Signals for B cell activation in antibody response

Zhang, Yang (2010). Signals for B cell activation in antibody response. University of Birmingham. Ph.D.

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Abstract

Germinal centres (GCs) are the sites where V-gene hypermutation and B cell selection are taking place. Testing specificity and affinity of GC B cell receptor by interaction with antigen on follicular dendritic cells (FDCs) may be an important selection process to select high affinity B cell clone. As antigen on FDC is present in the form of antigen-antibody immune complex, GC B cells are expected to have to compete with antibody to get access antigen. Initially this antibody will be of low affinity. However, during the course of an immune response, this affinity may increase. We have tested this competitive selection model by following the replacement of antibodies in the GC over the course of an immune response. The speed of this replacement is dependent on affinity. Antibody added during an ongoing GC reaction can replace antibody in the GC, but only, if it is of high enough affinity. Presence of high or low affinity antibodies on FDC influences centrocyte selection, leading to variations in apoptosis within the GC, serum affinity, and plasma cell output. Parallel in silico experiments support the idea that a dynamic GC selection threshold, dependent on the affinity of GC output cells increases affinity maturation, because it enhances selection efficiency over a longer period during the course of a GC reaction. A dynamic selection threshold may explain the termination of the GC reaction, when affinity of new B cell variants is not sufficient to overcome the affinity of antibodies produced outside the GC. IRF4 is essential for the plasma cell differentiation and Ig class switch. IRF4 mRNA and protein rapidly upregulate within one hour after naive B cells get stimulation with NP-Ficoll in QM×C57BL/6 mice, and then activated B blasts expressing intermediate level of IRF4 either go into the red pulp to form the early extrafollicular response by upregulating high level of IRF4, or travel into the follicle to differentiate into GC founding cells. IRF4 completely shuts down when cells becomes proliferating centrocytes. But IRF4 expresses again in centorcytes, which have been committed to differentiate into the plasmablasts. Its high level expression shows the GC emigrants. Here IRF4 is selected as the marker for the early plasmablats appearance on the GC-T zone interface at the beginning of the GC reaction. And further experiments by using cytokines such as IL-6, IL-10, IL-21, costimulatory signals OX40, CD30 deficient mice show that these signals can affect the development of these early IRF4\(^+\) plasmablasts on the GC-T zone interface in the TD antigen response.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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