Wk 8 - Humoral Immune Responses - Comprehensive Notes
Humoral Immune Responses
Humoral immunity is mediated by antibodies and eliminates extracellular microbes and toxins.
It's the main immune response against extracellular microbial protein antigens and non-protein antigens like polysaccharides and lipids.
Antibodies are produced by B lymphocytes which differentiate into antibody-secreting plasma cells and memory cells upon antigen-induced activation.
Naive B lymphocytes express membrane-bound IgM and IgD as antigen receptors.
Phases and Types of Humoral Immune Responses
Activation of B lymphocytes leads to proliferation and differentiation into plasma cells that secrete antibodies.
Naive B lymphocytes express IgM and IgD as antigen receptors.
Activated B cells can generate thousands of plasma cells, each producing thousands of antibody molecules per hour.
Heavy-chain class (isotype) switching allows B cells to produce antibodies with different effector functions.
Affinity maturation increases the affinity of antibodies for microbial proteins.
Figure shows the sequence of events in humoral immune responses, including antigen recognition, B cell activation, proliferation, differentiation, isotype switching, affinity maturation, and memory cell formation.
T-Dependent vs. T-Independent Antibody Responses
Antibody responses are classified as T-dependent or T-independent based on the requirement for T cell help, with proteins being T-dependent and polysaccharides, lipids, nucleic acids being T-independent.
T cells help B cell responses only to protein antigens because T cells can only recognize peptides derived from proteins and displayed by MHC molecules.
T-dependent antigens elicit class switching and affinity maturation, while T-independent antigens do not.
T-dependent antigens stimulate the generation of long-lived plasma cells and memory B cells; T-independent responses are relatively short-lived.
Follicular B cells make T-dependent responses, while marginal zone B cells and B-1 cells play greater roles in T-independent responses.
B Cell Subsets and Their Responses
Follicular B cells reside in lymphoid organ follicles and make T-dependent, class-switched, high-affinity antibody responses.
Marginal-zone B cells in the splenic white pulp respond to blood-borne polysaccharide and lipid antigens.
B-1 cells in mucosal tissues and the peritoneum also mainly respond to multivalent polysaccharide and lipid antigens.
Marginal-zone B cells and B-1 cells express limited diversity antigen receptors and make predominantly T-independent IgM responses.
Natural antibodies, produced spontaneously by B-1 cells, may help clear apoptotic cells and provide protection against some bacterial pathogens.
Primary vs. Secondary Antibody Responses
Primary responses differ quantitatively and qualitatively from secondary responses.
Secondary responses produce greater amounts of antibody.
Secondary responses to protein antigens exhibit increased heavy-chain class switching and affinity maturation due to repeated stimulation of helper T lymphocytes.
Figure shows the features of primary and secondary antibody responses, including lag time, peak response, antibody isotype, and antibody affinity.
Stimulation of B Lymphocytes by Antigen
Humoral immune responses begin when antigen-specific B lymphocytes recognize antigens in secondary lymphoid tissues.
Antigens are transported to and concentrated in the B cell–rich follicles and marginal zones in the spleen, and lymph nodes. Macrophages in the subcapsular sinus of lymph nodes may capture antigens and take them to adjacent follicles.
B lymphocytes can use their membrane Ig as receptors that recognize the intact antigen directly, without processing.
Antibodies secreted can bind to the native microbe or microbial product.
Antigen recognition triggers signaling pathways that initiate B cell activation, enhanced by innate immune reactions.
Antigen-Induced Signaling in B Cells
Antigen-induced clustering of membrane Ig receptors triggers biochemical signals that activate B cells, similar to T cell activation.
Receptor cross-linking occurs when two or more antigen molecules bind to adjacent membrane Ig molecules.
Signals are transduced by receptor-associated proteins Igα and Igβ containing ITAMs, forming the BCR complex.
Tyrosine kinases like LYN, FYN, and BLK phosphorylate ITAMs upon BCR cross-linking, recruiting SYK tyrosine kinase which activates downstream molecules.
Figure illustrates antigen receptor–mediated signal transduction in B lymphocytes.
Role of Innate Immune Signals in B Cell Activation
Antigen-induced signals are augmented by signals produced during innate immune responses to microbes, ensuring B cells respond preferentially to microbes.
