B cell activation, differentiation, and contraction

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[00:00:02]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.

[00:00:16]The key cells of the adaptive immune response are the lymphocytes, the B and T cells.

[00:00:22]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.

[00:00:34]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.

[00:00:44]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.

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[00:01:14]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.

[00:01:35]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.

[00:01:45]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.

[00:02:08]There are five major types of heavy chains which encode the isotypes or classes of immunoglobulins.

[00:02:15]IgM, IgD, IgG, IgA, and IgE.

[00:02:22]These five are encoded by heavy chain genes which are referred to by the Greek letters mu, delta, gamma, alpha, and epsilon.

[00:02:32]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.

[00:02:44]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.

[00:03:04]At this point, the B cell is mature but still naive. Having IgD on the B cell surface is 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.

[00:03:27]Once the B cells start to explore the body's lymphatic system, they travel from lymph node to lymph node in search of antigens.

[00:03:37]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.

[00:03:54]When B cells and T cells get into the lymph nodes, they first enter the paracortical region.

[00:04:00]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.

[00:04:10]If a B cell gets activated, it starts replicating within a follicle, and it forms a germinal center.

[00:04:16]And a follicle with a germinal center is called a secondary lymphoid follicle.

[00:04:22]Various antigens enter the lymph node through the afferent lymphatic vessel, and they percolate through the paracortex and through to the follicle.

[00:04:32]It looks a bit like a game of Plinko where the antigens get to interact with a lot of B cells in the follicle.

[00:04:38]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.

[00:04:56]In order for the B cell to be activated, the antigen first needs to bind to and induce the cross-linking of the B cell receptors. When two B cell receptors get cross-linked, their intracellular chains, the side chains, Ig alpha and Ig beta, and CD19 all cluster together.

[00:05:15]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.

[00:05:30]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 NF-κB and NFAT.

[00:05:48]These transcription factors increase the expression of certain cytokines and anti-apoptotic cell surface markers like BCL2, which are required for the proliferation and differentiation of B cells.

[00:06:02]An entirely different alternative way for a B cell to be stimulated is using the molecule CD21, which is also called CR2 because it was the second receptor identified for one of the complement fragments C3D.

[00:06:17]In the complement pathway, a variety of complement fragments are produced, many of which can bind non-specifically to antigens. C3D can bind to an antigen and then be bound by CD21 on a B cell.

[00:06:32]So, if a B cell has a B cell receptor that's bound to antigen, and it also has a CD21 that's bound to an antigen, then that will also initiate ITAM-mediated B cell activation.

[00:06:46]An activated B cell has two goals in mind: to differentiate into a plasma cell and secrete antibody, or to differentiate into memory cells.

[00:06:57]But there are five classes of antibodies that the plasma secrete. So, initially, the B cell will differentiate into an IgM-secreting plasma cell because that's ready to go since it's the basis for the B cell receptor. If, however, an activated CD4-positive T cell is present, it will help the B cell to isotype or class switch to change the isotype of the antibody it produces.

[00:07:24]Isotype switching requires a change in the DNA, and once the B cell switches its isotype, it cannot go back to making IgM again.

[00:07:35]Now, B cells are one type of antigen-presenting cell. So, they present antigen on an MHC class II molecule to a nearby CD4-positive T cell.

[00:07:46]If the T cell gets activated, it will express the molecule CD40 ligand on its cell surface, which binds to CD40 on the B cell surface.

[00:07:56]This causes the B cell to express cytokine receptors and causes the T cell to secrete cytokines instructing the B cell on the type of antibody to start producing.

[00:08:07]For example, if the T cell secretes IL-4 and IL-5, then the B cell will become an IgE-secreting plasma cell. Whereas if the T cell secretes IL-10, then the B cell will become an IgG-secreting plasma cell.

[00:08:23]The primary benefit of heavy chain isotype switching is that it allows the plasma cells to secrete a different antibody class against the very same antigen.

[00:08:34]It also helps to secrete a different antibody based on circumstances.

[00:08:38]For example, IgGs can bind to phagocytes and so are secreted against bacteria or viruses. Whereas IgEs can bind to eosinophils and so are secreted against larger microbes like helminths.

