CD40L/CD40 Interaction and B Cell Activation

• B lymphocytes are involved in antibody production, structure, and function.
• Lymphocytes originate from bone marrow stem cells and undergo maturation stages, expressing antigen receptors and acquiring mature cell characteristics.
• B lymphocytes partially mature in the bone marrow and complete maturation in peripheral lymphoid organs.
• T lymphocytes mature in the thymus before populating peripheral lymphoid tissues.
• Mature B and T cells are called naive lymphocytes.
• Lymphocytes undergo changes in phenotype and function upon antigen activation.
• Lymph nodes have distinct regions where lymphocyte classes are sequestered
• Lymph node follicles are B cell zones, with primary follicles containing mature, naive B lymphocytes.
• Germinal centers in lymph nodes develop upon antigenic stimulation and are sites of B cell proliferation, selection of B cells producing high-affinity antibodies, and memory B cell generation.
• T lymphocytes are located in the paracortical cords beneath and central to follicles, mainly CD4+ helper T cells with some CD8+ cells; these proportions can change during infection.
• An increase in CD8+ T cells may occur during a viral infection.
• Dendritic cells are concentrated in the paracortex of the lymph nodes.
• B cells use cell surface antigen receptors to recognize antigens, with the antigen receptor of a B cell being a cell surface immunoglobulin.
• Plasma cells produce large amounts of soluble proteins called antibodies, and are the terminally differentiated form of B cells
• Antibodies bind to antigens of pathogens, marking them through opsonization or inactivation through neutralization.
• The lymphatic circulation collects and transports lymph with lymphocytes to facilitate antigen encounters within B and T cell zones.
• Secondary lymphoid organs are where lymphocytes first encounter their specific antigens.
• Lymphocytes "camping" recognize and bind antigens which triggers cell division (proliferation)
• Non-specific lymphocytes exit through the lymphatic vessel and recirculate until they find their antigen or undergo apoptosis if an antigen is not found within a certain time period.

Subgroups of B Lymphocytes

• Follicular B cells, marginal zone B cells, and B-1 B cells are the major subsets of B cells, each found in distinct anatomic locations within lymphoid tissues.
• Follicular B cells recirculate, mediating T cell-dependent immune responses in secondary lymphoid organs.
• Marginal zone B cells reside near the splenic marginal sinus, mediating T cell-independent reactions to blood-borne antigens.
• B-1 cells are typically found in the peritoneum and mucosal sites in adults
• IgM secretion and multivalent antibody production are characteristics of B-1 cells, which respond to polysaccharide antigens with limited diversity.
• Follicular B cells recirculate in secondary immune organs and generate reactions dependent on T cells, usually creating protein antibodies
• In the splenic marginal sinus, marginal zone B cells typically control reactions independent of T cells, and produces IgM very quickly to kill microbes in the blood.
• B-1 cells develop earlier and respond to a restricted set of microbial antigens, providing rapid antibody production.
• Marginal zone B cells swiftly respond to blood-borne microbes and differentiate into short-lived plasma cells, expressing IgM and surface marker CD21.
• The majority of B lymphocytes arise from adult bone marrow progenitors and mature primarily in the spleen.
• Recirculating follicular B cells home to lymphoid follicles, and recognize and respond to foreign antigens.
• It takes ~ 2 to 3 days for a mature B cell to develop from a lymphoid progenitor.

B Lymphocyte Antigen Receptors

• B Cells have cell surface antigen receptors called antibody molecules,
• Antigen receptors can be IgM or IgD and recognize one type of antigen.
• Naive B cells can produce both IgM and IgD while functioning as membrane receptors for antigens.
• B Cells undergo isotype switching which changes the type of CH region that occurs when they are activated by an antigen which changes the antibody isotope
• Isotype switching allows the B cell to produce a different type of better type suited to eliminate the antigen
• Viral and bacterial responses usually are dominated by IgG
• Responses to helminths consists mainly of IgE

Professional Antigen-Presenting Cells

• They are important for naive T cell activation, effector T cell activation, and activation of effector T cells by B cells in the humoral immune response.
• Receptor-mediated endocytosis presents antigen to helper effector CD4+ T cells to stimulate B cell differentiation into plasma cells and antibody production.
• T cells produce cytokines to promote B cell activation and differentiation.
• MHC class ll molecules and costimulators are expressed by dendritic calls, macrophages and B lymphocytes making them capable of activating CD4+ T lymphocytes

B Cells and Humoral Immunity

• B cells have a vital role in the development of the humoral immune response specifically, differentiating into antibody-producing plasma cells and antibody producing memory cells
• Plasma cells produce antibodies and abundant cytoplasm, which makes them identifiable morphologically
• Memory cells express different surface proteins from naive and recently activated effector lymphocytes
• Memory B lymphocytes express certain membrane Ig classes and naive B cells express only IgM and IgD
• CD27 expression in humans is a good marker for memory B cells.

Activation and Clonal Expansion

• Immunoglobulin on the cell surface (BCR) recognizes antigen and mediates the humoral part.
• B cells usually interact with antigens in the secondary lymphoid organs, supporting B cell proliferation and suitable environment
• Antigens are recognized by B cells in the lymph node and blood cells, as well as on the surfaces of cells
• Antigens don't need to be presented by MHC molecules to initiate an immune response
• B Cells expand clonally when activated by their specific antigen
• Clonal expansion yields thousands of plasma cells producing billions of antibodies.
• Plasma cells do no express BCR but have the same specificity of produced antibodies
• Antibodies travel through the blood tissues and recognize pathogens despite their production site.