B lymphocytes express a receptor for complement protein C3d, called CR2 (CD21).
Microbial products directly activate B cells by engaging Toll-like receptors (TLRs).
Figure shows the role of innate immune signals in B cell activation, including complement activation and TLR engagement.
Functional Consequences of B Cell Activation by Antigen
B cell activation initiates proliferation and differentiation and prepares cells to interact with helper T lymphocytes if the antigen is a protein.
The activated B lymphocytes synthesize and secrete IgM, marking the early phase of the humoral immune response.
Protein antigens induce changes in B cells that enhance their ability to interact with helper T lymphocytes.
Protein antigens are efficiently endocytosed, processed, and displayed on class II MHC molecules.
Figure shows the functional consequences of antigen receptor–mediated B cell activation.
Functions of Helper T Lymphocytes in Humoral Immune Responses
B lymphocytes and helper T lymphocytes specific for the same protein antigen must interact to stimulate an antibody response.
This process requires the recognition of different epitopes of the same protein antigen by the two cell types.
Naive CD4+ T cells are activated by antigen presented by dendritic cells and differentiate into helper T cells.
Naive B cells are activated by an exposed epitope on the same protein.
Activation and Migration of Helper T Cells and B Cells
Helper T cells activated by dendritic cells migrate toward B cell follicles.
B lymphocytes activated by antigen in the follicles move out toward the T cells.
Activated T cells reduce CCR7 expression and increase CXCR5 expression.
Activated B cells decrease CXCR5 and increase CCR7 expression.
This regulated migration ensures that antigen-specific lymphocytes locate one another and interact productively.
Presentation of Antigens by B Lymphocytes to Helper T Cells
B lymphocytes bind protein antigens via membrane Ig antigen receptors, endocytose the antigens, process them, and display class II MHC–associated peptides for recognition by CD4+ helper T cells.
B cells are efficient APCs for antigens they specifically recognize.
Figure illustrates antigen presentation by B lymphocytes to helper T cells.
Hapten-Carrier Conjugates
Haptens are small chemicals recognized by B cells but require attachment to a carrier protein for strong antibody responses.
B cell binds hapten portion, ingests the conjugate, and displays peptides derived from the carrier to helper T cells.
Effective conjugate vaccines against microbial polysaccharides are developed using this concept.
Figure illustrates the principle of conjugate vaccines.
Mechanisms of Helper T Cell–Mediated Activation of B Lymphocytes
Activated helper T lymphocytes recognize antigen presented by B cells and use CD40 ligand (CD40L) and secreted cytokines to activate antigen-specific B cells.
Engagement of CD40 generates signals in B cells that stimulate proliferation and antibody synthesis.
Cytokines produced by helper T cells bind to cytokine receptors on B lymphocytes and stimulate more B cell proliferation and Ig production.
Figure shows the mechanisms of helper T cell–mediated activation of B lymphocytes.
Extrafollicular and Germinal Center Reactions
Initial T-B interaction outside lymphoid follicles results in low levels of antibodies.
Germinal centers form in lymphoid follicles and require specialized helper T cells.
Follicular helper T (Tfh) cells express high levels of CXCR5 and are drawn into follicles.
Tfh cells secrete cytokines like IL-4, IL-13, and IL-21.
In the germinal center, B cells undergo further class switching and somatic mutation of Ig genes.
Figure illustrates the germinal center reaction.
Heavy-Chain Class (Isotype) Switching
Helper T cells stimulate B lymphocytes to change the heavy-chain classes (isotypes) of antibodies they produce without changing antigen specificities.
Different antibody isotypes perform different functions, broadening the functional capabilities of humoral immune responses.
Heavy-chain class switching is induced by CD40L-mediated signals and cytokines.
Figure shows immunoglobulin heavy-chain class switching.
Molecular Mechanism of Class Switching
Switch recombination involves moving the VDJ exon adjacent to a different C region gene downstream in the Ig heavy chain locus.
Signals from CD40 and cytokine receptors stimulate transcription through switch regions.
Activation-induced deaminase (AID) plays a key role by converting cytosines in the transcribed switch region DNA to uracil.
The antibody isotype produced is influenced by the site of immune responses.
Figure illustrates the mechanism of immunoglobulin heavy-chain class switching.
