B Lymphocytes and Humoral Immune Response

1. What are B Lymphocytes?

• B lymphocytes are a type of white blood cell that differentiates into plasma cells and produces antibodies.

• Pre-B lymphocytes are generated in the bone marrow and complete their maturation within the bone marrow.

• On the surface of B lymphocytes, surface immunoglobulin (SIg) acts as an antigen recognition site and triggers the differentiation process.

2. B Lymphocyte Differentiation

B lymphocyte differentiation involves two main stages:

2.1 Stage 1: Differentiation in the bone marrow

• Bone marrow stem cells → Pre-B lymphocytes (lacking SIg, only IgM in cytoplasm) → Immature B lymphocytes (with SIgM) → Mature B lymphocytes (with surface antibodies SIgM, SIgD, and SIgG)

2.2 Stage 2: Activation and Differentiation into Plasma Cells

• Mature B lymphocytes migrate from the bone marrow to the peripheral blood, and then to the outer cortex of peripheral lymph nodes, the white pulp of the spleen, and lymphoid follicles.

• In this stage, B lymphocytes require antigen stimulation and help from T lymphocytes (for thymus-dependent antigens) to proliferate and differentiate into plasma cells.

3. B Lymphocyte Activation

• Thymus-dependent antigens: B lymphocytes need two simultaneous signals to differentiate into plasma cells that produce specific antibodies:

• Binding of antigen to the surface antibody of B lymphocytes: The antigen activates the BCR receptor on the surface of the B lymphocytes.

• Cytokines produced by activated helper T cells (Th): Th produces cytokines such as IL-2, IL-4, and IL-5 to support B lymphocyte activation.

• Thymus-independent antigens:

• Do not require T lymphocyte help.

• B lymphocytes are activated directly.

• The main antibody produced is IgM, and it does not create immune memory.

4. Humoral Antibodies (Immunoglobulins)

• These are all serum and urinary proteins with antigenic properties and a globulin-like structure, denoted as Ig.

5. Structure of Immunoglobulins

• Each immunoglobulin molecule consists of one or more basic units.

• Each unit is a protein molecule composed of four polypeptide chains:

• 2 heavy chains (H)

• 2 light chains (L)

• The polypeptide chains are linked together by disulfide bridges (S-S).

5.1 Light Chains (L)

• Divided into two parts:

• Constant region (C): Ends with COOH, consists of relatively constant amino acids.

• Variable region (V): Ends with NH2, the amino acid sequence always varies.

5.2 Heavy Chains (H)

• Divided into 5 classes: gamma, alpha, mu, delta, and epsilon, which determine the class of immunoglobulins.

• Each class has specific properties:

• gamma: IgG

• alpha: IgA

• mu: IgM

• delta: IgD

• epsilon: IgE

• Heavy chains are also divided into two parts:

• Constant region (C): Ends with COOH.

• Variable region (V): Ends with NH2, similar to the variable region of the light chain.

6. Enzyme Cleavage of Immunoglobulins

• Papain enzyme: Cleaves the antibody molecule into 3 fragments:

• 2 Fab fragments: Identical, each Fab fragment has only one antigen-binding site.

• 1 Fc fragment: The second half of the two heavy chains, has antigenic properties, can bind to other cells, and plays a role in complement activation.

• Pepsin enzyme: Cuts Ig at a position outside the S-S bridge of the heavy chain, yielding:

• Large F(ab’)2 fragment: Has 2 antigen-binding sites, functions as a complete antibody.

• Small Fc fragment: The end of the heavy chain.

7. Classes of Immunoglobulins

• 5 classes of immunoglobulins: IgG, IgA, IgM, IgD, and IgE

7.1 IgG

• Highest concentration in the blood.

• Divided into 4 subclasses: IgG1, IgG2, IgG3, IgG4.

• Chemical Properties:

• IgG1, IgG2, IgG3 have the ability to activate complement.

• IgG molecules can cross the placenta into the fetal blood.

• The main antibody class in the secondary immune response.

• The exclusive immunoglobulin class against toxins.

7.2 IgA

• Two types of IgA:

• Serum IgA: Circulates in the blood.

• Secretory IgA: Produced by plasma cells in the mucous membranes and has a structure composed of 2 or 3 IgA units, linked together by the J chain and the secretory component Sc of the mucous membrane. It is not destroyed by proteolytic enzymes in the mucous membrane, and it is present in secretions such as saliva, tears, etc.

• It is the local defense mechanism of the mucosal system, preventing antigens from entering the body.

7.3 IgM

• It is a pentamer, composed of 5 basic units forming a star-like shape with 5 points, linked together by the J chain.

• Functions:

• Has a strong ability to bind antigens (10 sites), making it easy to create agglutination reactions.

• It has the strongest complement-binding ability.

• The first antibody to appear when an antigen enters the body.

7.4 IgD

• Found on the surface of B cells.

• Plays a role as a receptor in the maturation and differentiation of B cells.

7.5 IgE

• Occupies the lowest percentage in serum Ig.

• Binds to mast cells and basophils.

• When a specific antigen binds to IgE -> release of chemical mediators from mast cells and basophils like histamine, serotonin -> vasodilation, increased vascular permeability -> redness, swelling in allergies and anaphylaxis.

Note:

• The structure of IgG, IgE, and IgD is similar.

• IgA and IgM have different structures.

8. Biological Functions of Immunoglobulins

• Specific recognition and response to antigens: Antibodies produced by a specific antigen only bind specifically to that antigen. The antigen-binding site of the antibody molecule is located in the Fab fragment, at the end (towards the NH2) of both the heavy and light chains.

• Antigen-antibody binding has the effect of neutralization, reducing the toxicity of toxins, creating an agglutination network with bacteria and fungi, limiting their ability to cause disease.

• Complement activation: The Fc region of IgG1, IgG2, IgG3, and IgM immunoglobulins has a receptor for C1q of complement. When an antigen binds to an antibody, it changes the Ig’s spatial structure -> exposing the complement-binding site, C1q will bind.

• Interaction with other cells:

• IgE, IgG4 can bind to the surface of mast cells and basophils via their receptors with Fc. When the Fab of Ig binds to an antigen -> activates these cells -> releases mediators (histamine, serotonin,…) -> increases capillary permeability, constricts smooth muscle -> antibodies in the blood and phagocytic cells pass through the blood vessels -> the site where the antigen invades.

• Macrophages and neutrophils have receptors for the Fc of IgG and IgM -> antigens that are bacteria coated with IgG and IgM are easily phagocytosed.

• Macrophages and neutrophils have complement receptors -> enhancing phagocytic ability when IgG and IgM are bound to complement.

• NK cells have receptors for the Fc of IgG -> easy access, target cell destruction, antibody-dependent cell-mediated cytotoxicity.