B-cell development

Your immune system is like the military - with two main branches, the innate immune response and the adaptive immune response.

The innate immune response is immediate and non-specific, meaning that although it can distinguish an invader from a human cell, it doesn’t distinguish one invader from another invader.

In contrast, the adaptive immune response is highly specific for each invader, and that’s because the cells of the adaptive immune response have receptors that differentiate friendly bacteria and potentially deadly ones from their unique parts - called antigens.

This adaptive immune response takes days to weeks to become activated, but is also responsible for immunologic memory.

Now, the key cells of the adaptive immune response are the lymphocytes- the B and T cells -which are generated during lymphopoiesis.

Lymphopoiesis has three goals - first, to generate a diverse set of lymphocytes - each with a unique antigen receptor, second, to get rid of lymphocytes that have receptors that are self-reactive meaning that they’ll bind to healthy tissue, and third, to allow lymphocytes that aren’t self-reactive to continue maturing in secondary lymphoid tissue.

Normally, hematopoietic stem cells, within the bone marrow mature into a common lymphoid progenitor cell, which then becomes either a B-cell or a T-cell.

To become a B cell, it has to develop into an immature B-cell in the bone marrow and then complete its maturation into an antibody secreting B cell, called a plasma cell, in the lymph nodes and spleen.

To become a T cell, it has to migrate to the thymus and become a thymocyte, where it completes its development into a mature T cell.

So, “B” for bone marrow and “T” for thymus.

Throughout B cell development, the developing cells are interacting closely with the stromal cells of the bone marrow, which are largely composed of mesenchymal stem cells.

Mesenchymal cells are multipotent and can differentiate into various cells including macrophages and endothelial cells.

Mesenchymal cells provide B cell with adhesion molecules they can use to attach and important growth factors like interleukin 7, they can use to grow and proliferate.

As they develop, B cells go through 6 stages: They start as common lymphoid progenitor cells, then become early pro-B cells, then late pro-B cells, then large pre-b cells, then small pre-B cells, and finally immature B cells.

As the cell develops it makes permanent changes in its DNA so that by the time it’s an immature B cell it has DNA that uniquely codes for a B cell receptor that can bind to foreign antigens but isn’t self-reactive.

The B cell receptor has two chains, a heavy chain and a light chain.

The heavy chain contains regions that determine the type of antibody it will become as well as whether the B cell receptor will be surface bound or secreted, like an antibody.

The region where the heavy chain and light chain come together form a unique protein structure capable of binding proteins, carbohydrates, or lipids that the B cell might eventually encounter - and this is called the antigen binding site.

The antigen binding site of the B cell receptor is made up of three protein segments that are called V for variable, D for diversity, and J for joining.

The heavy chain is made up of 1 V segment, 1 D segment, and 1 J segment; while the light chain only contains a V and J segment - this is easy to remember - just think of it as the extra segment making the heavy chain heavier.

Every person inherits multiple genes that encode the V, D, and J protein segments, and these segments can be mixed and matched to make a unique structure.

A bit like how you might have several pairs of shoes, pants, and shirts and can mix and match them to create lots of different outfit combinations.

For the heavy chain, each person has 44 V gene segments, 27 D segments, and 6 J segments! And there are even more V and J segments for the light chain.

So one B cell might have a B cell receptor with a heavy chain that has a VH1-DH3-JH5 combination and a light chain that’s VL7-JL2, and another B cell might have a B cell receptor with a heavy chain that has a VH44-DH10-JH1 combination and a light chain that’s VL2-JL3.

And that would mean that these two B-cells would have completely different B cell receptors and therefore different antigen specificities.

Now, to have a fully functioning B cell receptor, a B cell has to get through a series of successful gene rearrangements, first for the heavy chain and then the light chain. And if the B cell fails at any stage, it dies!

It all starts with a common lymphoid progenitor cell which has various V, D, and J gene segments all lined up in its germline DNA.

Two enzymes, Rag-1 and Rag-2, start getting expressed, and that signifies that the cell is now an early pro-B cell.

Rag-1 and Rag-2 help to splice together D and J segments on both chromosomes, and the chromosome that successfully rearranges first will then suppress the other chromosome from rearranging - a process called allelic exclusion.

If a cell successfully joins a D segment to a J segment, then it’s considered a late pro-B cell.

Next, the late pro-B cell has to attach its D-J gene segment to a V gene segment, with the help of an additional enzyme called V(D)J recombinase.

Once the VDJ segment are combined, the full heavy chain’s antigen binding site is complete and needs to be recombined with the mu gene, which codes for the constant region of the antibody. T

he mu gene codes for the protein that makes the IgM constant region and it’s the first of the different types of antibody constant regions that are expressed on B cells.