[00:08:54]Now, it turns out that every heavy chain locus, gamma, alpha, mu, epsilon, and delta, has two spare exons. One for membrane coding and one for secretion coding. So, for example, an IgM-expressing B cell, which hasn't undergone isotype switching and isn't a plasma cell, has a constant mu region expressed with membrane-bound exon.

[00:09:21]Once the B cell's CD40 gets bound by the T cell CD40 ligand, an enzyme called activation-induced deaminase or AID gets activated and breaks the intervening DNA removing all of the constant region between the VDJ and the decided on antibody.

[00:09:42]So, as an example, an IgG-secreting plasma cell would be left with the rearranged VDJ region, the IgG region, and the secretion-coding exon.

[00:09:53]Alternative splicing will allow the cell to still have some surface bound IgG and that allows the cell to have antigen stimulation while it produces IgG.

[00:10:04]At this point, the cell is a fully differentiated plasma cell.

[00:10:09]The AID enzyme is also responsible for another key feature of B cell differentiation called affinity maturation.

[00:10:18]The enzyme often makes errors while snipping through the DNA. Sometimes this leaves behind extensive mutations in the VDJ region which encodes for the variable region of the BCR resulting in either an increase or decrease in the B cells affinity for the antigen.

[00:10:35]>> [clears throat] >> Cells with decreased affinity become unresponsive to the antigen and eventually simply stop getting activated. Meanwhile, cells with increased affinity will keep getting stronger and stronger over the generations allowing them to act against even small amounts of antigen.

[00:10:54]Now, plasma cells generated independently of T cells usually live for about 6 weeks and they don't divide.

[00:11:02]If you haven't cleared the antigen by the time the plasma cell dies, new B cells develop into plasma cells to take its place. On the other hand, plasma cells specifically generated from T cell activation develop into plasma blasts or memory cells.

[00:11:18]Plasma blasts migrate into the bone marrow or mucosal tissues and live on for years or even decades producing high affinity antibodies.

[00:11:28]Whereas memory cells live for a few months to years but don't secrete antibodies.

[00:11:33]Instead, they set up tent in the lymph nodes, blood or peripheral tissues ready to spring surprise attacks on unsuspecting antigens entering their territory.

[00:11:46]Now, once the infection is cleared, the immune response contracts which means that the immune system reverts to its baseline state by withdrawing its warriors, the lymphocytes, from the battlefield.

[00:11:58]The B cells are unique in that they regulate their own contraction through a unique mechanism called antibody feedback.

[00:12:05]Towards the end, as there's less antigen around, antibodies, usually IgGs, bind to the residual antigen to form antigen-antibody complexes.

[00:12:16]The antigen portion may be recognized by receptors of B cells specific to the antigen. At the same time, the FC tail of the antigen-bound IgG can bind to special FC receptors present on B cells and that sends a signal inhibiting B cells from differentiating into plasma cells.

[00:12:35]In addition, the elimination of the microbe also leaves the B cells without the stimuli required for their activation. In the end, a B cell that doesn't activate becomes anergic and an anergic B cell won't differentiate into a plasma cell and eventually dies off.

[00:12:53]All right, as a quick recap, when B cells finish developing in the bone marrow, they use alternative splicing to co-express IgM and IgD on their surface.

[00:13:04]If a B cell finds its antigen, the antigen cross-links two B cell receptors and that activates the B cell. If there's no T cell, it differentiates into an IgM secreting plasma cell also using the process of alternative splicing to allow for some of the IgM to be secreted and some to remain surface bound.

[00:13:26]If there is a T cell nearby, the CD40-CD40 ligand interaction combined with cytokines secreted by the T cell help the B cell class switch to produce IgG, IgE, IgA or IgD. Activated B cells also undergo affinity maturation under the influence of CD4 positive T cells.

[00:13:49]Finally, once the infection is cleared, the B cell response contracts due to two things: antibody feedback mainly from IgGs bound to residual antigens and the lack of stimulatory signals needed for the activation of B cells which leaves them anergic.

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