B Cell Activation

Humoral immunity
What is Humoral immunity?
Humoral immunity is aspect of immunity which is mediated by macromolecules included secreted
antibodies, which are produced by cells of the Blymphocyte lineage.

AntigenRecognition and Antigen-InducedB CellActivation ;To initiate antibody

responses, antigens have to be captured and transported to the B cell areas of secondary lymphoid
organs. The antigens then initiate the process of B cell activation,often working in concert with other
signals that are generated during innate immune responses triggered by microbes or by adjuvants in
vaccines.

AntigenCapture and Delivery to B Cells Antigen may be delivered to naive B cells in lymphoid
organs by multiple routes. 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 of antigens include the following;

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 Bcell zone through conduits that extend between the subcapsular sinus and the underlying follicles
In some cases, small antigens may gain access to the follicles by diffusion.

• Subcapsular sinus macrophages capture large microbes and antigen-antibody complexes and deliver
these to follicles.

• 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. Recirculating follicular B cells may also capture
antigens via CR2 and deliver them into follicles. Immune complexes that are delivered into lymphoid
follicles may bind to CR2 or Fc receptors for IgG on the surface of follicular dendritic cells (FDCs), and the
antigens in these complexes are then presented to antigen- specific B cells in a sustained manner (over
days to weeks).

• 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.

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 Iga and Igß proteins that deliver
signals for B cell activation. The B R complex plays two key roles in Bcell responses. First, binding of
antigen to the receptor delivers biochemical signals to the B cells that initiate the process of activation.
As discussed later, signaling is more robust with multivalent T-independent antigens than with -T
dependent protein antigens. Antigen-induced biochemical signals are initiated by S C family kinase-
mediated phosphorylation of the immune receptor tyrosine-based activation motif (ITAM) tyrosine of
Iga and IgB, followed by the recruitment and activation of SYK. Second, the B C 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 I MHC molecules on the Bcell surface for recognition by helper Tcells. This antigen-
presenting function of B cells will be considered later in the context of T-dependent B cell activation.
Although antigen recognition can initiate Bcell responses, by itself it is usually inadequate to stimulate
significant B cell proliferation and differentiation, even for T-independent antigens. For full r e s p o n s e
s to be induced, other stimuli cooperate with B C engagement, including complement proteins, paern
recognition receptors, and, in the case ofprotein antigens, helper Tcells.

The interaction of different types of antigens (multivalent structures or proteins) with the BCR initiates B
cell proliferation and differentiation in different ways.Signals from the BCR may be sufficient to keep the
B cells alive, induce changes in chemokine receptor expression, and promote antigen endocytosis Most
T-independent antigens, such as polysaccharides, contain multiple identical epitopes on each molecule.
Such multivalent antigens can effectively cross-link many B cell antigen-receptors and initiate responses
even though they are not recognized by helper T lymphocytes.such protein antigens, in their functionally
monovalent form, cannot simultaneously bind to and cross-link multiple Ig molecules-they do not
typically induce signals that can drive B cell proliferation and differentiation. Some protein antigens may
be displayed as multivalent arrays on the surfaces of cells in these cases, protein antigens can induce B
cell proliferation and differentiation.Effects of B Cell Antigen Receptor Engagement on B
Cells:Phenotypic Change(Phenotypic Change,Increased expression of B7 costimulators,Increased
expression of receptors for T-cell cytokines,Increased expression of anti- apoptotic
proteins)ThesechangesmaybeinducedbybindingofproteinantigenstotheBcellreceptor After specific B
cells recognise antigens activation of B cells by protein antigens and helper T cells.((Helper T Cell–
Dependent Antibody Responses to Protein Antigens))antibody responses required cooperation between
B cells and T cells.most helper T cells are CD4+CD8 − lymphocytes that recognize peptide antigens
presented by class II major histocompatibility complex (MHC) moleculesProtein 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 CD4+ T cells and B
cells in the follicles are activated by the same antigen migrate toward one another and interact at the
edges of the follicles, where the initial antibody response develops.((Initial Activation and Migration of
Helper B Cells and T Cells))The contemporaneous activation of specific B and T cells by a protein antigen
induces changes that bring them into proximity to enhance the likelihood of the antigen-specific B and T
cells colocalizing and interacting with one another the specific B and T cells have to find each other and
physically interact to generate strong antibody responses.naive T cells reside in the T cell zone because
they express the chemokine receptor CCR7, which binds to the chemokines CCL19 and CCL21 produced
in these zones, and naive B cells remain in the follicles because they express CXCR5, which recognizes
CXCL13 produced by FDCs helper T cells downregulate CCR7 and increase the expression of CXCR5 and,
as a result, leave the T cell zone and migrate toward the follicle in response to CXCL13 B cells respond to
antigen- mediated BCR triggering by reducing cell surface expression of the chemokine receptor CXCR5
and increasing expression of CCR7. These cells also upregulate EBI2 Activated B cells thus migrate
toward the T cell zone drawn by a gradient of CCL21, the major ligand for CCR7, and oxysterols. The net
result of these changes is that antigen-activated T and B lymphocytes are drawn toward each
other.((Antigen Presentation by B Cells and the Hapten-Carrier Effect))Protein antigens that are
recognized by specific BCRs are endocytosed and processed to generate peptides that bind to class II
MHC molecules and are presented to CD4 + T cells.Sequence of events in humoral immune responses to
T cell–dependent protein antigens. 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.Some of the T cells that are activated in the extracellular focus develop
into follicular helper T cells and migrate back into the follicles, together with some activated B cells, a to
form a germinal center.

