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B Cell Activation (The Basics)

B cells, along with T cells, are lymphocytes that bear antigen receptors that have been randomized for their binding specificity during development (see my earlier post). On the B Cell, the antigen receptor is aptly named: B Cell Receptor, or more commonly, BCR.

Like the T cell Receptor (TCR) on T Cells, the BCR is a transmembrane protein expressed on the plasma membrane, where it can bind by antigen. Unlike the TCR, B Cells are not ‘presented’ antigen by other cells in the context of an MHC molecule. Instead, B Cells ‘see’ antigens in their native state – imagine these as soluble toxins or cell-surface antigens on bacteria of viruses.

APC : T Cell Interaction   vs  Native Antigen : B Cell

Image

Another difference between T Cell and B Cell activation is that T Cells become activated, but do not change their expression of their antigen receptor. B Cells, on the other hand, may react in one of several different ways.  In general terms, this means differentiation into either Memory Cells or Plasma Cells.

Memory B Cells proliferate, but retain their membrane-bound receptors. This makes sense because the purpose of these cells is to lie in wait until antigen is seen again, so they need their receptors to ‘see’ it.

c18Plasma cells lose their membrane-bound receptors, but continue to express the same molecule in a soluble form called Antibody. In fact, they grow in size and fill with ER and Golgi Apparatus to handle the extreme output of protein that they begin producing (~2000 molecules / sec according  to  Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002. ).

ImageAntibody comes in a number of varieties, but all share a similar core structure as the one pictured to the right. It consists to two heavy chains and two light chains, creating two unique binding sites for antigen.

Events following B Cell Activation

Once cells become activated, they may either immediately become short-lived plasma cells (SLPCs) that secrete antibody identical to the BCR for a short time and then die off, or they may enter into Germinal Center (GC) Reactions. In the GC, B cells get T Cell help and compete for antigen in a poorly understood manner whilst undergoing hypermutation of the BCR’s antigen-binding site.  This results in BCR / Antibodies with higher affinity (greater binding ability) for antigen that may then differentiate into either Long-Lived Plasma Cells (LLPCs) of memory cells. These several differentiation paths can be seen in the illustration below.

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To Summarize:

1. B Cells are activated as a result of crosslinking BCRs by native antigen

2. B cells do require help from T Cells to enter germinal center reactions and produce LLPCs and memory cells (although getting help was not discussed here)

3. B cells become activated and either start producing antibody right away as SLPCs or enter genrminal center reactions.

4. Once in a germinal center, B cells undergo hypermutation of the antigen-binding section of  their BCR/Antibody.

5. Following the GC reaction, B cells bearing high-affinity BCR/antibody will differentiate into LLPCs or memory cells.

 
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Posted by on May 12, 2013 in Uncategorized

 

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A quick description of Lymphocyte Development and Activation

Lymphocytes Development and Activation

Lymphocytes (B cells and T cells – we’ll not talk about NK cells here) go through a generalizable sequence of maturation events. Each starts in the Bone Marrow (BM) as a Hematopoietic Stem Cell (HSC), where it starts its development. T cells leave the BM relatively sooner and go to the Thymus, while B cells remain in the BM for most of their development and then finalize development in the spleen.

 Positive Selection for BCR/TCR Development

Regardless of the type of cell (T or B), development occurs in two stages – First, each cell will attempt to make a unique lymphoid receptor (B cells have a BCR; T cells have a TCR). In order to do this, genetic material must be shuffled. While this shuffling does randomize the binding pocket of the lymphoid receptor, it may also destabilize these same receptors’ structure. To account for this, lymphocytes undergo a ‘positive selection’ period that ensures that a viable receptor is formed. This is actually done twice: once to ensure that a ‘Pre-Lymphoid Receptor’ is formed and again to for a ‘Mature Receptor.’  However, both are considered positive selection. Failure to pass this selection point leads to death of the cell. (In the figure below, Pre-Lymphocyte receptors are colored red, mature receptors are grey)

Negative Selection Against Self-Reactive BCR/ TCRs

Once cells have survived positive selection, they are considered Immature Lymphocytes. Although the terminology is poor here, these immature cells have mature lymphocyte receptors. At this point, these receptors have to be tested against all possible ‘Self ‘- antigens. In this case, binding means that these cells have the potential to react against the self – this is a no, no. The Immune System turned against the self is extraordinarily dangerous. Therefore, self-reactive cells are eliminated during this negative selection process. (In the figure below, mature lymphocytes have grey nucleus, all prior stages have red nuclei).

LymphosFollowing these developmental stages, the cells that have survived both positive and negative selection are 1) stable, mature lymphocyte receptors and 2) not reactive to ‘self’. These cells then enter the immune repertoire for that organism and are available to react against any foreign threats. Again, it is important to emphasize that each lymphocyte has a unique receptor and therefore will only get activated by a unique foreign antigen.

I may write more later to discuss some of the details that distinguish B and T cell development, but for now, this generalizable description will suffice.

Clonal Selection

Once a part of the immune repertoire, lymphocytes are on the lookout for foreign antigen that is capable of being bound by that cell’s receptor. Depending on the cell type, this interaction may be in one of several contexts (either in the context of MHC I, MHC II or as a naïve, soluble antigen), but regardless of the context, these ‘naïve’ lymphocytes will become activated by binding of their lymphocyte receptor. And once activated, lymphocytes will proliferate and differentiate. Differentiation typically goes in one of two general directions:

1)   generating activated effector cells (these secrete antibody if B cells, kill target cells, if CD8 T cells, or become helpers if CD4 T cells)

–or-

2)   generating memory cells, cells that act the same as the mature naïve cell that was activated, but are more numerous and can, themselves be activated upon stimulation.

An example of this activation is shown below in this HHMI video about how CD8 T cells can be stimulated to activate and then kill any target cells. This video also does a good job of illustrating how antigens get digested within a cell and expressed in the context of MHC I.

http://www.hhmi.org/biointeractive/media/antigen_ctl-lg.mov

 
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Posted by on April 25, 2013 in Uncategorized

 

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Enzyme Regulation Animation

 
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Posted by on September 18, 2012 in Uncategorized

 

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