Immunology I - B Cell Mediated Immune Responses

B Cell Mediated Immune Responses

Introduction

• The session covers types and biological activities of antibody classes.

• Two major lymphocyte populations in adaptive immunity:

  • B lymphocytes (B cells)

  • T lymphocytes (T cells)

• B lymphocytes mature in bone marrow and express a unique antigen-binding receptor known as the antibody (B-cell receptor).

• Antigen binding to the antibody causes B cells to divide rapidly.

• Daughter B cells differentiate into:

  • Memory B cells

  • Effector B cells/plasma cells

• Effector B cells/plasma cells secrete a large number of antibodies into circulation, serving as major effector molecules of humoral immunity (B-cell mediated immunity).

Antigens and Epitopes

• Antigens are generally complex structures not entirely recognized by B cells or antibodies.

• Antibodies recognize specific regions on an antigen called antigenic determinants or epitopes.

• Epitopes are the active regions on the antigen that bind to the antibody receptor.

• Antibodies recognize various epitopes on bacteria, viruses, proteins, glycoproteins, polysaccharides, or lipopolysaccharides on invading pathogens.

• The part of the antibody that recognizes and binds to the epitope is known as a paratope.

Antibody Mediated Immune Response

• Antigens (foreign proteins, viruses, bacteria, parasites, fungi) interact with B cells.

• B cells differentiate into antibody-secreting plasma cells.

• Antibodies bind to antigens and facilitate their clearance from the body.

Structure of Antibody Molecule

• The antibody molecule consists of light chains and heavy chains.

• It includes a hinge region and antigen-binding sites.

• The variable portion is responsible for antigen recognition, while the constant portion determines functional properties.

• The light chains can be either kappa (κ) or lambda (λ).

• The heavy chain determines the isotype (IgG, IgA, IgM, IgD, IgE).

• Fab region: Fragment antigen-binding region.

• Fc region: Fragment crystallizable region. Determines functional properties of the antibody.

• Heavy chain: Contains one variable VH domain, followed by a constant domain CH1, a hinge region, and two more constant domains CH2 and CH3.

• Light chain: Contains one variable VL and one constant CL domain. Can be either kappa (κ) or lambda (λ).

Light Chains

• Light chains in the constant region are of two types: kappa (κ) and lambda (λ).

• A single antibody contains either kappa or lambda light chains, but not both.

• If a B lymphocyte generates an antibody with a kappa light chain, it will bear this kappa light chain throughout its lifetime.

Constant Region

• Regions of constant sequence are called C regions: CL on the light chain and CH on the heavy chain.

• The C-terminal fragment is called the Fc region, which determines the functional properties of the antibody.

Antibody Effector Functions

• Antibodies bind to antigens and stimulate immune responses for antigen removal and pathogen death.

• Antibodies do not kill pathogens simply by binding to them; they must stimulate immune responses.

• Effector functions play a major role in humoral or antibody-mediated response.

Humoral Response

• The variable Fab region is responsible for binding to the antigen.

• Antigen binding alone cannot initiate an immune response.

• Antibodies facilitate binding of immune cells/proteins or tissues through the Fc region (constant region of the heavy chain).

• Effective immune response requires both:

  • Binding of antigen to the Fab region

  • Interaction of immune cells/proteins to the Fc region.

Antibody Classes (Isotypes)

• The Fc region of the antibody molecule defines the five antibody classes:

  • Immunoglobulin G (IgG)

  • Immunoglobulin M (IgM)

  • Immunoglobulin A (IgA)

  • Immunoglobulin D (IgD)

  • Immunoglobulin E (IgE)

• Fc region or antibody classes bind to different serum proteins or cell-membrane receptors based on the immune response needed.

• Each antibody class (IgM, IgG, IgA, IgD, IgE) has different functional properties, distributions, and functions in the body.

Immunoglobulin Characteristics and Functions

Immunoglobulin G (IgG)

• Most abundant antibody class in serum (about 80% of total serum immunoglobulins).

• Subdivided into four subclasses based on differences in amino acid γ-chain sequence:

  • IgG1

  • IgG2

  • IgG3

  • IgG4

IgG Subclasses

• Distinguished by:

  • Size of the hinge region

  • Number and position of interchain disulfide bonds between heavy chains.