Affinity Maturation
Affinity maturation increases the affinity of antibodies produced in response to a protein antigen with prolonged or repeated exposure.
Affinity maturation is seen only in responses to helper T cell–dependent protein antigens.
Affinity maturation occurs in the germinal centers of lymphoid follicles.
Figure illustrates affinity maturation in antibody responses.
Somatic Hypermutation and Selection of High-Affinity B Cells
Somatic hypermutation introduces point mutations into Ig genes of rapidly dividing B cells.
The enzyme AID plays a critical role in somatic mutation.
Selection of B cells with the most useful antigen receptors occurs in germinal centers.
Figure illustrates selection of high-affinity B cells in germinal centers.
Generation of Plasma Cells and Memory B Cells
Activated B cells in germinal centers may differentiate into memory cells or long-lived plasma cells.
Memory B cells do not secrete antibody but can home to tissues and secondary lymphoid organs.
High-affinity B cells differentiate into antibody-secreting plasma cells.
Antibody Responses to T-Independent Antigens
Polysaccharides, lipids, and other nonprotein antigens elicit antibody responses without helper T cells.
Extensive cross-linking of BCRs by multivalent antigens may activate B cells strongly enough.
Polysaccharides also activate the complement system, and many T-independent antigens engage TLRs.
Regulation of Humoral Immune Responses
B cell responses are regulated by the products of B cells themselves (antibodies) and by cell-intrinsic mechanisms.
B cells use a special mechanism for shutting off antibody production, called antibody feedback.
Figure and Table summarize features of antibody responses to T-dependent and T-independent antigens
Antibody Feedback
Antibody feedback is when IgG antibody binds to antigen, forming immune complexes. B cells bind the antigen part of immune complex by their Ig receptors, and a special type of Fc receptor expressed on B cells, called FcγRIIB, binds to the Fc portion of IgG.
This Fc receptor is an inhibitory receptor containing an ITIM.
Figure illustrates the mechanism of antibody feedback.
B Cell Signal Attenuation by Other Inhibitory Receptors
Several inhibitory receptors other than FcγRIIB dampen B cell responses and raise the threshold for B cell activation, including CD22 and CD72. These inhibitory receptors contain cytoplasmic ITIMs that are phosphorylated after the BCR is engaged.
Summary of Humoral Immunity
Humoral immunity is mediated by antibodies that bind to extracellular microbes and toxins.
Humoral immune responses are initiated by recognition of antigens by specific membrane Ig antigen receptors of naive B cells.
In humoral immune responses to a protein antigen, called T-dependent responses, protein antigen binds to specific Ig receptors of naive B cells in lymphoid follicles.
The early T-dependent humoral response occurs in extrafollicular foci and generates low levels of class-switched antibodies that are produced by short-lived plasma cells.
Activated B cells induce the further activation of T cells and their differentiation into T follicular helper (Tfh) cells.
The full T-dependent humoral response develops in germinal centers and leads to extensive class switching and affinity maturation.
Heavy-chain class switching is stimulated by the combination of CD40L and cytokines.
Affinity maturation is initiated by signals from Tfh cells, resulting in migration of the B cells into follicles and the formation of germinal centers.
Polysaccharides, lipids, and other nonprotein antigens are called T- independent antigens because they induce antibody responses without T cell help.
Secreted antibodies form immune complexes with residual antigen and shut off B cell activation by engaging an inhibitory Fc receptor on B cells.
B Cell Biology
Adaptive humoral immunity is mediated by B lymphocytes.
B lymphocytes develop in the bone marrow and are morphologically identical to T lymphocytes.
Activated B cells differentiate into effector B cells called plasma cells.
Plasma cells secrete a soluble form of the B cell receptor, known as antibody, which has potent anti-microbial activity.
Innate vs. Adaptive Immunity
The innate immune system is critical early in infection.
If the innate immune system is overwhelmed, the adaptive immune system takes over.
Lymphocytes and antibodies are critical components of the adaptive immune system.
There are two types of lymphocytes:
B lymphocytes (bone marrow-dependent) for humoral immunity.
T lymphocytes (thymus-dependent) for cellular immunity.
Each lymphocyte clone expresses a unique receptor with specificity for an antigen.
Cells of the Adaptive Immune System
T and B cells are morphologically indistinguishable.
