fc Receptors Secreted antibodies inhibit continuing B cell activation by forming antigen-antibody complexes that simultaneously bind to antigen receptors and inhibitory Fcγ receptors on antigen-specific B cells This is the explanation for a phenomenon called antibody feedback, which refers to the downregulation of antibody production by secreted IgG antibodies Antibody Feedback Antibody Feedback: Regulation of Humoral Immune Responses By Fc Receptors IgG antibodies inhibit B cell activation by forming complexes with the antigen, and these complexes bind to a B cell receptor for the Fc portions of the IgG, called the Fcγ receptor II (FcγRIIB, or CD32) The cytoplasmic tail of FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) B cell membrane Ig and the receptor on B cells for the Fc portions of IgG, called FcγRIIB, are clustered together by antibody-antigen complexes This activates an inhibitory signaling cascade through the cytoplasmic tail of FcγRIIB that terminates the activation of the B cell Humoral immune response Summary In humoral immune responses – B cells are activated by antigen and secrete antibodies that act to eliminate the antigen Protein (contribution of CD4+ helper T cells) and nonprotein antigens stimulate antibody responses A B cell that recognizes an epitope of a protein antigen, ingest the protein, processes it, and displays a peptide derived from the protein on its class II MHC for recognotion by Th cells Humoral immune response Summary Activated lymphocytes interact at the edges of follicles, where the B cells present the peptie antigen to antigen-specific Th cells Activated Th cells express CD40 ligand (CD40L) which engages CD40 on the B cells, and the T cells secrete cytokines that bind to cytokine receptors on the B cells. The combination of CD40 and cytokine signals stimulates B cell proliferation and differentiation. Stimulation of activated B cells at extrafollicular sites by helper T cells leads to the formation of extrafollicular foci where isotype switching occurs and short-lived plasma cells are generated. Humoral immune response Summary Helper T cell–derived signals, including CD40L and cytokines, induce isotype switching in B cells by a process of switch recombination, leading to the production of various immunoglobulin (Ig) isotypes Affinity maturation occurs in germinal centers and leads to increased affinity of antibodies during the course of a T cell–dependent humoral response Some of the progeny of germinal center B cells differentiate into antibody-secreting plasma cells that migrate to the bone marrow. Other progeny become memory B cells that live for long periods, recirculate between lymphoid organs and peripheral tissues, and respond rapidly to subsequent exposures to antigen by differentiating into high-affinity antibody secretors. Humoral immune response Summary T-independent (TI) antigens are generally nonprotein antigens that induce humoral immune responses without the involvement of helper T cells. Many TI antigens, including polysaccharides, membrane glycolipids, and nucleic acids, are multivalent, can cross-link multiple membrane Ig molecules on a B cell, and activate complement, thereby activating the B cells without T cell help. Toll-like receptor (TLR) activation on B cells by microbial products may facilitate T-independent B cell activation TI antigens stimulate antibody responses in which there is limited heavy chain class switching, affinity maturation, or memory B cell generation because these features are largely dependent on helper T cells, which are not activated by nonprotein antigens Humoral immune response Summary Antibody feedback is a mechanism by which humoral immune responses are downregulated when enough antibody has been produced and soluble antibody– antigen complexes are present. B cell membrane Ig and the receptor on B cells for the Fc portions of IgG, called FcγRIIB, are clustered together by antibody-antigen complexes. This activates an inhibitory signaling cascade through the cytoplasmic tail of FcγRIIB that terminates the activation of the B cell. 50 Humoral immunity ©2024 Ross University School of Veterinary Medicine. All rights reserved.