• Subclasses are more than 90% identical but differ in antigen binding, immune complex formation, complement activation, triggering of effector cells, half-life, and placental transport.

• Main biological activities:

  • Activation of compliment pathway

  • Binding to Fc receptors of phagocytes

  • Crossing the placenta to protect the developing fetus from infectious agents.

• IgG1, IgG3, and IgG4 readily cross the placenta and bind to Fc receptors on phagocytic cells to mediate opsonization.

• IgG1 and IgG3 are involved in the complement activation pathway.

• IgG2: Antibody response against encapsulated bacteria (e.g., Streptococcus pneumoniae).

• IgG4: Allergens are inducers; antibodies are often formed following repeated or long-term exposure to antigens in a non-infectious setting.

Functional Properties of IgG Subclasses

Immunoglobulin M (IgM)

• Accounts for 5%–10% of total serum immunoglobulin, with an average serum concentration of 1.5 mg/ml.

• Secreted by plasma cells as a pentamer held together by disulfide bonds.

• Each pentamer contains an additional Fc-linked polypeptide called the J (joining) chain, required for polymerization.

• First immunoglobulin class produced in a primary response to an antigen and synthesized by newborn babies.

IgM Structure and Function

• Pentameric structure with 10 antigen-binding sites gives it a higher valency (combining power).

• More efficient at activating the classical complement pathway than IgG.

• Due to its large size, IgM does not diffuse well.

Functional Properties of IgM

Summary of IgM Functions

• Increases phagocytosis.

• Participates in agglutination and opsonization.

• Features a significant number of antigenic sites, facilitating efficient immune activation.

Immunoglobulin A (IgA)

• Constitutes 10%–15% of the total immunoglobulin in serum.

• Predominant immunoglobulin class in external secretions (milk, saliva, tears, mucus).

• Exists primarily as a monomer in serum but also in polymeric forms (dimers, trimers, tetramers).

• Polymeric forms of IgA contain a J chain, which facilitates polymerization.

Secretory IgA

• Secreted by epithelial cells of mucous membranes.

• Comprises a dimer or tetramer, a J-chain, and a secretory component.

• The secretory component consists of five immunoglobulin-like domains that bind to the Fc region domains of the IgA dimer.

• Protects IgA antibodies from proteolytic degradation.

• Prevents attachment to the host epithelial surface.

Function of Secretory IgA

• Daily production of secretory IgA is greater than that of any other immunoglobulin class.

• Serves as an important protective barrier at mucous membrane surfaces.

• Active against Salmonella, Vibrio cholerae, Neisseria gonorrhoeae, and viruses such as polio, influenza, and reovirus.

• Cross-links large antigens with multiple epitopes.

• Prevents attachment of pathogens to mucosal cells, inhibiting viral infection and bacterial colonization.

• Complexes of secretory IgA and antigen are entrapped in mucus and eliminated by ciliated epithelial cells or peristalsis.

Functional Properties of IgA

Summary of IgA Functions

• Present in all secretions, including colostrum and milk.

• Crucial for respiratory and gastrointestinal defense.

• Essential for the passive acquisition of immunity by a nursing infant.

• Enhances the effectiveness of lysozyme, particularly against gram-negative bacteria.

• Neutralizes viruses.

Immunoglobulin E (IgE)

• Found in respiratory and gastrointestinal system linings and responds to allergic reactions.

• IgE antibodies mediate immediate hypersensitivity/allergic reactions.

• Exists in extremely low concentration in serum (0.0003mg/ml) but has potent biological activity.

• Binds to Fc receptors on the membranes of blood basophils and tissue mast cells.

IgE Mechanism of Action

• Cross-linkage of receptor-bound IgE molecules by antigen (allergen) induces basophils and mast cells to translocate their granules to the plasma membrane.

• Granules are released into the extracellular environment (degranulation).

• Releases pharmacologically active mediators (such as histamines) into the circulation, giving rise to allergic reactions.

Functional Properties of IgE

Immunoglobulin D (IgD)

• Serum concentration of 0.03mg/ml, constitutes about 0.2% of total immunoglobulin in serum.

• Functions as a receptor on the surface of mature B-cells.

• Involved in their activation and differentiation.

• Serves as a signal for B cells to start the differentiation process.

• No biological effector function has been identified for IgD.

IgD Function

• Acts as a B-cell receptor.

Functional Properties of IgD