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What is humoral immunity mediated by?
Humoral immunity is mediated by antibodies produced by B lymphocytes.
How are B cells activated?
B cell activation occurs when an antigen binds to membrane IgM & IgD on naive B cells.
What happens after antigen binding on B cells?
The binding triggers B cell proliferation and differentiation into plasma cells.
What are the final outcomes of B cell activation?
Plasma Cells: Secrete antibodies.
Memory B Cells: Provide long-term immunity.
What is the characteristic of antibodies secreted by plasma cells?
have the same specificity as the original antibody that served as the antigen receptor (BCR) on the surface of the naive B cell.
What is the structure of secreted IgG antibody?
Heavy chain
Light chain
Fab region (tip of heavy and light chains, responsible for antigen binding)
Fc region (stem region, responsible for immune cell interactions)
What is the structure of membrane IgM on B cells?
Antigen-binding site (tip of heavy and light chains)
Plasma membrane (embedded on B cells)
What are the steps in the humoral immune response once a naive B cell binds to an antigen?
Naive B cell (IgM+ IgD+) binds to antigen.
✅ 1. Helper T cells and other stimuli activate the B cell.
✅ 2. B cell proliferates and differentiates into one of three paths:
1. Plasma cell: Produces IgM for antigen secretion.
2. IgG-expressing B cell: Undergoes isotype switching to produce IgG.
3. High-affinity Ig-expressing B cell: Undergoes affinity maturation (produces high-affinity IgG or memory B cells).
What is heavy-chain isotype switching in B cells?
During their differentiation, some B cells switch to producing antibodies of different heavy-chain isotypes (or classes).
These isotypes mediate different effector functions and are specialized to combat various types of microbes.
What are the different immunoglobulin (Ig) isotypes and their functions?
IgD: Activates B cells.
IgE: Involved in allergic responses and parasite defense.
IgG: Provides long-term immunity and neutralizes toxins.
IgM: First antibody produced, activates complement.
IgA: Protects mucosal surfaces (e.g., gut, respiratory).
What is the T-independent antibody response?
Triggered by polysaccharides, nucleic acids, lipids, and multivalent antigens.
What is the T-dependent antibody response?
Triggered by protein antigens.
Stimulates isotype switching, affinity maturation, and long-lived plasma and memory B cells.
What happens during T-dependent antibody responses?
Follicular B cells with IgM bind protein antigen.
Helper T cell activation leads to:
Isotype switching (IgG, IgA, IgE).
High-affinity antibodies.
Memory B cells and long-lived plasma cells.
What happens during T-independent antibody responses?
B-1 cells and marginal zone B cells with IgM bind polysaccharide antigen.
Other signals (e.g., complement proteins) lead to:
Mainly IgM production.
Low-affinity antibodies.
Short-lived plasma cells.
What are the features of a primary antibody response?
Smaller response.
IgM > IgG production.
Lower average affinity.
More variable.
Occurs for all antigens.
** activation of previously unstimulated naive B cells
What are the features of a secondary antibody response?
Larger response.
Relative increase in IgG (often IgA, sometimes IgE).
Higher average affinity (affinity maturation).
Occurs only for protein antigens.
** stimulation of expanded clones of memory B cells
What is the role of follicular (FO) B cells in antibody responses?
Found in secondary (peripheral) lymphoid organs.
Antibody responses to protein antigens.
Typically involved in T-dependent antibody responses.
What is the role of marginal zone (MZ) B cells and B-1 cells?
Found in the spleen (MZ B cells) and mucosal tissues/peritoneum (B-1 cells).
peritoneum recognize multivalent antigens.
Involved in T-independent antibody responses.
How are most antigens transported to lymph nodes?
Most antigens from tissue sites are transported to lymph nodes by afferent lymphatic vessels.
What is the role of subcapsular sinus macrophages in antigen capture?
Capture large microbes and deliver them to follicles in the lymph nodes
How do marginal zone B cells contribute to antigen delivery?
Transfer immune complex–containing antigens to follicular B cells for further processing.
What is required for antigen receptor-mediated signal transduction?
Requires the bringing together of two or more membrane Ig molecules.
How do multivalent antigens affect B cell activation?
Can effectively cross-link many B cell antigen receptors, initiating responses even without helper T lymphocyte recognition.
What happens when B cell receptors are cross-linked by antigens?
become activated when their receptors are cross-linked by antigens.
What is the composition of the BCR complex?
Composed of membrane Ig molecules that bind antigens and associated Igα and Igβ proteins.
What role do Igα and Igβ proteins play in B cell activation?