Migration of B cells and helper T cells and T cell–B cell interaction.Antigen-activated helper T cells and B
cells move toward one another in response to chemokine signals and make contact adjacent to the edge
of primary follicles. CD40L, CD40 ligand.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.In a T cell–
dependent B cell response to a specific protein antigen, at least two different epitopes of the protein
participate in the process:native protein and a linear peptide which is subsequently released by
proteolysis, binds to class II MHC molecules, and is recognized by helper T cells membrane Ig on B cells is
capable of binding conformational epitopes of proteins, and the same Ig is secreted by plasma cells
derived from those B cells.In fact, a single B lymphocyte specific for a native epitope may bind and
endocytose a protein and present multiple different peptides complexed with class II MHC molecules to
different helper T cells The principles outlined here for T cell–B cell collaboration help to explain a
phenomenon that is known as the hapten-carrier effect.This passage discusses the conformational
epitopes recognized by B cells in T-dependent responses to protein antigens. It highlights the role of
antigen presentation by B lymphocytes in the development of humoral immune responses. The
response to hapten-carrier conjugates has provided insights into the characteristics of anti-hapten
antibody responses. These characteristics include the requirement of hapten-specific B cells and
protein-specific helper T cells, the physical linkage of the hapten and carrier portions, and the MHC
restriction in the interaction between helper T cells and B lymphocytes.

The antigen-presenting functions of B lymphocytes are explained, wherein hapten-specific B cells bind
the antigen, internalize the hapten-carrier conjugate, digest the protein component, and present
peptides from the carrier protein to carrier-specific helper T lymphocytes. The hapten facilitates the
efficient internalization of the carrier protein into the B cell, leading to the requirement of physical
linkage between hapten and carrier. The interaction between T cells and B cells is MHC-restricted as the
T cells recognize self MHC-associated peptides.These characteristics of humoral responses observed in
hapten-carrier conjugates can be extended to all protein antigens where a conformational determinant
is recognized by B cells, and a linear peptide associated with class II MHC is recognized by helper T cells.
This concept is utilized in the development of conjugate vaccines against encapsulated bacteria, wherein
carbohydrate molecules act as the hapten and carrier proteins present the peptide epitope. In summary,
the passage explains the characteristics of B cell recognition of conformational epitopes in T-dependent
responses to protein antigens. It emphasizes the role of B cell antigen presentation in the development
of humoral immune responses. The response to hapten-carrier conjugates has revealed that a successful
antibody response requires hapten-specific B cells and protein-specific helper T cells, physical linkage
between the hapten and carrier, and MHC restriction in the interaction between B cells and T cells.
Hapten-specific B cells bind the antigen, internalize the hapten-carrier conjugate, present carrier-
derived peptides to helper T cells, and cooperate to recognize different epitopes of the same antigen.
These findings can be generalized to other protein antigens that involve B cell recognition of
conformational epitopes and helper T cell recognition of linear peptide epitopes.
The concept is applied in the development of conjugate vaccines against encapsulated bacteria, where
carbohydrate molecules serve as haptens and carrier proteins present peptide epitopes.