Upon activation, lymphocytes increase in size and enlarge their nucleus.
After repeated division and differentiation, lymphocytes become effector cells.
The effector cell of the B cell lineage is the plasma cell.
Clonal Selection
The adaptive immune system works via clonal selection.
A vast array of lymphocyte clones with unique specificities is generated during development, independent of foreign antigen.
In an immune response, antigen selects and expands clones of the appropriate specificity.
Memory and Specificity
The adaptive immune system remembers antigen.
Secondary responses are bigger and faster.
B Cell Receptor vs. T Cell Receptor
B cell receptor (BCR) is membrane-bound antibody (Ig).
T cell receptor (TCR) recognizes mainly peptides displayed by MHC molecules on APCs.
BCRs recognize macromolecules (proteins, polysaccharides, lipids, nucleic acids) and small chemicals through conformational and linear epitopes.
TCRs recognize linear epitopes.
Each clone has a unique specificity; potential for >10^9 distinct specificities for BCRs and >10^{11} for TCRs.
Antigen recognition is mediated by variable (V) regions of heavy and light chains of membrane Ig for BCRs and V regions of α and β chains of the TCR for TCRs.
Signaling functions are mediated by proteins (Igα and Igβ) associated with membrane Ig for BCRs and proteins (CD3 and ζ) associated with the TCR for TCRs.
Effector functions are mediated by secreted Ig for BCRs; TCR does not perform effector functions.
B Cell Receptor
The B cell receptor is surface-bound antibody.
The BCR of Naive B cells are IgM and IgD.
Antibody has two identical heavy chains and two identical light chains.
The BCR has an intracellular signaling domain that soluble antibodies lack.
CDRs and Antigen Binding
The CDRs (complementarity-determining regions) of the heavy and light chains come together to form the antigen-binding site.
Antibodies recognize "free" antigen.
Antibody Isotypes
B cells produce 5 different classes (isotypes) of antibody: IgA, IgD, IgE, IgG, and IgM.
IgA:
Subtypes: IgA1, 2 (α1 or α2).
Serum concentration: mg/ml.
Serum half-life: days.
Secreted form: Mainly dimer, also monomer, trimer.
Functions: Mucosal immunity.
IgD:
None subtype.
Trace serum concentration.
Serum half-life: days.
Secreted form: Monomer.
Functions: Naive B cell antigen receptor.
IgE:
None subtype.
Serum concentration: mg/ml.
Serum half-life: days.
Secreted form: Monomer.
Functions: Defense against helminthic parasites, hypersensitivity.
IgG:
Subtypes: IgG1-4 (γ1, γ2, γ3, or γ4).
Serum concentration: mg/ml.
Serum half-life: days.
Secreted form: Monomer.
Functions: Opsonization, complement activation, antibody-dependent cell-mediated cytotoxicity, neonatal immunity, feedback inhibition of B cells.
IgM:
None subtype.
Serum concentration: mg/ml.
Serum half-life: days.
Secreted form: Pentamer.
Functions: Naive B cell antigen receptor (monomeric form), complement activation.
Monoclonal Antibodies
Monoclonal antibodies can be generated, producing unlimited amounts of antibody with a single defined specificity.
Importance of Antibodies
Antibodies protect us from infection with extracellular microbes.
Antibodies are important in viral infection by blocking binding to virus receptor and fusion event.
Antibodies protect us from helminth infestation, with IgE being the active antibody.
Most vaccines work by eliciting long-lived plasma cells and memory B cells.
Antibody immunodeficiencies lead to susceptibility to infection from pyogenic bacteria.
Clinical Significance of Antibodies
Monoclonal antibodies against T cell checkpoint inhibitory molecules promote cellular immunity in cancer patients.
Monoclonal antibodies against cancer antigens are used to kill cancers (e.g., Rituximab).
In some autoimmune diseases, B cells are autoreactive, and antibodies are pathogenic.
Monoclonal antibodies against proinflammatory cytokines are used to treat patients in some autoimmune diseases (e.g., Infliximab is anti-TNF).
Antibodies are used in diagnosis (e.g., ELISA to detect prostate-specific antigen in a blood test).
Antisera are used to neutralize venoms.
Antibodies can provoke allergic (hypersensitive) reactions.
Key Cellular Events in Humoral Immune Response
Primary antibody response: IgM is produced first, followed by isotype switching.