Contain immunoreceptor tyrosine-based activation motifs (ITAMs) which are critical for B cell signal transduction.
What receptors do follicular and marginal zone B cells express?
Follicular B cells and marginal zone B cells express the complement receptor CR2.
How does microbial antigen bound to C3d activate B cells?
binds to CR2 on B cells, then CD81 further enhances BCR signaling, leading to proliferation and differentiation.
How do TLRs contribute to B cell activation?
Microbial antigens (PAMPs) bind to TLRs on B cells, enhancing BCR signaling, which leads to proliferation and differentiation of B cells.
What happens during the cross-linking of membrane Ig by antigen in B cells?
Antigen binding to membrane Ig triggers tyrosine phosphorylation events in B cells.
What do tyrosine phosphorylation events lead to in B cell activation?
These events lead to the activation of biochemical intermediates and active enzymes that regulate transcription factors.
What are the key transcription factors involved in B cell activation?
Myc - (Ca+ dependent enzymes) -NFAT (PKC) - NF-kB (ERK, JNK pathways)- AP-1
-1. Myc
-2. NFAT
-3. NF-kB
-4. AP-1
How are protein antigens recognized in helper T cell-dependent antibody responses?
ndependently recognized by specific B and T lymphocytes in secondary lymphoid organs.
What happens after activation of B and T cells in helper T cell-dependent antibody responses?
initiate humoral immune responses.
What is the process that occurs after dendritic cells present antigens to naive CD4+ T cells?
Dendritic cells with antigen bind to naive CD4+ T cells, resulting in the activation of helper T cells.
The initial T-B interaction leads to migration of helper T cells and B cells to the extrafollicular focus for the production of short-lived plasma cells.
Some helper T cells move to the germinal center where they interact with follicular dendritic cells and germinal center B cells.
How are protein antigens recognized and processed in helper T cell-dependent antibody responses?
BCRs are endocytosed and processed to generate peptides that bind to class II MHC molecules, which are presented to CD4+ T cells.
How do naive CD4+ T cells get activated in helper T cell-dependent responses?
activated in the T cell zones by MHC II-associated peptides presented by dendritic cells (DCs).
What happens when a B cell receptor binds to a conformation epitope of an antigen?
leading to receptor-mediated endocytosis of the antigen, which is then processed and presented on class II MHC molecules for CD4+ T cell recognition.
What occurs in the lymph node during antigen presentation and T cell activation?
T cell activation occurs in the T cell zones of the lymph node.
CCR7 decreases and CXCR5 increases, leading to the migration of activated T cells to the edge of the follicle.
B cells present the antigen to the activated helper T cells, leading to B cell activation.
What happens to B cells after activation in helper T cell-dependent responses?
EBI2 and CCR7 increase, which leads to the migration of activated B cells to the edge of the primary follicle in the lymph node.
What is a hapten?
lacks the ability to stimulate an immune response by itself.
Hapten is combined with a carrier molecule?
forms a hapten-carrier conjugate, which can induce an immune response.
What is the principle behind conjugate vaccines?
combine a polysaccharide (e.g., bacterial capsular polysaccharide) with a carrier protein (e.g., tetanus toxoid). This conjugation allows the immune system to recognize the polysaccharide as a foreign antigen and enhances the immune response.
How do principle behind conjugate vaccines work the mechanism?
The polysaccharide-specific B cell binds to the conjugate (bacterial capsular polysaccharide conjugated to protein) Tetanus toxoid protein
The B cell processes the carrier protein (e.g., tetanus toxoid) and presents the peptide to helper T cells.
The helper T cells recognize the peptide and activate the B cell, triggering B cell activation and differentiation.
The germinal center reaction produces high-affinity IgG antibodies, long-lived plasma cells, and memory B cells.
What is the role of CD40L:CD40 interaction in B cell activation?
CD40L on activated helper T cells binds to CD40 on B lymphocytes, ensuring that only T and B cells in physical contact engage in productive interactions.
Actions on B cells:
Proliferation and antibody secretion: Stimulates B cells to proliferate and secrete antibodies.
Heavy-chain isotype switching: Promotes class switching of antibodies.
Affinity maturation: Enhances the affinity of the antibodies produced.
How does the CD40L-CD40 interaction affect B cell activation?
Activated helper T cells express CD40L and secrete cytokines.
The CD40L on helper T cells binds to CD40 on B cells, which activates the B cells.
This interaction triggers cytokine release, leading to B cell proliferation and differentiation.
What is the function and structure of lymph node follicles?
specialized regions within lymph nodes that contain B cells, follicular dendritic cells, and are critical for immune responses.
