Study Notes on B Cell Receptor and Immunoglobulin Structure

Basic Structure
- Immunoglobulin is composed of four polypeptide chains:
- Light Chains (LCs): Two small chains with a molecular weight of 22 kDa.
- Heavy Chains (HCs): Two larger chains with a weight of 55 kDa.
- Disulfide Bonds: Connect the polypeptide chains, maintaining the Y-shaped structure typical of immunoglobulins.
- Hinge Region: Provides flexibility to the antibody structure, allowing enhanced mobility of the upper arms and increasing antigen-binding potential.
Chain Classification
- Both chains are classified into regions:
- Variable Regions (V): Responsible for antigen specificity.
- Constant Regions (C): Define the class of immunoglobulin.
- Humans possess two types of light chains:
- Kappa (κ)
- Lambda (λ)
- An individual immunoglobulin can have either:
- Two κ chains
- Two λ chains
- It is important to note that NEVER can there be both types within a single immunoglobulin. (Reference from Janeway, 5th edition, 2001)

Antigen-binding Fragment (Fab)
- The Fab region is integral for antigen recognition, consisting of:
- One constant domain and one variable domain from both heavy and light chains.
- Each immunoglobulin (Ig) molecule has:
- A molecular weight between 150-250 kDa.
- Two identical heavy chains and two identical light chains.
Ig Classes (Isotypes)
- There are five classes of immunoglobulins, determined by the type of heavy chains:
- IgM (μ)
- IgG (γ)
- IgA (α)
- IgE (ε)
- IgD (δ)
- Heavy Chains:
- Each heavy chain has 1 variable region and 3 constant regions (CH1, CH2, CH3).
- Light Chains:
- Each light chain consists of 1 variable region and 1 constant region.

Heavy Chain Structure
- Consists of:
- 1 Variable Region (VH)
- 3 Constant Regions (CH1, CH2, CH3)
Light Chain Structure
- Composed of:
- 1 Variable Region (VL)
- 1 Constant Region (CL)
Fab Region
- The variable regions from the heavy and light chains combine to form the antigen-binding function of the antibody.
- The interaction between these regions leads to the formation of the two Fab portions of each molecule.
Fc Region
- The constant regions C2 and C3 from each heavy chain combine to form a single Fc (crystalline fragment) region.
- The Fc region is responsible for:
- Mediating complement activation.
- Facilitating immune adherence such as phagocytosis.
Hinge Region
- Provides sufficient flexibility that enhances the binding capacity of the antibody.

Light and Heavy Chain Interaction
- Chains are connected through:
- Non-covalent interactions.
- Two disulfide bonds that help promote interaction between heavy chains.
Heavy Chain Types
- There are five types of mammalian heavy chains:
- γ (IgG)
- α (IgA)
- μ (IgM)
- δ (IgD)
- ɛ (IgE)
- Each isotype has unique structural features and functional roles.

IgM (μ): Initial response antibody.
IgG (γ): Most abundant in blood and tissue fluid; important for secondary immune response.
IgA (α): Found in mucosal areas; protects body surfaces exposed to foreign substances.
IgE (ε): Associated with allergic responses and defense against parasitic infections.
IgD (δ): Function mainly as an antigen receptor on B cells.

Gene Locations
- Heavy chains are encoded on chromosome 14.
- Light chains are on:
- Chromosome 22 for λ (lambda chains).
- Chromosome 2 for κ (kappa chains).
Diversity in Heavy Chains
- Generated by:
- Variable gene segments (VH).
- Joining segments (JH).
- Diversity gene segments (DH).
- Maximum diversity possible is calculated as:
- $Diversity = VH imes JH imes DH$
Diversity in Light Chains
- For kappa (κ) light chains:
- Diversity is derived from $VK imes JK$ (no D segment, with one constant region CK).
- For lambda (λ) chains:
- $Vλ imes Jλ$ with a constant region (5Cλ).
Statistical representation of kappa and lambda:
- Approximately 60% of immunoglobulins are kappa, while 40% are lambda.
- Differences between κ and λ containing immunoglobulins are not understood.

Gene Recombination
- Heavy and light chains undergo random recombination for diversity.
- This includes:
- Random joining of V, D, and J gene segments.
- Potential combinations of VDJ are not fully understood due to ongoing gene discovery.
Sources of Diversity
1. Existence of multiple V(D)J gene segments in the B cell germline.
2. Junctional diversity at segment joining sites.
3. Random pairing of heavy and light chains.
Somatic Hypermutation
- Contributes to diversity in antigen recognition after naive B cells encounter antigens.
- Mechanism causes alterations in the V regions during B cell differentiation.
Clinical Implications
- Random rearrangement can lead to autoreactive B cells associated with autoimmune diseases.
- Clonal deletion and receptor editing are mechanisms for eliminating potentially harmful specificities.

Function
- Converts cytidine residues in DNA to uridine residues.
- Involved in:
- Somatic hypermutation
- Class-switch recombination.

Isoforms of Ig Proteins
- Membrane-bound Ig (mIg):
- Contains a transmembrane domain and forms the BCR complex with Igα/Igβ. Displayed on B cell surface.
- Soluble Ig (sIg):
- Secreted by plasma cells (no transmembrane domain).
- Found in body fluids, undergoes modifications to enhance secretion into external body fluids (e.g., tears, mucus).
- Modification Understanding:
- mIg cannot transform into sIg or vice versa; this process is transcriptionally regulated.
BCR Complex
- Noncovalent association between mIg and Igα/Igβ heterodimer (CD79a/CD79b) forms the B cell antigen receptor complex.
- Antigen binding results in intracellular signals being transduced via immunoreceptor tyrosine-based activation motifs (ITAMs).
Igα/Igβ Composition
- Long tails in both chains interact with signaling molecules for B cell activation.
Signal Transduction
- mIg provides specificity for antigen recognition:
- C-terminal of mIg facilitates signaling although it is short, limiting interaction with tyrosine kinases.
- Both Igα and Igβ contain ITAMs which are crucial for signal transduction leading to B cell activation and differentiation.

The B cell receptor is a central component of adaptive immunity that facilitates recognition of antigens and plays a crucial role in the activation and differentiation of B cells, ultimately leading to an effective immune response.