Immunoglobulin Structures & Functions

Immunoglobulin Structures & Antibody Functions

• Immunoglobulins, or antibodies, have a structure and function intimately linked.
• Antibodies have two key functions: recognizing antigens and activating effector mechanisms to eliminate antigens.
• Antibody recognition sites differ between antibodies, making up the variable region (V region).
• Antibodies of the same class (isotype) trigger identical effector mechanisms through their constant region (C region).

Ig Structure

• Antibody molecules are Y-shaped, composed of two heavy (H) and two light (L) polypeptide chains connected by disulfide bonds.
• The molecular weight (MW) of antibodies is roughly 150 kDa. The heavy chains are about 50 kDa and the light chains are about 25kDa.
• Light chains can be either kappa (κ) or lambda (λ) in type.
• In humans, the ratio of κ to λ light chains is roughly 2:1. In mice, it’s approximately 20:1.
• The constant region (C region) of heavy chains determines the antibody class.
• Heavy chains (μ, δ, γ, α, ε) specify class – IgM, IgD, IgG, IgA, IgE.

Ig Structure - Domains

• Each antibody chain consists of repeating units of approximately 110 amino acids. The antibodies are made of structural domains, both within the heavy and light chains, that are defined by specific sequences of amino acids. Further substructure has been identified in the chains.
• The N-terminal domains are highly variable in sequence and are labeled V₁ (heavy chain variable) and V₂ (light chain variable).
• C-terminal domains (CL, CH1, CH2, CH3), are constant for each isotype, forming the C region of the antibody molecule.
• V and C domains create similar structures with beta-sheets arranged like a beta-sandwich. These beta-sandwiches are stabilized by disulfide bonds.
• V regions have specific, hypervariable regions (HV1-3) within the antigen binding sites (Fab) which mediate antigen recognition. The framework regions (FR) are less variable. The amino acid sequences within the HV1-3 regions vary significantly, and account for much of the variability between unique antibodies. The antibody binding site is formed by associating the light and heavy chain variable domains in specific configurations.
• The immunoglobulin fold, found in many proteins like immunoglobulins and T cell receptors, utilizes these 4-strand and 5-strand structures. This fold is critical for maintaining the antigen-binding site's function.

Antigen Binding Sites

• The antigen-binding site is composed of the V regions of the heavy and light chains.
• The hypervariable regions (HV1-3) of the V domains are key to the high variability in specificity and affinity between antibodies, making up the complementary determining regions (CDRs) or antigen contact regions.
• The framework regions (FR1-4) form the beta-strand structure.
• The hypervariable regions (HV1, HV2, HV3) are collectively termed complementarity-determining regions (CDRs) as they form a surface for antigen interactions.
• The combination of different heavy (H) and light (L) chains leads to the vast diversity of antigen-binding sites, called combinatorial diversity. An antibody that binds to an antigen often has unique CDR regions for that antigen contact.
• The interactions between antibodies and antigens are driven by different topological and chemical factors.

Antigen-Antibody Interactions

• The part of an antigen that an antibody attaches to is the epitope.
• Epitopes can be continuous or discontinuous amino acid sequences on the antigen surface.
• Covalent or non-covalent interactions, such as ionic, hydrogen, hydrophobic, and Van der Waals forces, stabilize antigen-antibody interactions.
• B cells bind to various molecules like proteins, carbohydrates, and small molecules.

Antibody Function – Classes

• There are five antibody classes (isotypes): IgM, IgD, IgG, IgA, and IgE, each with different functions and properties within the immunology system.
• Class differences relate to constant region sequences, number of constant regions, location and number of disulfide bonds, and presence of different glycans.
• IgG is the most abundant in serum and extracellular fluid (∼80%). Specific subclasses of IgG (IgG1, IgG2, IgG3, IgG4) vary in structure in terms of hinge regions and the number/location of disulfide bonds within the molecule structure. Individual subclasses have their own unique functions regarding pathogen clearance and interactions with the immune system. Different antibodies have varying degrees of functionality in terms of activating complements and opsonizing pathogens.
• IgM is the primary class of antibodies in the primary adaptive immune response and is the largest immunoglobulin. It circulates as a pentamer (five linked Y-shaped structures).
• IgA is predominant in external secretions (mucosy membrane functions).
• IgE antibodies attach to mast cells and basophils, playing a role in allergic reactions.
• IgD is involved in B-cell activation.

Antibody Responses

• There are three types of antibody responses:
  • T-cell-independent (TI) response: a rapid, innate-like response to repetitive antigens, predominantly producing IgM antibodies.
  • Early T-cell-dependent (TD) response: produces a higher affinity antibody response involving marginal zone and follicular B cells.
  • Germinal center reaction: a secondary antibody response that involves a germinal center within B-cell follicles, resulting in long-lived plasma cells secreting highly specific antibodies.

Humoral Response

• The primary response involves naive B cells, producing IgM.
• The secondary response is more rapid and produces higher IgM and IgG responses with higher affinity.

This quiz explores the critical structure and functions of immunoglobulins, or antibodies. It covers their Y-shaped composition, the functions of different regions, and the differences in light chains among species. Test your knowledge on how antibodies recognize antigens and activate immune responses.