B Cell Development, Activation, and Antibody Production
B cells originate from pluripotent stem cells in the bone marrow and mature through heavy- and light-chain rearrangements to form a functional B cell receptor (BCR) complex on the membrane. Key markers include CD19 and CD21; heavy and light chain rearrangements occur in the bone marrow with surrogate light chains during development.
Naive B cells express membrane immunoglobulins IgM and IgD as BCRs and circulate to survey for antigen. Upon antigen encounter, they interact with helper T cells in secondary lymphoid organs and undergo clonal expansion and differentiation.
Signal transduction through the B cell receptor involves an ITAM-bearing immunoreceptor tyrosine-based activation motif (ITAM) in associated chains, leading to changes in gene expression (e.g., upregulation of costimulatory molecules like B7).
Activated B cells differentiate into plasma cells that secrete antibody and memory B cells that provide long-term protection. Isotype switching occurs to IgG, IgA, or IgE under helper T cell cytokines and CD40–CD40L signaling.
B Cell Receptors, Signaling, and Isotype Switching
The BCR complex includes membrane-bound IgM or IgD associated with signaling chains containing ITAMs, enabling antigen recognition and signal transduction. ITAM
Primary B cell activation is influenced by CD40–CD40L interactions with helper T cells and cytokines, which also drive isotype switching (e.g., IFN-γ, IL-4). The result is the production of different Ig isotypes (IgG, IgA, IgE).
Immunoglobulins are produced as membrane-bound BCRs on naive B cells (IgM, IgD) and as secreted antibodies by plasma cells.
Germinal Center Reactions: Somatic Hypermutation and Affinity Maturation
Germinal centers (GC) in secondary lymphoid organs are sites of somatic hypermutation and affinity maturation, selecting high-affinity B cells for survival and differentiation.
Outcomes include high-affinity plasma cells (antibody-secreting) and memory B cells; affinity maturation improves the quality of the humoral response over time.
Isotype switching continues during GC reactions, leading to IgG (and other isotypes) with improved functional properties.
Antigen Presentation and Helper T Cell Collaboration
B cells can present antigen to helper T cells; B cells present their specific antigen and receive help via CD40–CD40L and cytokine signals, driving B cell activation and differentiation.
Antigen presentation by B cells is highly efficient (roughly 100,000-fold more efficient for specific antigen than for nonspecific antigen), enhancing cognate T cell help.
Helper T cells provide cytokines and surface signals (e.g., CD40L) that promote B cell proliferation, isotype switching, and maturation.
Lymph Node Architecture and Antigen Delivery to B Cells
Lymph nodes contain primary follicles (B cell zones) and secondary follicles with germinal centers, separated from T cell–rich paracortical areas.
Antigen delivery to follicles occurs via subcapsular sinus macrophages, conduits, and dendritic cells; small antigens are delivered through conduits to follicles.
The organization supports efficient B–T cell interactions required for TD (T cell–dependent) antibody responses and GC reactions.
Isotype Switching and Immunoglobulin Classes
IgM and IgD mark naïve B cells; upon activation, B cells switch to IgG, IgA, or IgE, guided by helper T cell cytokines and CD40L signaling.
IgG subclasses (e.g., IgG1, IgG3) have distinct effector functions and tissue distribution; IgA is important for mucosal immunity; IgE mediates allergic responses and anti-helminth activity.
Secretory IgA is produced as a dimer with a J chain and secretory component for mucosal surfaces.
Complement System: Pathways, Regulation, and Effects
The complement system comprises over 30 circulating and membrane-bound proteins that act in a cascade to opsonize, lyse, and promote inflammation.
Three initiation pathways:
Classical pathway: initiated by immune complexes (Ag–Ab) and activation units C1qrs, leading to C4b2a (C3 convertase) and MAC formation (C5–C9). ext{C4b2a}
ightarrow ext{C3 convertase}
Lectin pathway: initiated by mannose-binding lectin (MBL) binding microbial surfaces, with MASP proteases forming C4b2a-like convertase.
Alternative pathway: activated directly on pathogen surfaces via C3bBb (C3 convertase) with properdin stabilization.
The cascade converges on the formation of the membrane attack complex (MAC): ext{MAC} = ext{C5b-9}, which lyses target membranes.