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 is a
member of the tumor necrosis factor (TNF) receptor superfamily Its ligand, CD40L (CD154), is a trimeric
membrane protein that is homologous to TNF CD40-induced signals are also crucial for subsequent
germinal center reactions In addition, T cell–mediated DC and macrophage activation involves the
interaction of CD40L on activated helper T cells with CD40 on DCs and macrophages Interestingly, a
DNA virus called the Epstein-Barr virus (EBV) infects human B cells and induces their proliferation. This
may lead to immortalization of the cells and the development of lymphomas In addition to CD40L on
helper T cells activating B cells, helper T cells also secrete cytokines that contribute to B cell responses. T
cell–derived cytokines are essential for germinal center reactions.

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 cellactivation generate low-affinity antibodies that can
circulate and limit the spread of an infection B cells that are activated by helper T cells through CD40L in
the extrafollicular foci undergo isotype switching The antibody-secreting cells that are generated in
extrafollicular foci, including plasmablasts and tissue plasma cells ,In secondary lymphoid organs,
plasmablasts downregulate CXCR5 and CCR7, upregulate CXCR4, and migrate into the red pulp (in the
spleen) or medullary cords (in lymph nodes) in response to the CXCR4 ligand CXCL12
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 TFHcells,
which express high levels of the chemokine receptor CXCR5, are drawn into lymphoid follicles by
CXCL13, the ligand for CXCR5, and play critical roles in germinalcenter formation and function .
Differentiation of T cells from naive CD4+ T cells requires twosteps: initial activation by antigen-
presenting DCs and subsequentactivation by B cells activation by B cells The choice between a Th1, Th2,
orTh17 fate on the one hand or a THF fate on the other depends partlyon the strength of the initial
interaction between peptide–class IIMHC complexes on DCs and the T cell receptor (TCR) on naiveCD4+
T cells Strong TCR activation by DCs induces THF cells by promoting expression of the BCL-6
transcriptional repressor andreducing the levels of the α chain of the IL-2 receptor (IL-2R),A number of
molecules on B cells and helper T cells are known to play key roles in the generation of T cells. SAP is
mutated in patients with X linked lymphoproliferative syndrome (XLPwhich is associated with defects in
antibody and cytotoxic T cell responses
Know we will tell some features of both Extrafollicular and Germinal Center B Cell Responses ,,, first :
Extrafollicular Response located at Medullary cords of lymph nodes and at junctions between T cell zone
and red pulp of spleen while Germinal Center Response located at Germinal centers of secondary
follicles the both has AID expression and Isotype switching and also both required CD 40 signals but the
Affinity maturation of antibody is low in Extrafollicular Response and high in Germinal Center Response
.. Extrafollicular Response has Short life span approximately 3 days while Germinal Center
Response has long life span which migrate to bone marrow, and memory cells
.The generation of T follicular helper (Tfh) cells requires sequential activation of T cells, first by dendritic
cells and then by activated B cells. Inducible costimulator (ICOS) ligand (ICOS-L)- ICOS interactions are
essential for Tfh cell differentiation. The differentiated Tfh cells migrate into germinal centers, where
they activate B cells The defining cytokine produced by T cells is IL-21. This cytokine is required for
germinal center development and contributes to the generation of plasma cells in the germinal center
reaction. IL-21 secreted by T cells also facilitates germinal center B cell selection events and the
differentiation of activated B cells into plasmablasts. In addition to IL-21, T cells secrete other cytokines,
including IL-4 and IL-13 and likely low levels of IFN-γ as well; some of these cytokines are known to
participate in isotype switching.

