Humoral Immunity & B-Lymphocyte Antigens

Introduction to Humoral Immunity

• Humoral immunity is mediated by antibodies, which neutralize and eliminate extracellular microbes and microbial toxins.
• It is the main defense against microbes with capsules rich in polysaccharides and lipids.
• The humoral immune response is initiated through antibody-antigen interactions.
• The phases of humoral immune responses include: -Antigen recognition -Activation of B cells -Proliferation and differentiation -Antibody secretion

B-Lymphocyte Antigens

• B-cell antigens specifically interact with an antibody, leading to antibody production and an immunological response.
• These antigens can include biologic molecules
• There are 3 types of B-Lymphocyte antigenic determinants -Conformational determinants which are accessible in native proteins but lost when denatured. -Linear determinants: exposed only when the protein unfolds. -Neodeterminants rise from postsynthetic modifications like peptide bond cleavage.
• Antigen recognition by antibodies involves noncovalent, reversible binding including: -Electrostatic Forces -Hydrogen Bonds -Van der Waals Forces -Hydrophobic Interactions
• The interactions depend on the structures of the binding site of the individual antibody and the antigenic determinant.

Basic Structure of Antibody Molecule

• An antibody monomer has a four-polypeptide subunit structure linked by disulphide bonds.
• The subunits include two identical "heavy" polypeptide chains and two identical "light" polypeptide chains.
• Variable regions differ in amino acid sequences, leading to differences in antibody variable region surface conformation.
• Variable regions contain hypervariable domains at their tips for specific antigen recognition which is used to discriminate between different toxins, like diphtheria and tetanus.
• Structural differences in variable and hypervariable domains enable different antibodies to recognize different structural epitopes.
• The basic classes of antibodies are: -IgM (heavy chain constant region defined as μ) -IgA (heavy chain constant region defined as α) -IgD (heavy chain constant region defined as δ) -IgG (heavy chain constant region defined as γ) -IgE (heavy chain constant region defined as ɛ).
• There are two light chain constant region classes, k and λ, but that do not mediate different antibody effector functions.

Clonal Selection and Expansion

• Naive B lymphocytes in the body can recognize the same epitope.
• Meeting an antigen and a naive B lymphocyte happens through antigen delivery to spleen, lymph nodes, and local lymphoid tissue in mucosal surfaces and skin.
• Proportions of naïve B lymphocytes recirculate from lymphoid tissue through lymph and blood circulations, encountering circulating antigens.
• The subsequent antigen-driven selection of a specific B-lymphocyte clone leads to repeated cell divisions.
• Some daughter cells differentiate into short-lived plasma cells that secrete antibodies of different classes to combat the initial primary antigen exposure.
• Other clonal daughter cells become long-lived B-lymphocyte memory cells populating lymphoid tissue.
• This yields immunological memory to generate a more rapid and pronounced secondary response upon subsequent exposure to the original antigen.
• Clonal selection and expansion to form memory cell populations is the basis of vaccination.
• Initial antigen introduction causes a primary response with a significant latent period before increased serum antibody levels are observed.
• The main antibody response is IgM production, with some IgG synthesized and secreted.
• Secondary response: -Reduced latent period between antigen challenge and increased antibody levels. -Antibody response dominated by IgG, more pronounced with higher serum levels.

Humoral Immune Effector Functions

• Neutralization of antigen by secreted antibody -IgG, IgA and IgM can bind antigen and sterically hinder the interaction of toxins, viruses, bacteria with host cell surfaces. -Secondary response: IgG is the main antibody that fulfils this role -Primary response: IgM is the main antibody -IgA: specific roles in mucosal immunity.
• Opsonization of antigen -Antibody, in particular IgG, opsonizes antigenic material and promote association with phagocyte membranes. -Fc receptor occupancy by the antibody serve to activate a phagocyte’s killing mechanisms.
• Mucosal immunity -Involves the interaction of antibody with antigen at mucosal surfaces like the gastrointestinal tract, lung, or urogenital tract -The major antibody is IgA, existing as a dimer of two monomer units (antigen valency of 4). -IgA will neutralize antigen and may also serve as an opsonin -IgA is present in secretions, but has a limited role in systemic immunity.
• Antibody-dependent cell cytotoxicity (ADCC) -Specific binding to antigen upon membranes perceived as foreign, microbial/virally infected/transformed cells -Antibody can direct association of Neutrophils, Eosinophils, NK cells and cytotoxic T lymphocytes -The antibody's Fc domain binds to the respective Fc receptor present on the surface membrane of the 'killing' cell. -The release of cytotoxic molecules enables efficient and targeted release of cytotoxic molecules -IgG is the main antibody of systemic body fluids and acts as an ADCC mediator, but IgE and IgA may undertake this role in certain circumstances.
• Neonatal immunity -The neonate lacks the ability to mount a full immunological response -Maternal IgG is transported across the placenta late in pregnancy and absorbed across the gastrointestinal tract from breast milk. -Maternal IgA secreted into breast milk provides mucosal protection for the neonate.
• Activation of the classical complement pathway -A complement cascade can be activated through specific antibody-antigen interactions -Initiation requires specific binding of IgG or IgM to antigen. -Complement protein C1 (single C1q subunit, two C1r subunits, two C1s subunits) binds to Fc domains in the antibody-antigen complex. -C1 activation happens through the catalytic activity of C1r and C1s subunits.