Regulation is essential to prevent host tissue damage; regulators include C1 inhibitor (C1INH), Factor I, Factor H, CR1, MCP/CD46, DAF/CD55, and MIRL/CD59 which inhibit convertases or MAC formation.
Complement receptors (CR1/CD35, CR2/CD21, CR3/CD11b/CD18, CR4/CD11c/CD18) mediate immune complex handling, phagocytosis, and B cell co-stimulation.
Immunoglobulin Structure and Subclasses
Immunoglobulins are glycoproteins with heavy and light chains held by disulfide bonds; variable (V) and constant (C) regions determine specificity and effector function.
IgG, IgM, IgA, IgD, and IgE differ in structure (monomer, pentamer, dimer), distribution, half-life, and function:
IgG: monomer, major serum antibody, placental transfer, opsonization, complement activation, Fc receptor functions.
IgM: pentamer, first antibody in response, strong complement activation.
IgA: dimer (secretions), mucosal protection, secretory component; no placental transfer.
IgD: monomer, B cell receptor co-receptor; role largely in activation.
IgE: monomer, allergic reactions, defense against helminths; binds FcεR I on mast cells and basophils.
Vaccines: Types and Administration Routes
Vaccine approaches include:
Genetic vaccines: RNA, DNA encoding antigen; deliver via mechanisms like lipid coats or electroporation.
Viral vector vaccines: non-replicating or replicating vectors delivering antigen.
Subunit vaccines: purified proteins or viral fragments.
Attenuated (weakened) and inactivated vaccines.
Routes of administration include intramuscular (IM), intradermal (ID), often with adjuvants to enhance response.
Immune outcomes include humoral (B cell–driven) and cell-mediated responses depending on antigen and delivery method.
Hypersensitivity Reactions (Types I–IV)
Type I (Immediate): IgE-mediated mast cell degranulation causing localized or systemic allergic reactions. Mediators include histamine, leukotrienes; rapid onset after exposure.
Type II (Cytotoxic): IgG or IgM antibodies target cells/tissues, activating complement or phagocytosis; examples include transfusion reactions and autoimmune hemolytic anemia.
Type III (Immune Complex): Soluble antigen–antibody complexes deposit in tissues, activate complement, attracting neutrophils; examples include Arthus reaction and serum sickness.
Type IV (Delayed-type): T cell–mediated hypersensitivity; macrophage activation and cytokine-mediated inflammation; examples include contact dermatitis and tuberculin reaction.
Immunodeficiencies: B-, T-, and Combined; Phagocytes; Complement
B cell deficiencies: agammaglobulinemia (e.g., X-linked Bruton’s), CVI, IgA deficiency; presentation ranges from recurrent bacterial infections to selective antibody defects.
T cell deficiencies/combined: DiGeorge syndrome (thymic hypoplasia), SCID (IL-2Rγ, ADA, RAG mutations), WAS, AT; increased susceptibility to viral, fungal, and opportunistic infections.
Complement deficiencies: defects in classical, alternative, or lectin pathways (e.g., C1, C2, C4, C3, C5–C9) lead to immune complex diseases, Neisseria infections, or undesired inflammation; regulatory deficiencies can cause hereditary angioedema.
MHC and Antigen Presentation
MHC class I presents endogenous (cytosolic) peptides to CD8+ T cells; class II presents exogenous antigens to CD4+ T cells.
Antigen processing involves proteasomal degradation (for MHC I) and endosomal processing with invariant chain and CLIP (for MHC II).
T helper cells (CD4+) provide crucial help via cytokines and costimulation (e.g., CD40L) to B cells and cytotoxic T cells; this drives clonal expansion, isotype switching, and memory formation.
Clinical relevance includes graft rejection, vaccine design, and genetic matching in transplantation.
Quick Reference: Key Concepts
B cells mature in bone marrow; naive B cells express IgM and IgD; activation requires T cell help for TD antigens and leads to plasma cells and memory B cells.
Complement amplifies humoral and innate responses through classical, alternative, and lectin pathways; regulated by multiple factors to prevent host damage.
Hypersensitivity types I–IV occupy different immune mechanisms (IgE-mediated, cytotoxic, immune complex–mediated, and T cell–mediated, respectively).
Immunodeficiencies span B-, T-, combined, phagocyte defects, and complement deficiencies, with characteristic patterns of infections and laboratory tests.
Vaccines harness these principles to induce robust and lasting memory responses via TD or TI antigens and various delivery platforms.