Humoral Immunity - Plasma Cells and Memory B Cells

 Humoral Immunity - Plasma Cells and Memory B Cells

Humoral immunity is the branch of adaptive immunity mediated by antibodies (immunoglobulins) produced by B lymphocytes. Its central purpose is the recognition, neutralization, opsonization, and complement-mediated clearance of extracellular pathogens, viruses, and toxins circulating in body fluids (humors).

The process that results in the production of plasma cells and memory B cells can be divided into three stages

·       Generation of mature, immunocompetent B cells (maturation)

·       Activation of mature B cells when they interact with antigen

·       Differentiation of activated B cells into plasma cells and memory B cells.

In vertebrates, including humans and mice, bone marrow generates B cells, which includes an orderly sequence of Ig-gene rearrangements and progresses in the absence of antigen. This is the antigen-independent phase of B-cell development.  A mature B cell leaves the bone marrow expressing membrane- bound immunoglobulin (mIgM and mIgD) with a single antigenic specificity. These naive B cells, which have not encountered antigen, circulate in the blood and lymph and are carried to the secondary lymphoid organs, especially to the spleen and lymph nodes.

If a B cell is activated by the antigen specific to its membrane-bound antibody, the cell proliferates (clonal expansion) and differentiates to generate a population of antibody-secreting plasma cells and memory B cells. In this activation stage, affinity maturation and class switching occur.  Affinity maturation increases the average affinity of the antibodies produced and class switching is the change in the isotype of the antibody produced by the B cell from µ to α, ε, or γ.  Every antigen-activated B cell multiplies and becomes a plasma cell (antibody-secreting cell) or a memory B cell (a long-lived cell ready for rapid activation upon re-exposure to the same antigen).  Plasma cells are terminally differentiated, non-dividing cells that constitutively secrete very large quantities of soluble antibody, providing immediate and sustained humoral protection.  Memory B cells are quiescent cells that persist for months to decades and mediate fast, high-affinity secondary (anamnestic) responses upon re-exposure.  This stage is the antigen-dependent phase of B-cell development.

B-cell development (Kuby Immunology)

B-cell development (Kuby Immunology)

 

B Cells Proliferation in Bone Marrow

The generation of mature B cells first occurs in the embryo and continues throughout life. Before birth, the yolk sac, fetal liver, and fetal bone marrow are the major sites of B-cell maturation; after birth, generation of mature B cells occurs in the bone marrow.  90% of the B cells produced each day die without ever leaving the bone marrow. This is due to negative selection and elimination (clonal deletion) of immature B cells that express autoantibodies against self-antigens in the bone marrow. 

·       B-cell selection begins in the bone marrow with positive selection, where developing cells must successfully assemble a functional B-cell receptor (BCR) that delivers essential, antigen-independent survival signals.

·       Developing immature B cells then undergo negative selection in the bone marrow to eliminate high-affinity reactivity against self-antigens.  Autoreactive immature B cells initially attempt receptor editing to replace their light chains with a non-self-reactive specificity.

·       Cells that fail receptor editing are eliminated via apoptosis (clonal deletion), while those exposed to soluble self-antigens are rendered functionally unresponsive (anergy).  Anergy is a state of immune unresponsiveness in which a lymphocyte remains structurally intact and alive but becomes functionally inactivated and unable to respond to its specific antigen.

·       Immature B cells then migrate to the spleen to be tested against peripheral self-antigens that were not present in the bone marrow. Non-autoreactive cells compete for and receive essential signals from the survival cytokine BAFF (B-cell Activating Factor), which rescues them from default apoptosis and completes their maturation into functional naive B cells.

·       This dual-stage screening ensures that only fully immunocompetent, self-tolerant naive B cells enter the mature lymphocyte pool.  They express membrane-bound, monomeric immunoglobulin — principally mIgM and mIgD which are non-covalently associated with the signal-transducing heterodimer Igα/Igβ (CD79a/CD79b).

 

B-Cell Activation and Proliferation

After export from bone marrow, B Cells reach the periphery and activation, proliferation, and differentiation occur in the presence of antigen. Antigen-driven activation and clonal selection of naive B cells lead to generation of plasma cells and memory B cells. In the absence of antigen-induced activation, naive B cells in the periphery have a short lifespan. They die within a few weeks by apoptosis.

Depending on the nature of the antigen, B-cell activation proceeds by two different routes. one dependent upon TH cells, and the other is not dependent upon TH cells.

(Kuby Immunology)

The B-cell response to thymus-dependent (TD) antigens requires direct contact with TH cells.  Antigens that can activate B cells in the absence of direct participation by TH cells are known as thymus-independent (TI) antigens.  TI antigens are divided into types 1 and 2. Some bacterial cell-wall components, including lipopolysaccharide (LPS), function as type 1 thymus-independent (TI-1) antigens. There are polyclonal B-cell activators (mitogens).  They are able to activate B cells regardless of antigenic specificity. Some TI-1 antigens will stimulate proliferation and antibody secretion by one third of all B cells.  Type 2 thymus-independent (TI-2) antigens are highly repetitious molecules such as polymeric proteins (e.g., bacterial flagellin) or bacterial cell-wall polysaccharides with repeating polysaccharide units.

The response to TI antigens is generally weaker, no memory cells are formed, and IgM is the predominant antibody secreted.  Response to TD antigens involves generation of memory B cells, affinity maturation, and class switching.

Sequence of events in B-cell activation by a thymus-dependent antigen (Kuby Immunology)

Step 1: Antigen Binding and Presentation (Signal 1) - The B cell's surface antibody (mIg) binds the antigen, sending Signal 1 into the B cell. The B cell swallows (endocytoses) the antigen, chops it into peptides, and displays them on its surface bound to MHC Class II molecules.  The B cell increases expression of costimulatory B7 molecules and CD40.

Step 2: Helper T () Cell Activation -  A  cell binds the presented peptide–MHC II complex using its T-cell receptor (TCR). The B7 molecule on the B cell engages CD28 on the  cell, fully activating the helper T cell.

Step 3: Direct T–B Contact (Signal 2) - Once activated, the  cell displays CD40 Ligand (CD40L) on its surface.  CD40L binds to CD40 on the B cell, delivering Signal 2, which moves the B cell out of the resting  phase into .

Step 4: Cytokine Signalling, Proliferation, and Differentiation - The activated B cell expresses cytokine receptors.  The  cell secretes directed cytokines (such as IL-4 and IL-21) directly onto the B cell.  Cytokine binding drives the B cell into DNA synthesis (S phase) and mitosis, resulting in clonal expansion, class switching, and differentiation into antibody-secreting plasma cells and memory B cells.  

Plasma Cells are terminally differentiated, non-dividing effector cells that constitutively secrete high levels of soluble antibody and Memory B cells are long-lived, quiescent cells that persist for years to provide rapid, high-affinity secondary responses upon re-exposure.