Secondary antibody response: IgG is produced, with plasma cells in bone marrow and memory B cells.
Phases of Humoral Immune Response
If no T cell help, IgM is produced.
With T cell help, IgG, IgA, and IgE are produced.
Needs T cell help for isotype switching to IgG, IgA, and IgE.
Activation of B lymphocytes leads to proliferation and differentiation into antibody-secreting plasma cells.
Helper T cells and other stimuli promote isotype switching and affinity maturation.
B Cell Receptor Signaling
Signaling through the B cell receptor is similar to TCR signaling.
Membrane proximal events: tyrosine phosphorylation activates enzymes and creates docking sites for adaptor proteins.
Formation of multimolecular signaling complexes.
Common biochemical second messengers amplify the cell surface signal and transduce it to the nucleus.
Activation of transcription factors leading to gene transcription.
The B cell receptor has a tiny cytoplasmic domain and associates with two signaling chains, Igα and Igβ, which have ITAM motifs in their cytoplasmic domain.
Src family kinases (Fyn, Lyn, Blk) phosphorylate the ITAMs of Igα and Igβ.
Syk is the tyrosine kinase that binds to the phosphorylated tyrosines of Igα and Igβ and is then phosphorylated by Fyn, Lyn, or Blk.
Syk then phosphorylates adaptor proteins, which activate 2nd messenger pathways.
Complement and B Cell Signaling
A B cell co-receptor complex consists of CR2 (Complement receptor, aka CD21), CD19, and CD81.
If complement is bound to antigen, CD21 signals via CD19 to lower the threshold of signaling required for B cell activation.
Downstream Consequences of B Cell Receptor Signaling
Antigen binding to and cross-linking of membrane Ig leads to changes in activated B cells:
Expression of proteins that promote survival and cell cycling.
Increased B7 expression.
Increased expression of cytokine receptors.
Increased expression of CCR7.
These changes result in increased survival, proliferation, antigen presentation, interaction with helper T cells, responsiveness to cytokines, migration from follicle to T cell zone, and generation of plasma cells, leading to antibody secretion (IgM).
T Cell-Dependent vs. T Cell-Independent Antibody Responses
T-dependent responses involve protein antigens and helper T cells, leading to isotype-switched, high-affinity antibodies, memory B cells, and long-lived plasma cells (IgG, IgA, IgE).
T-independent responses involve polysaccharide antigens, B-1 cells, marginal zone B cells, and other signals (e.g., complement protein, microbial product), leading mainly to IgM, low-affinity antibodies, and short-lived plasma cells.
T Cell-Independent Antibody Responses
Can be very important in immunity to capsulated bacteria by targeting the bacteria for phagocytosis.
Antigens that promote T-independent antibody responses are often polyvalent (e.g., polysaccharides).
They can cross-link the B cell receptor and induce B cell activation without the need for T cell help.
T-independent antigens may activate Pattern Recognition Receptors (PRRs) in B cells; PAMPs attached to antigens can costimulate B cells.
Signal 1 is the BCR, and Signal 2 is the PRR.
T Cell-Dependent Antibody Responses
Produce high affinity, isotype-switched antibodies, memory, and long-lived plasma cells.
Occur in secondary lymphoid organs: B cells in B cell follicles, T cells in T cell zones.
Kinetics of Humoral T-Dependent Immune Response
Isotype switching: First antibody produced is IgM, peaking around day 7, then diminishes as B cells switch to other isotypes (e.g., IgG).
Immunological memory: Primary response peaks around day 14; secondary response is greater and quicker upon re-exposure.
Affinity maturation: Early in the immune response, the affinity of antibody produced is low but improves with time; the affinity of antibody produced in a secondary immune response is generally higher than that produced in the primary immune response.
Secondary Responses
Quicker, larger, and higher affinity compared to primary responses.
Lag after immunization is shorter (1-3 days vs. 5-10 days).
Larger response.
Relative increase in IgG and, under certain situations, in IgA or IgE (heavy-chain isotype switching).
Higher average affinity (affinity maturation).
Germinal Center Reaction
Site of intense B cell proliferation and differentiation within the B cell follicles of secondary lymphoid organs during an adaptive immune response.
A feature of T cell-dependent antibody responses.
