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.
• Phagocyte defects: CGD (oxidative burst defect), leukocyte adhesion deficiency; susceptibility to catalase-positive organisms.
• 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.
• Antibody classes provide distinct effector functions: IgG (opsonization, neutralization, placental transfer), IgM (early response, strong complement activation), IgA (mucosal immunity), IgE (allergy, helminths).
• 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.