B Cell Activation and Antibody Production

• B lymphocytes are activated by antigens during humoral immune responses which leads to the secretion of antibodies which eliminates the respective antigen
• Antibodies are produced by both protein and non-protein antigens.
• B cell responses to protein antigens need assistance from CD4+ helper T cells

B Cell Receptor Signaling

• B cell activation occurs when the antigen receptors (membrane IgM and IgD on naive B cells) are crosslinked through the binding of multivalent antigens
• The activation of B cells requires antigen recognition in lymphoid tissues.
• Follicular or recirculating B cells enter, circulate and try to find cognate antigen.
• Chemokine CXCLl3, which attracts B cells into the follicles by binding to the CXCR5 chemokine receptor on recirculating B cells, is secreted by follicular dendritic cells (FDCs)
• B cell survival, proliferation, and differentiation also need BAFF (B lymphocyte stimulator)
• Iga and Igb chains transmit signals for activation.
• After binding, the receptor is internalized followed by peptides presentation by helper T cells

T Cell-Dependent B Cell Response

• Initial naive T cell and B cell activation is a response to protein antigens, and occurs in the respective T cell zones and lymphoid follicles in lymphoid organs.
• Follicles is where B cells are presented to helper T cells which requires those lymphocytes migrate towards each other and interact at the edges of follicles
• B cells engage and activate when they express CD40L to engage CD40 on B cells, and and secretion of cytokines to bind to their receptors
• Initial B cell proliferation and differentiation and extrafollicular foci creation for antibody-secreting occurs in the presence of CD40 and cytokine signals
• TNF receptor family member CD 40 is constitutively expressed
• CD40 engages T cell membrane protein CD40L (CD154)
• conformational alteration of preformed CD40 trimers causes TRAFs (TNF receptorassociated factors) to associate with the cytoplasmic domain of CD40

Isotype Switching

• Isotype switching is induced by helper T cell signals.
• Process needs enzyme AID (cytidine deaminase)
• This allows access to downstream heavy chain loci, and occurs when germinal centers are activated within follicles
• Antibody specificity remains unchanged
• Effector function changes, for example through responses to CD40

Affinity Maturation

• Increases antibody affinity for a particular antigen along with the help of T dependent humoral responses This enables high affinity to target neutralize and eliminate microbes
• Helper T cells and interactions for CD40 and CD40L are required for optimal maturation
• The process happens only within the specific responses with helper T cells.

Memory B Cells

• Differentiate into
  • Antibody secreting plasma cells
  • Long lived Memory Cells that reside in peripheral lymphoid organs
  • Bone Marrow: for long antibody production

Immunoglobulin Function

• Surface of the cell BCR is how the antigen is recognized
• Plasma cells mediate any kind of B Immune Response with antibodies
• B cell recognition of antigen is often accompanied by B cell proliferation in the secondary lymphoid organs

Antibodies and Production

• Antibodies (immunoglobulins) are glycoproteins produced by B cells
• Antibodies bind specifically to the antigen to mediate B cell humoral immune response
• Antibodies express their effector function away from the site of production (lymphatic organ, bone marrow) to the blood, mucosal organs, and intestine.
• Plasma cells produce about 10 to the 18th power antibody molecules per day in the body.

Neutralization

• Antibody molecule binds to part or masks part of the pathogen's receptor for the cell being attacked
• Antibodies bind to toxins to impede the active part of toxins.
• Plasma sells produce surprisingly large amounts of nearly 108 antibody parts ever day
• Domains are responsible and variable
• Specific antibodies make the antigens covered by B cells incapable of binding to cell surface
• High affinity
• This means animal or toxins are inhibited from exerting their effect.

Antibody Structure

• Antibodies have structural units with 2 identical heavy chains and 2 light chains
• N terminal variable domains form antigen binding sites

Fc Receptors

• Fc region of antibodies is not a variable, and are similar across the regions.
• They interact with immune cells using various cell surface receptors
• This provides a bridge between the immunized pathogen and the immunocyte.
• IgG subclasses bind to phagocyte Fc receptors facilitate antibody coding
• Also activates complement
• Mast cells activate the lge which triggers it
• B cell function is specified through the binding of B cells
• The process occurs in specific heavy chains

Antibody Responses.

• Microbes use the alternative pathway to respond with C3b
• Complement fragments facilitate a B lymphocytes which activate by using C3B

Complement Activation

• MACs can result from
  • Complement mediated cytolysis
  • Activation with binding to antigens

Immunoglobulin Class

• Based on heavy chains and structure.
• IgM
• ige
• lGD
• lgG
• IgA

IsoTypes

• G
• Can actively transport through FC receptors
• From to maternal circulation to fetuses
• M and A

B memory cells

• Are present in the surface
• IsoTypes
• g e d
• e and A
• Activated with cell function
• A main function
• It can protect

CD40L/CD40 interaction facilitates downstream signaling, crucial for B cell activation in germinal centers. Non-functional CD40L impairs B cell activation, impacting the adaptive immune response. TRAFs mediate CD40 signaling; mutations preventing TRAF binding compromise this pathway.