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 , Germinal centers consist of two distinct regions: a dark zone that
is densely packed with rapidly proliferating B cells and appears dark in histologic sections stained with
hematoxylin; and a light zone, where high-affinity B cells are selected to survive and differentiate further
but many cells die, that stains weakly with the same dye TFH cells are present only in the light zone The
light zone also contains a type of stromal cell called a follicular dendritic cell (FDC).
The germinal center reaction consists of a number of sequential steps : the steps are 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 I will explain three of them ,,,Initiation of the germinal center by T cells: The
germinal center reaction begins with the migration of T cells into the follicle, guided by the chemokine
CXCL13 blinding to CXCR5 on the T cells.
B cell proliferation: B cells that have been triggered by TFH cells via CD40L-CD40 interactions
repeatedly proliferate, forming the dark zone of the germinal center. The doubling time of these
proliferating germinal center B cells is estimated to be 6 to 12 hours, so that within 5 days, a single
lymphocyte may give rise to as many as 5000 progeny
8. Differentiation into long-lived plasma cells: After some rounds of selection, high-affinity B
cells exit the germinal center asplasmablasts that will home to the bone marrow and differentiate into
long-lived plasma cells. How the decision is made for selected high-affinity light zone B cells to not
return to the dark zone but to instead exit the germinal center is not known. What is known is that once
this decision is made, high-affinity light zone B cells reexpress EBI2 and leave the germinal center.
Germinal center formation is defective in humans and in mice with genetic defects in T cell development
or activation or with mutations of either CD40 or its ligand,

Heavy Chain Isotype (class) Switching

In T-dependent immune responses, activated Bcells can undergo heavy chain isotype switching,
resulting in the production of antibodies with different heavy chain classes (such as y, a, and &).
This process can occur both outside the follicles, driven by extrafollicular pre-germinal center Tcells, and
within germinal centers, driven by Tcells in the light zone. Isotype switching allows for the generation of
diverse antibody isotypes, each with unique effector functions and roles in defense against specific types
of pathogens. By changing the constant regions of the heavy chains while preserving the same variable
regions, Bcells can produce antibodies with different heavy chain classes and specialized functions.
Cytokines produced by activated helper Tcells in response to specific pathogens play a crucial role in
regulating isotype switching. These cytokines provide the necessary signals for B cells to undergo
switching to specific heavy chain classes. For example, IFN-y induces switching to IgG subclasses in mice,
while in humans, the specific cytokines responsible for isotype switching to IgG subclasses (IgG1, IgG2,
IgG3, and IgG4) are yet tobe determined. However, human Tcells expressing higher levels of IL-21
relative to IL-4 are implicated in driving the switch from IgM to IgG. In immune responses against
helminthic parasites, the dominantantibody isotype involved in defense may differ. The specific
cytokines and mechanisms regulating isotype switching in this context are not mentioned in the given
information., during immune responses against helminthic parasites, Ig antibodies and the production of
Th2-type cytokines, such as IL-4 and IL-13, play a crucial role in combating the parasites and mediating
allergic reactions. Different anatomical sites may exhibit preference for specific antibody isotypes, with g
A being dominant in mucosal tissues. Isotype switching is regulated by various factors, including
cytokines like TGF-B, BAFF, and APRIL, a s well a s CD40 signaling combined with cytokines. The enzyme
AID is essential for isotype switching and affinity maturation. Understanding the mechanisms of isotype
switching and the factors involved can provide insights into the immune response against helminthic
parasites and other pathogens. The molecular mechanism underlying isotype switching is called switch
recombination. This process involves cutting and recombining the Ig heavy chain DNA in Bcells. The
switch regions, located in the introns between the J and C segments, are critical for switch
recombination. Cytokine signals induce transcription from specific Iregion promoters, leading to the
generation of germline transcripts. These transcripts facilitate the generation of DNA double-strand
breaks at the switch regions and promote recombination events. This rearrangement allows for the
production of antibodies with different heavy chain classes.Cytokines, such as IL-4, play a crucial role in
determining which constant heavy chain region will undergo germline transcription and contribute to
the production of specific antibody isotypes, such as IgE.
The key enzyme for isotype switching is AID, which is induced by CD40 signals from activated Tcells. AID
removes amino groups from cytosines in single-stranded DNA, creating uracil residues. AID targets
switch regions, which have GC-rich tetranucleotide motifs abundant in their sequences. Transcription
through switch regions forms stable DNA-RNA hybrids and open single-stranded DNA loops called R-
loops. AID targets the single-stranded DNA and converts C residues to U residues.
Uracil N-glycosylase (UNG) and endonuclease APE1 then remove the U residues and create nicks,
leading to double-strand breaks in both the donor and acceptor switch regions. These breaks are
repaired by nonhomologous end joining, resulting in the fusion of the rearranged Vregion DNA with a
new constant region. Overall, this process allows for the production of antibodies with different heavy
chain classes through the rearrangement and fusion of DNA segments in B cells.

