B cell differentiation

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Introduction

B-cell differentiation - B. Catchpole, RVC 2008

Mature B cells that undergo stimulation by an antigen undergo class switching, and differentiate into either plasma or memory cells.

In the paracortex region of lymph nodes binding to MHC II and the presence of Il-4 produced by CD4⁺ T cells (Th2 type) causes B cells to differentiate. Most B cells become plasma cells, however small number become memory cells .

Antigen Presentation by Follicular Dendritic Cells

Follicular dendritic cell are present in the follicles. They absorb the whole of the antigen onto their surface to present to B cells to stimulate an immune response.

Plasma cells

Appearance

Plasma cells are oval, around 9µm and have a round prominent nucleus. The cytoplasm is extensive and stains strongly basophilic. It contains large amounts of rough endoplasmic reticulum and the Golgi apparatus is large and appears as a clear crescent-shaped structure near the nucleus. Some plasma cells accumulate considerable quantities of, perhaps abnormal, antibody and this appears as a large eosinophilic blob filling the cytoplasm and displacing the nucleus to one side. These blobs are called "Russell Bodies".

Function

Plasma cells produce immunoglobulins/antibodies (thousands a second). The immunoglobulin binding specificity is identical to the binding specificity of the BCR on the B cell that the cell has differentiated from. This means that when a B cell has a BCR that can effectively bind to an antigen the immunoglobulins produced by the plasma cell can bind to that antigen.

Although they can live for months most plasma cells only live for a few days and do not replicate in this time.

Interaction of a B-cell with antigen results in clonal expansion, as does activation by T-cells. The majority of B-cell clones mature into plasma cells. Plasma cells are found in the splenic red pulp, lymph node medulla and bone marrow. Plasma cells are the terminal differentiation state of B-cells. They migrate to the medullary cords where their whole function is to secrete antibody.

Class switching

Initially plasma cell produce IgM however this is not always the most appropriate Ig to be produced and therefore stimulation by T cells and interleukins causes the plasma cells to undergo class switching to produce different classes of Ig.

• In mucosal B cells plasma cells CD40 interaction (with Th2 CD40L) and Il-10 stimulates class switching to IgA
• Eosinophils produce Il-13 which promotes class switching to IgE

Plasma cells produced in the first immune response to an antigen are mainly of the class IgM whereas those produced from memory cells in the second immune response are mainly of the IgG class.

For more information on class switching click here

T-Cell Dependent and Independent Responses

There are two types of B cell response to antigen. The T cell independent response does not require T cell help and the T cell dependent response does require T cell help.

T-Cell Independent Response

Diagram of the T Cell Independent Repsonse - Copyright nabrown RVC

• Does not require T cell help
• Activation of B cells by non-protinaceous antigens
  • E.g. Activation by lipopolysaccharides only lead to IgM production
  • Act as mitogens for the B cells by stimulating cell division
• Antigens only stimulate primary immune responses (production of IgM)
• Do not stimulate memory cells
• There is no diference between the antibody response of the first exposure compared to sunsequent eposures of antigen

T-Cell Dependent Response

Diagram showing the T cell dependent response (primary and secondary phases) - Copyright nabrown RVC

• Response to protinaceous antigens
• Needs T cell help to respond appropriately
• Response occurs in germinal centres of follicles in secondary lymphoid tissues
• B cells act as antigen presenting cells on MHC II
• T cells interact via cell surface receptors with B cells
  • CD40L on the T cell
  • CD40 on the B cell
• T cells produce cytokines
  • E.g. IL-4
• Class switching occurs from IgM
• Memory B cells are formed

Primary T Cell Dependent Response

• The first exposure of an individual to a particular antigen is referred to as priming
• The measurable antibody response is called the primary immune response
• Delay of 5-7 days before antibody is produced which is called the Lag Phase
• B cells undergo cloanal expansion and form plasma cells
• IgM antibody is produced first and will begin to appear in the blood. This stage is called the Log Phase
• The log phase will peak after about 10-14 days
• The Plateau Phase will then occur
• Class switching occurs replacing decresing levels of IgM with IgG
• Antibody levels will then begin to decline as plasma cells undergo apoptosis
• After primary immunisation, it usually takes around 7-10 days for a measurable antibody response to become detectable
• This latent period is the time necessary for the antigen to contact specific cells, for the cells involved to interact and expand, and for plasma cells to secrete antibody
• The first antibody to be produced in any immune response is IgM
  • This is because the gene that codes the constant domain of IgM (Cμ) is directly downstream to the genes that code the variable antibody domain
• During primary response, IgG production lags about a week behind that of IgM

Secondary T Cell Dependent Response

• The production of antibody to any antigen ceases within a few weeks of immunisation as the antigen disappears from the body
• However, the animal retains immunological memory of the antigen
• Occurs after the primary response, i.e. the second and subsequent exposures to the specific antigen
• There is an expanded pool of memory B and T cells from the first exposure to the particular antigen
• Shorter lag phase
• Longer plateau phase as antibody persists
• There is a higher antibody titre overall due to cloanal expansion
• Long-lived memory cells which are qualitatively distinct are produced
• Retention of antigen within the immune system
  • On the surface of follicular dendritic cells
  • Can stimulate the immune system for years
• The level of IgM antibody production is similar to the primary response
• The increase in antibody production occurs with IgG

In pathology

• Plasma cell tumour

Memory cells

The differentiated cells that remain in the cortex become memory cells and these proliferate and form germinal centres in the lymph node.

Memory cells are long lived and responsible for long term immunity providing the immune system with a memory of previously encountered antigens. When they experience an antigen again they proliferate and differentiate into plasma cells. This response produces up to ten times more plasma cells than the original exposure to the antigen and is why the second immune response to an antigen is both more rapid and much stronger than the first response.

Links

T Cell Development

Lymphopoiesis

Immunoglobulins

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