B-cell activation, differentiation, and contraction

The adaptive immune response is highly specific for each invader. The cells of the adaptive immune response have receptors that differentiate one pathogen from another by their unique parts - called antigens. The key cells of the adaptive immune response are the lymphocytes - the B and T cells. B cells develop in the bone marrow where they undergo a process called VDJ rearrangement to generate a massively diverse set of B cell receptors.

The B cell receptor is essentially an antibody except that it has a transmembrane part that goes through the membrane attaching the receptor to the surface of the B cell. The B cell receptor has two heavy chains and two light chains, and the region or fragment of the B cell receptor that binds the antigen is called the fragment-antigen binding or Fab region.

The Fab region is where the ends of the heavy and light chains meet, and there are two Fab fragments on each B cell receptor. The remainder of the heavy chain makes up the fragment-crystalline region, also called Fc, which crystallizes in solution and is also constant or identical in every antibody of a particular type.

The two heavy chains are linked to one another by disulfide bonds, and each heavy chain is also linked to a light chain by a disulfide bond. Each B cell receptor has two identical heavy and light chains, resulting in two identical antigen binding sites. As the B cell develops into a plasma cell, the B cell receptor gets secreted as an antibody with the exact same antigen specificity. However, the heavy chain actually changes as the B cell develops.

There are 5 major types of heavy chains which encode the isotypes or classes of immunoglobulins: IgM, IgD, IgG, IgA, and IgE. These five are encoded by heavy chain genes which are referred to by the Greek letters mu, delta, gamma, alpha, and epsilon.

When a B cell is first developing it initially expresses the mu heavy chain, and as a result all of the B cell receptors are IgMs that are on the cell surface.

When the B cell finishes developing, it undergoes a process called alternative splicing. Alternative splicing is a process by which the cell expresses the heavy chain exons for both mu and delta allowing for both IgM and IgD to be simultaneously expressed on the surface.

At this point the B cell is mature but still naive. Having IgD on the B cell surface is a like a young adult with a driver’s license; they’re able to go out and explore the world – in the B cell’s case, that means all of the body’s lymphatic system - but the cells haven’t been exposed to much and don’t know how they’ll react to foreign antigens.

Once the B cells start to explore the body’s lymphatic system they travel from lymph node to lymph node in search of antigens.

Lymph nodes are scattered throughout your body, and each one is a highly organized structure where millions of B cells, T cells, antigens, and antigen presenting cells pass through every day - like a busy airport.

When B cells and T cells get into the lymph nodes, they first enter the paracortical region. The T cells remain there, while the B cells migrate to the neighboring cortical region of the lymph node, where they form the primary lymphoid follicles. If a B cell gets activated, it starts replicating within a follicle, and it forms a germinal center. And a follicle with a germinal center is called a secondary lymphoid follicle. Various antigens enter the lymph node through the afferent lymphatic vessel, and they percolate through the paracortex and through to the follicle. It looks a bit like a game of plinko where the antigens get to interact with lots of B cells in the follicle. B cells, unlike T cells, can recognize a wide variety of antigens including peptides, carbohydrates, and lipids in their native form, meaning that they don’t require antigen presenting cells to process or present the antigen.

In order for the B cell to be activated, the antigen first needs to bind to and induce the crosslinking of the B cell receptors. When two B cell receptors get crosslinked, their intracellular chains, the side chains - Ig alpha and Ig beta, and CD19 all cluster together. Each of these side chains have something called an immune receptor tyrosine-based activation motif, or ITAM for short. The ITAM is a conserved sequence of amino acids that includes two tyrosine amino acids. Binding of the antigen to the B-cell receptor signals the phosphorylation of these tyrosine molecules, which then triggers a chain of events within the cell that ends with the activation of the major transcription factors - NFkappaB and NFAT. These transcription factors increase the expression of certain cytokines and anti-apoptotic cell surface markers like Bcl-2, which are required for the proliferation and differentiation of B cells.