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 cells and CD40- CD40L
interactions are required for somatic mutation to be initiated, and, as a result, affinity maturation is
observed only in antibody responses to T-dependent protein antigens .
In proliferating germinal center B cells in the dark zone, rearranged Ig V genes undergo point mutations
at an extremely high rate. This rate is estimated to be 1 in 103 V gene base pairs per cell division, which
is approximately 1000 times higher than the spontaneous rate of mutation in other mammalian genes.
For this reason, mutation in rearranged Ig V genes is also called somatic hypermutation. The V genes of
expressed heavy and light chains in
each B cell contain a total of approximately 700 nucleotides; thus, mutations will accumulate in
expressed V regions at an average rate of almost one per cell division. Ig V gene mutations continue to
occur in the progeny of individual B cells. As a result, any B cell clone can accumulate more and more
mutations during its life in the germinal center. It is estimated that as a consequence of somatic
mutations, the nucleotide sequences of IgG antibodies derived from one clone of B cells can diverge as
much as 5% from the original germline sequence. This usually translates to up to 10 amino acid
substitutions. The mutations are clustered in the V regions, mostly in the antigen-binding
complementarity- determining regions (CDRs) and the presence of mutations correlates with increasing
affinities of the antibodies for the antigen that induced the response.
The enzyme AID, discussed earlier in the context of isotype switching, also plays an essential role in
affinity maturation. The DNA deaminase activity of AID converts C residues to U residues at specific
tetranucleotide (AGCT) hotspots that are found all over the genome but are targeted primarily in
rearranged V regions (or in switch regions as discussed above). AID may recognize sequences in the
location of the rearranged VDJ exon, which explains at least partially why rearranged V regions are
highly susceptible to mutations. However, the mechanism by which these rearranged VDJ exons are
specifically targeted is still unclear. The Us that are generated from Cs may be changed to Ts when DNA
replication occurs, thus generating a common type of C to T mutation, or the U may be excised by UNG,
and the abasic site thus generated is repaired by an error-prone DNA repair process, eventually
generating substitutions with any of the four DNA nucleotides at each site of AID-induced cytidine
deamination. Two enzymes, MSH2 and MSH6, involved normally in the process of DNA mismatch repair,
are important participants in somatic hypermutation. MSH2 and MSH6 can recruit nucleases that
remove not only uridine nucleotides (which are normally present in RNA) but also adjacent nucleotides.
This mutated stretch is then repaired by an error-prone. DNA polymerase, thus extending mutations to
residues beyond the C residues that are targeted by AID.
B Cell Differentiation Into Antibody-Secreting Plasma Cells
Plasma cells are morphologically distinct, terminally differentiated B cells commied to abundant
antibody production (see Chapter 2). They are generated after the activation of B cells through signals
,from the BCR, CD40, TLRs, and other receptors including cytokine receptors.

