B Cell Activation and humoral immunity

What is the major topic of Towne's lecture?

B-cell activation and humoral immune responses

What branch of adaptive immunity is the focus of this lecture?

Humoral immunity mediated by B cells and antibodies

What is the principal target of humoral immunity?

Extracellular pathogens

Why are B cells and antibodies principally effective against extracellular pathogens?

Antibodies normally cannot enter host cells, so they bind targets located outside cells

What major question does the first part of the lecture address?

How a mature naïve B cell becomes activated

What happens after successful B-cell activation?

The B cell proliferates and can undergo germinal-center reactions before differentiating into plasma cells and memory B cells

What major question does the second part of the lecture address?

What different antibody classes do and how antibodies fight infection

Where did the previous B-cell development lecture primarily occur?

The bone marrow

Where does the current B-cell activation lecture primarily occur?

Blood, lymph, and secondary lymphoid tissues such as lymph nodes

What does Towne mean by the "periphery"?

Essentially locations outside the primary immune organs of bone marrow and thymus, including blood, lymph, lymph nodes, and other secondary lymphoid organs

Where do mature B cells primarily encounter antigen?

Secondary lymphoid tissues, especially lymph nodes, although antigen encounters can also occur in blood and lymph

What is the basic developmental sequence Towne reviews before discussing activation?

Heavy-chain rearrangement → pre-BCR checkpoint → light-chain rearrangement → complete IgM BCR expression → self-reactivity check → exit to periphery

Which immunoglobulin is initially produced during B-cell development?

IgM

What does expression of a complete IgM BCR indicate?

The B cell successfully produced both functional heavy and light chains

What is the purpose of the pre-BCR checkpoint?

To verify that a functional heavy chain has been produced and can signal appropriately

What happens if a developing B cell cannot produce a functional heavy chain?

It eventually dies

What happens if the pre-BCR does not signal appropriately?

The developing B cell dies

What happens after successful heavy-chain rearrangement?

Light-chain rearrangement occurs

What must occur after a complete BCR is produced?

The B cell must be checked for recognition of self

What is the purpose of negative selection in developing B cells?

To prevent strongly self-reactive B cells from entering the periphery

What happens to strongly self-reactive developing B cells?

They are removed or undergo receptor editing

Does antigen activation normally occur while B cells are developing in bone marrow?

No. Antigen-mediated activation should occur after the B cell reaches the periphery

Why does Towne emphasize knowing where B-cell developmental steps occur?

The location of a developmental failure can help determine the cause of an immunodeficiency

What is a mature naïve B cell?

A mature B cell that successfully completed development but has not yet encountered the antigen that will activate it

Where do mature naïve B cells go after leaving bone marrow?

Secondary lymphoid organs and the circulation

Through what specialized vessel can B cells enter secondary lymphoid tissue?

A high endothelial venule

How long can an unactivated mature naïve B cell circulate according to Towne?

For several weeks

What happens if a mature naïve B cell does not encounter its antigen after several weeks?

It undergoes apoptosis

Why does the body allow unused naïve B cells to die?

It reduces the chance that a B cell that escaped central tolerance and recognizes self will persist long enough to become pathologically activated

What receptor defines antigen specificity on a mature B cell?

The B-cell receptor or BCR

What is the BCR structurally related to?

Immunoglobulin

What signaling components accompany the BCR according to Towne?

Alpha and beta signaling molecules

Are B cells antigen-presenting cells?

Yes

Which MHC molecules do B cells express?

MHC class I and MHC class II

What important costimulatory molecule does Towne emphasize on B cells?

CD80, also called B7

Why does Towne emphasize knowing B-cell surface molecules such as CD40 and B7?

Defects in these molecules can cause clinically important immunodeficiencies

What are the two broad types of antigens capable of activating B cells?

T-independent antigens and T-dependent antigens

What is another name for a thymus-independent antigen?

A T-cell-independent antigen

Does a T-independent B-cell response require helper T-cell involvement?

No

What type of antigen commonly produces T-independent B-cell activation?

Polysaccharides

How can a polysaccharide activate a B cell without T-cell help?

It cross-links many B-cell receptors simultaneously and provides a sufficiently strong activation signal

What does BCR cross-linking mean?

One antigen containing repeated structures simultaneously binds multiple BCRs on the same B cell

What does a B cell activated by a T-independent antigen primarily become?

A short-lived plasma cell

What antibody is primarily produced during a T-independent response?

IgM

Does a classic T-independent response produce strong immunologic memory?

No

What is the high-yield T-independent response pattern?

Polysaccharide → extensive BCR cross-linking → B-cell activation without T-cell help → short-lived plasma cells → mostly IgM → little or no memory

What is the major limitation of T-independent activation?

It produces a relatively limited response without the robust germinal-center maturation and memory associated with T-dependent activation

What type of antigen does Towne use to illustrate T-dependent B-cell activation?

A protein antigen

What happens first during T-dependent B-cell activation?

A B cell specifically binds an antigen using its BCR

What does the B cell do with bound protein antigen?

It internalizes and digests the antigen

What happens to peptides generated from the internalized antigen?