Follicular Dendritic cells (FDC) and T Follicular Helper cells (TFH) play a role within germinal centers.
Follicular Dendritic Cells (FDC)
Not conventional Dendritic cells; they are mesenchymal and not bone marrow-derived.
They don’t process antigen and present it on MHC.
Act as an antigen depot; intact antigen is stuck on the FDC surface via Fc and complement receptors.
Ag-specific B cells acquire antigen from FDC-displayed Ag via the BCR.
T Follicular Helper Cells
Another type of T helper cell found within B cell follicles.
Specialized in driving B cell proliferation, isotype switching, and affinity maturation.
B Cells Present Antigen to T Follicular Helper Cells
B cells acquire antigen via their B cell receptor (from FDC).
They endocytose, digest, and process the antigen.
Peptide fragments are presented on class II MHC to TFH.
TFH cell/B cell interactions are critical in T cell-dependent antibody responses.
T Cell Help Drives B Cell Proliferation and Differentiation
B cells present antigen to T cells on MHC II.
T cells stimulate B cells with CD40L and cytokines, driving B cell survival, proliferation, and differentiation.
Germinal Center Zones
Dark zone: B cells proliferate
Light zone: interactions with T helper cells and follicular dendritic cells
Affinity maturation and isotype switching take place within germinal centers.
The germinal center reaction produces long-lived plasma cells and memory B cells.
Biological Affinity
A thermodynamic expression of the strength of interaction between two molecules.
A dissociation constant is often used to describe the affinity between a ligand and a protein; the smaller the dissociation constant, the tighter the binding.
Affinity Maturation
Low affinity antibody is produced early in an immune response.
During the germinal center reaction, the enzyme AICD (Activation Induced Cytidine Deaminase) introduces somatic point mutations in the Ig V genes through a process known as somatic hypermutation.
B cell clones that display high affinity mutations are selected in the germinal center reaction.
Selection of High Affinity B Cells
Antigen is limited in the germinal center and is presented on the surface of follicular dendritic cells.
High affinity B cells outcompete low affinity B cells for antigen from FDC.
They endocytose this antigen and present it (on MHC II) to T follicular helper cells (TfH).
TfH provide germinal center B cells with survival and proliferation signals.
Low affinity B cells can't acquire antigen and therefore receive no T cell help; they die by apoptosis.
Molecular and Cellular Basis of Affinity Maturation
In the dark zone of the germinal center reaction, AICD introduces point mutations in the V genes of B cells, creating clones with variable affinities.
In the light zone, high affinity B cells outcompete low affinity B cells for antigen (from FDC) and help from TFH.
High Affinity B cells proliferate and differentiate into plasma cells and memory B cells.
Low affinity B cells die by apoptosis.
T Cell Help Drives Isotype Switching
B cells present antigen to T cells on MHC II.
T cells drive B cell isotype switching via CD40L and cytokines.
Cytokines and Isotype Switching
IgM is the default isotype; without T cell help (and cytokines), B cells will produce IgM.
IFNγ drives (some subclasses of) IgG.
IL-4 drives IgE.
TGFβ drives IgA.
Mechanism of Isotype Switching
Adjacent to each constant region gene is a switch region (S).
Upon CD40L and cytokine signaling, AICD alters nucleotides in the switch region.
The switch regions are then cleaved by other enzymes and joined to downstream switch regions.
DNA is “looped out” and lost from the genome.
Antibody Feedback
B cells express an inhibitory Fc receptor (FcγRIIB).
Late in an immune response, when there is excess antibody, FcγRIIB will recognize immune complexes and transduce signals that inhibit B cell activation.
Here's a breakdown of the key aspects you asked about:
B Cell Biology
Development: B lymphocytes develop in the bone marrow and are morphologically identical to T lymphocytes.
Function: After activation, the effector cell of the B cell lineage is the plasma cell, which secretes a soluble form of the B cell receptor, known as antibody.
B cell receptor (BCR): The BCR of Naive B cells are IgM and IgD. The BCR has an intracellular signaling domain that soluble antibodies lack.
Antibody structure: Antibody has two identical heavy chains and two identical light chains.The CDRs (complementarity-determining regions) of the heavy and light chains come together to form the antigen-binding site. Antibodies recognize \"free\" antigen.