There are 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 T-dependent 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 antibody-
secreting cells. They continue to proliferate (like activated B cells) but express lile or no CD20, the
marker of mature B cells.
B cell selection in germinal centers.Somatic mutation of V genes in germinal center B cells generates
antibodies with different affinities for antigen. Binding of the B cells to antigen displayed on follicular
dendritic cells is necessary to rescue the B cells from programmed cell death. B cells may also present
antigen to germinal center T follicular helper (Tfh) cells, which promote B cell survival. The B cells with
the highest affinity for antigen thus have a selective advantage for survival as the amount of
available antigen decreases during an immune response. This leads to an average increase in the affinity
of antibodies for antigen as the humoral immune response progresses.
The differentiation of B cells into antibody-secreting 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 e to the secreted form .

.
Generation of Memory B Cells
Memory Bcells 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 Bcells develop in germinal centers in a T-dependent manner, some IgM
expressing memory B cells are generated without Tcell 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. Some memory Bcells may
remain in the lymphoid organ where they were generated,where as
others exit germinal centers and recirculate between the blood and
lymphoid organs. B cells can be activated without the help of T
cells by T-independent (TI) antigens, which are mainly recognized by marginal zone and B-1 subsets of
Bcells. TI responses occur in
the spleen, peritoneal cavity, and mucosal sites. Memory Bcells are generated during T-dependent
immune responses and
primarily develop in germinal centers. They can make rapid responses to subsequent antigen exposure
and survive for long periods due to high levels of anti-apoptotic protein BCL-2. Effective vaccines must
induce both long-lived plasma cells and memory B
cells, which can be achieved by activating helper Tcells. Conjugate vaccines, which link polysaccharides
to foreign proteins, are particularly effective at inducing protective immunity in infants and young
children.
Antibody Responses to T-Independent Antigens
Many nonprotein antigens, such as polysaccharides, lipids, and nucleic acids, stimulate antibody
production in the absence of helper Tcells, and these antigens and the responses they elicit are termed
thymus independent (TI). These antibody responses differ

in several respects from responses to Tcell-dependent protein antigens The antibodies that are
produced in the absence of Tcell help are generally of low affinity and consist mainly of IgM, with limited
isotype switching to some IgG subtypes and also to IgA. Subsets of B Cells That Respond to T-
Independent Antigens
T-independent antigens can activate Bcells without the help of T cells. Marginal zone and B-1 subsets of
Bcells are important for antibody responses to TI antigens. These responses mainly occur in the spleen,
peritoneal cavity, and mucosal sites. Marginal zone macrophages efficiently trap polysaccharides, which
persist on their surfaces and are recognized by specific Bcells. TI responses exhibit little isotype
switching, but some non-protein TI antigens can induce Ig isotypes other than IgM.
Mechanisms of T-Independent Antibody Responses T-independent antigens can activate B cells without
the help of T
cells. They include polysaccharides, glycolipids, and nucleic acids, and are often composed of repeated
identical antigenic epitopes. Multivalent antigens can cross-link many BCR molecules on
specific Bcells, leading to activation without Tcell help. Polysaccharides can also activate the
complement system, which augments B cell activation. TI responses typically exhibit little isotype
switching, but some non-protein TI antigens can induce lg isotypes other than IgM. Cytokines produced
by non-T cells may stimulate isotype switching in TI responses, including BAFF and APRIL produced by
cells of myeloid origin. TGF-B secreted by nonlymphoid cells at mucosal sites may contribute to the
generation of IgA antibodies directed against nonprotein antigens. 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 F
receptors on antigen-specific Bcells, the regulation of humoral immune responses is a complex process
involving various inhibitory receptors and signaling pathways.
Antibody feedback mediated by Fc receptors is a physiologic control mechanism that blocks further
antibody production by inhibiting Bcell activation. CD22 is another inhibitory receptor that regulates B
cell activation by recruiting the phosphatase SHP1 to dephosphorylate key signaling molecules.
Dysregulation of these inhibitory pathways can lead to autoimmune diseases and uncontrolled antibody
production. Understanding these mechanisms is important for developing effective vaccines and
therapies for immune-related disorders.

The end