They are displayed on MHC class II on the B-cell surface

Which cell recognizes peptide-MHC II displayed by the B cell?

A helper T cell

What is Towne's analogy for antigen presentation by a B cell?

The B cell essentially tells the helper T cell, "Here's what I ate"

What does recognition by the appropriate helper T cell communicate to the B cell?

The presented antigen is foreign and the B cell should be activated

Where do B cells and helper T cells meet for T-dependent activation?

In secondary lymphoid tissue, especially the lymph node

What analogy does Towne use for B-cell and T-cell encounters?

Speed dating because the B cell must find a T cell whose receptor matches the peptide-MHC being presented

Why can't any random helper T cell activate a given B cell?

The T cell must specifically recognize the peptide-MHC complex presented by that B cell

What must a helper T cell recognize on a B cell?

The appropriate antigen-derived peptide presented on MHC

What happens if a B cell binds an antigen but cannot obtain appropriate T-cell help?

It becomes functionally inert or anergic

Why is B-cell anergy useful?

It provides a peripheral tolerance mechanism against accidental activation of self-reactive B cells

How could a self-reactive B cell escape the bone marrow but still fail to cause autoimmunity?

It may bind self antigen in the periphery but fail to receive matching helper T-cell signals, causing anergy

What is the central logic of requiring T-cell help for B-cell activation?

Multiple independent checkpoints decrease the chance of accidentally activating an inappropriate or self-reactive B cell

What important receptor is expressed on B cells for T-dependent activation?

CD40

What corresponding molecule is expressed on activated helper T cells?

CD40 ligand or CD40L

What happens when CD40L on a helper T cell binds CD40 on a B cell?

It provides a critical activation signal to the B cell

What other costimulatory interaction occurs between B and T cells?

B7 on the B cell binds CD28 on the T cell

Which interaction primarily helps activate the B cell?

CD40 on the B cell binding CD40L on the helper T cell

Which interaction helps activate the helper T cell?

B7 on the B cell binding CD28 on the T cell

Why does Towne describe B-cell and T-cell activation as reciprocal?

The B cell helps activate the T cell through B7-CD28 while the T cell helps activate the B cell through CD40-CD40L and cytokines

How long can the B-cell and T-cell conjugate remain physically associated according to Towne?

Up to about four hours

Why do B and T cells remain conjugated for an extended period?

The prolonged interaction allows the multiple receptor and cytokine signals required to confirm appropriate activation

What happens to B7 expression when a B cell takes up and presents antigen?

B7 is upregulated

What happens after the helper T cell receives adequate activation signals?

It produces cytokines directed toward the B cell

What cytokine does Towne visually demonstrate being secreted onto a B cell?

IL-4

What do helper T-cell cytokines promote in activated B cells?

Proliferation, differentiation, and class switching

What does Towne say Signal 3 represents during lymphocyte activation?

Cytokines

What happens if a lymphocyte receives Signal 1 without adequate Signal 2?

It becomes anergic

Why should you compare B-cell activation with T-cell activation?

Both require coordinated antigen recognition, costimulation, and cytokine signals but use different receptor-ligand interactions and antigen-recognition mechanisms

What happens to an activated helper T cell after activation?

It clonally expands

Why do activated T cells clonally expand?

One cell is insufficient for an infection, so expansion creates many cells capable of helping other immune cells

What molecule do activated helper T-cell clones express that is especially important for B-cell help?

CD40 ligand

What is clonal expansion?

Proliferation of an antigen-specific lymphocyte to generate many cells with the same antigen specificity

What happens to the successfully activated B cell after receiving T-cell help?

It proliferates and enters further maturation pathways including the germinal-center reaction

What is a germinal center?

A highly active region within a lymphoid follicle where activated B cells proliferate and improve their antibody response

What happens to B-cell numbers in the germinal center?

They undergo extensive clonal expansion

What is the overall purpose of the germinal-center reaction?

To generate better antibodies and long-lived humoral immunity

What major processes occur in germinal centers?

Class or isotype switching, somatic hypermutation, affinity maturation, selection, and differentiation toward memory or plasma-cell fates

When do combinatorial and junctional diversity occur relative to antigen encounter?

Before antigen encounter during lymphocyte development

Do combinatorial and junctional diversity occur in both B and T cells?

Yes

Which two post-antigen processes does Towne emphasize as occurring only in B cells?

Somatic hypermutation and isotype or class switching

Does a T cell undergo somatic hypermutation after activation?

No

Does a T cell undergo immunoglobulin class switching?

No

What is somatic hypermutation?

Introduction of point mutations into the variable antigen-binding regions of activated B-cell receptors

What is the goal of somatic hypermutation?

To generate BCR variants that may bind antigen with higher affinity

Is somatic hypermutation the same as somatic recombination?

No

When does somatic recombination or V(D)J recombination occur?

During lymphocyte development before antigen exposure

When does somatic hypermutation occur?

After antigen activation in germinal-center B cells

What enzyme is required for somatic hypermutation?

AID

What does AID stand for?

Activation-induced cytidine deaminidase

Does Towne expect you to memorize the full biochemical name of AID?

No. She explicitly says to know AID