Primary follicles contain naive B cells, while secondary follicles are formed after antigen exposure and include a germinal center.
What are the characteristics and functions of extrafollicular reactions in immune responses?
Initial T-B Interactions:
Occur outside of lymph node follicles between T helper (Th) cells and B cells.
Antibody Production:
Low levels of antibodies are produced, which may be of switched isotypes, but they generally have low affinity.
Plasma Cell Formation:
Short-lived plasma cells are generated that produce antibodies for a few weeks.
Memory B Cell Generation:
Few memory B cells are generated in extrafollicular reactions compared to germinal center reactions.
What happens on Day 0 of B cell activation and germinal center formation?
T cells bind to dendritic cells (DCs) in the T cell zone.
Activated T cells move to the interfollicular region, where primary follicles with follicular B cells, antigen, antibody, activated B cells, and follicular dendritic cells (FDCs) are located.
What occurs on Day 1 during B cell activation?
T cells and dendritic cells (DCs) dissociate.
Antibody from activated B cells leaves the primary follicle and binds to T cells in the interfollicular region.
What happens on Day 2 of the immune response involving T and B cells?
TCR (T cell receptor) binds to MHC on B cells.
CD40L on helper T cells binds to CD40 on B cells in the interfollicular region.
What is the process on Day 3 in germinal center formation?
TFH (T follicular helper) cells move into the follicle.
Some activated B cells start producing antibodies and migrate to a nearby region, becoming early plasmablasts.
What occurs on Day 4 of B cell activation and germinal center formation?
B cells enter the center of the follicle, where they begin dividing and pushing aside other B cells.
This forms an early germinal center (GC), which is now called a secondary follicle.
What happens during Days 5 and 6 in germinal center formation
he germinal center (GC) grows rapidly as B cells continue to divide.
What structural changes occur in the germinal center by Day 7?
The germinal center (GC) organizes into two zones:
Dark zone: Dense with rapidly dividing B cells.
Light zone: Contains TFH cells and support cells (FDCs).
Where do germinal centers develop, and when do they appear after T-dependent B cell activation?
secondary lymphoid organs (lymph nodes and spleen) about 4 to 7 days after the initiation of a T-dependent B cell response.
What are the key characteristics of germinal centers?
Affinity maturation
Generation of long-lived plasma cells
Generation of memory B cells
Ongoing isotype switching.
What happens to B cells in the dark zone of the germinal center?
B cells undergo somatic hypermutation of immunoglobulin (Ig) V genes.
What happens when B cells migrate into the light zone of the germinal center?
Follicular dendritic cells (FDCs) displaying antigen
T follicular helper (Tfh) cells.
How are B cells selected in the germinal center?
highest-affinity Ig receptors are selected to survive and continue the immune response.
What is the process B cells undergo in the germinal center before differentiating into memory B cells or antibody-secreting cells?
undergo multiple rounds of mutation and selection. Eventually, they differentiate into:
Memory B cells
Antibody-secreting cells (plasma cells).
Where are germinal centers formed?
lymphoid follicles.
What are the CD4+ T cells that migrate into B cell-rich follicles called?
follicular helper T (Tfh) cells.
What molecule is required for the generation of follicular helper T (Tfh) cells?
ICOS (Inducible T-cell Co-Stimulator).
What cytokines are produced by follicular helper T (Tfh) cells?
IFN-γ
IL-4
IL-17
IL-21.
What is the step-by-step process in the generation of T follicular helper (Tfh) cells?
Dendritic Cell Activation: Dendritic cells present the antigen to naive CD4+ T cells, initiating activation.
Expression of CXCR5: The activated CD4+ T cell expresses CXCR5, which guides it toward the B cell-rich follicles.
Differentiation into Tfh Cells: The activated T cell differentiates into T follicular helper (Tfh) cells in the follicle, driven by ICOS signaling.
B Cell Activation: Tfh cells interact with activated B cells through CD40-CD40L, providing signals for B cell activation, proliferation, and differentiation into germinal center B cells.
Release of IL-21: Tfh cells release IL-21, which supports the affinity maturation and isotype switching of B cells, ultimately leading to the generation of long-lived plasma cells and memory B cells.
What is the step-by-step process of the Germinal Center Reaction?
Activation of B Cells: B cells are activated by helper T cells and migrate into the germinal center in the lymphoid follicles.
B Cell Proliferation and Somatic Hypermutation: In the dark zone, B cells undergo proliferation and somatic hypermutation to alter their IgV genes.
High Affinity B Cell Selection: B cells with high-affinity antibodies are selected and continue to proliferate in the dark zone.