Antibody Isotypes: B cells produce 5 different classes (isotypes) of antibody: IgA, IgD, IgE, IgG, and IgM.
Situations Where Antibodies Play a Major Role
Protection from extracellular microbes: Antibodies protect us from infection with extracellular microbes.
Viral infection: Antibodies are important in viral infection by blocking binding to virus receptor and fusion event.
Helminth infestation: Antibodies protect us from helminth infestation, with IgE being the active antibody.
Vaccines: Most vaccines work by eliciting long-lived plasma cells and memory B cells.
Immunodeficiency: Antibody immunodeficiencies lead to susceptibility to infection from pyogenic bacteria.
Cancer Treatment: Monoclonal antibodies against cancer antigens are used to kill cancers (e.g., Rituximab).
Autoimmune Diseases: In some autoimmune diseases, B cells are autoreactive, and antibodies are pathogenic. Monoclonal antibodies against proinflammatory cytokines are used to treat patients in some autoimmune diseases (e.g., Infliximab is anti-TNF).
Cellular Events in B Cell Signaling and Activation
Antigen Recognition: Humoral immune responses are initiated by recognition of antigens by specific membrane Ig antigen receptors of naive B cells.
B Cell Receptor Signaling: Signaling through the B cell receptor is similar to TCR signaling.
Membrane proximal events: tyrosine phosphorylation activates enzymes and creates docking sites for adaptor proteins.
Formation of multimolecular signaling complexes.
Common biochemical second messengers amplify the cell surface signal and transduce it to the nucleus.
Activation of transcription factors leading to gene transcription.
ITAM motifs: The B cell receptor has a tiny cytoplasmic domain and associates with two signaling chains, Igα and Igβ, which have ITAM motifs in their cytoplasmic domain.
Src family kinases (Fyn, Lyn, Blk) phosphorylate the ITAMs of Igα and Igβ.
Syk is the tyrosine kinase that binds to the phosphorylated tyrosines of Igα and Igβ and is then phosphorylated by Fyn, Lyn, or Blk.
Syk then phosphorylates adaptor proteins, which activate 2nd messenger pathways.
Complement and B Cell Signaling:A B cell co-receptor complex consists of CR2 (Complement receptor, aka CD21), CD19, and CD81. If complement is bound to antigen, CD21 signals via CD19 to lower the threshold of signaling required for B cell activation.
Downstream Consequences of B Cell Receptor Signaling. Antigen binding to and cross-linking of membrane Ig leads to changes in activated B cells such as Expression of proteins that promote survival and cell cycling, Increased B7 expression, Increased expression of cytokine receptors, and Increased expression of CCR7.
B cell activation initiates proliferation and differentiation and prepares cells to interact with helper T lymphocytes if the antigen is a protein.
The activated B lymphocytes synthesize and secrete IgM, marking the early phase of the humoral immune response.
T Cell-Dependent vs. T Cell-Independent Antibody Responses
T-dependent responses: involve protein antigens and helper T cells, leading to isotype-switched, high-affinity antibodies, memory B cells, and long-lived plasma cells (IgG, IgA, IgE).
T-independent responses: involve polysaccharide antigens, B-1 cells, marginal zone B cells, and other signals (e.g., complement protein, microbial product), leading mainly to IgM, low-affinity antibodies, and short-lived plasma cells.
Features Associated with T Cell-Dependent Antibody Response
Require T cell help for isotype switching to IgG, IgA, and IgE.
The full T-dependent humoral response develops in germinal centers and leads to extensive class switching and affinity maturation.
Activated B cells induce the further activation of T cells and their differentiation into T follicular helper (Tfh) cells.
Heavy-chain class switching is stimulated by the combination of CD40L and cytokines.
Affinity maturation is initiated by signals from Tfh cells, resulting in migration of the B cells into follicles and the formation of germinal centers.
Kinetics of Humoral T-Dependent Immune Response: Isotype switching: First antibody produced is IgM, peaking around day 7, then diminishes as B cells switch to other isotypes (e.g., IgG).Immunological memory: Primary response peaks around day 14; secondary response is greater and quicker upon re-exposure.Affinity maturation: Early in the immune response, the affinity of antibody produced is low but improves with time; the affinity of antibody produced in a secondary immune response is generally higher than that produced in the primary immune response.