Isotype Switching: B cells undergo isotype switching, changing the class of antibodies they produce.
Exit of High-Affinity Cells: In the light zone, follicular dendritic cells (FDCs) and Tfh cells interact with the high-affinity B cells, selecting those with the highest affinity.
Differentiation and Memory Formation: High-affinity antibody-secreting cells (plasma cells) and memory B cells exit the germinal center for long-term immunity.
What is the role of IgM in heavy chain isotype switching?
IgM is the first antibody produced during an immune response.
It activates complement and helps initiate the immune response.
What are the functions of IgG subclasses (IgG1, IgG3) in isotype switching?
Facilitate opsonization and phagocytosis by immune cells.
Activate complement for enhanced immune response.
IgG1 is crucial for neonatal immunity by transferring across the placenta for fetal protection.
What is the function of IgE in heavy chain isotype switching?
involved in immunity against helminths.
It triggers mast cell degranulation, leading to an inflammatory response.
IgE also plays a key role in immediate hypersensitivity reactions, like allergies.
What is the role of IgA in heavy chain isotype switching?
IgA provides mucosal immunity by protecting mucosal surfaces.
It transports across epithelial cells, ensuring immune protection in mucosal areas such as the respiratory and gastrointestinal tracts.
What is the process of isotype switching in B cells?
involves moving the VDJ exon (encoding the variable domain of the Ig μ heavy chain) to a downstream constant (C) region.
This allows the B cell to produce antibodies with the same antigen specificity but a different effector function due to the new heavy chain.
What is affinity maturation in antibody production?
process where the affinity of antibodies produced in response to a protein antigen increases over time with prolonged or repeated exposure to the antigen.
This occurs through somatic hypermutation and selection of B cells with higher affinity for the antigen.
What is the process of affinity maturation and how does it occur?
Occurs in response to T cell-dependent protein antigens
Happens during persistent or recurrent infections
Point mutations in the V regions of immunoglobulin genes lead to somatic mutations
Selection of high-affinity B cells:
Low affinity mutations are replaced by high-affinity antibodies
The process continues with increased antibody affinity
How are high-affinity B cells selected in germinal centers?
B cell activation: B cells are activated by protein antigens and helper T cells
Migration: Activated B cells migrate into germinal centers
Somatic mutation: B cells undergo somatic hypermutation of Ig V genes, producing Igs with varying affinities for the antigen
Selection process:
B cells with high-affinity antigen receptors bind antigens presented by follicular dendritic cells (FDCs)
High-affinity B cells ingest antigens and present peptides to helper T cells
Only B cells that successfully recognize antigen on FDCs or interact with helper T cells are selected to survive
Other B cells that do not meet these criteria die off
What happens to B cells after they undergo isotype switching and affinity maturation?
Antibody-secreting cells:
The plasmablasts enter circulation, eventually migrating to the bone marrow or mucosal tissues to become plasma cells.
Plasma cells continue producing high-affinity antibodies, even after the antigen is eliminated.
Memory B cells:
Some activated B cells, particularly isotype-switched high-affinity B cells, do not differentiate into antibody-secreting plasma cells.
Instead, they become memory B cells, which persist long-term and can respond more rapidly upon re-exposure to the same antigen.
Outcome: The immune system is primed for long-term protection through the sustained production of high-affinity antibodies and the presence of memory B cells for faster immune responses.
What are the characteristics and function of memory B cells?
No antibody secretion: Memory B cells do not secrete antibodies.
Circulate and reside: They circulate in the blood and reside in mucosal and other tissues.
Rapid response: Memory B cells are ready to respond quickly if the antigen is reintroduced into the body.
Longevity: They can survive for months or years without continued antigenic stimulation.
Anti-apoptotic protein: Memory B cells express high levels of BCL-2, an anti-apoptotic protein, allowing them to survive long-term.
Outcome: Memory B cells provide long-term immunity and enable faster and stronger responses to future infections by the same pathogen.
What are the features of antibody responses to Thymus-dependent antigens?
Antigen Type: Proteins
Isotype Switching: Yes (IgM, IgG, IgE, IgA)
Affinity Maturation: Yes
Plasma Cells: Long-lived
Secondary Response: Memory B cells are formed.
What are the features of antibody responses to Thymus-independent antigens?
Antigen Type: Polysaccharides, glycolipids, nucleic acids, polymeric antigens
Isotype Switching: Low-level switching (IgM to IgG)
Affinity Maturation: Little or no affinity maturation
Plasma Cells: Short-lived
Secondary Response: Memory B cells form in only some polysaccharide antigens.
