Humoral Immune Response

Let's get pumped for a little bit more on B-cells!

Describe primary and secondary immune response

I've mentioned the primary and secondary immune response in an earlier post for PHGY350, but now I'll be going into a tiny bit more detail.

In the primary immune response (i.e. the response following the first encounter with an antigen), it's mainly naïve mature B-cells that are responding. They secrete IgM, because naïve B-cells just have IgM and IgD (as you might recall from learning about the generation of B-cells). It takes several days for a decent amount of antibodies to form, so there is a lag phase associated with the primary immune response. Further into this immune response, there may be some class-switching, allowing the generation of some IgG. As an added bonus, cells containing IgG may have undergone somatic hypermutations (affinity maturation), possibly allowing for an increase in antibody effectiveness. (Affinity mutation is associated with class switching due to both processes using the same enzyme.) Memory cells are created following the primary immune response.

In the secondary immune response, memory cells are the first to respond. Due to the presence of these memory cells, there is a significantly shorter lag time. A majority of the antibodies that are produced in this response are IgG, rather than IgM, and have a higher affinity for the targets as compared to the antibodies of the primary immune response.

Describe the mechanism of B-cell activation and antibody production

B-cell activation usually requires the help of a T-helper cell. The process is kicked off by a B-cell endocytosing an antigen and presenting it on MHC-II to a T-helper cell, usually in secondary lymphoid organs such as the spleen and lymph nodes. There are three main signals in this process:

1. Antigen binding to the membrane antibody. This causes the Igα:Igβ heterodimer to kick off the signalling cascade, ultimately leading to an increase in MHCII and B7 expression. Once this signal is initiated, the endocytic pathway of antigen presentation occurs, resulting in a peptide presented on MHC-II, which the T-helper cell can recognise.
   When the T-helper cell recognises the peptide bound to MHC-II, and B7 on the B-cell binds to CD28 on the T-cell (if these sound familiar, that's because I mentioned them on the T-cell post), the T-helper cell is activated and formation of CD40L (CD40 ligand) on the T-helper cell membrane is induced.
2. CD40-CD40L interaction. This activates the NFκB transcription factor, ultimately leading to the expression of cytokine receptors on the B-cell.
3. Cytokine binding. Cytokines then bind to the newly-formed receptors on the B-cell, inducing B-cell proliferation (a.k.a. clonal expansion, since you're creating lots of clones of a B-cell) and differentiation (into antibody-secreting plasma cells or long-lasting memory cells), as well as other processes such as class switching.

It's important to note that not all cytokines have to come from T-helper cells. Cytokines may come from a range of cells, including macrophages and dendritic cells.

Cytokine Secretion

Let's backpedal a little and talk about cytokine secretion. One interesting thing about secretion of cytokines is that it is directional- that is, the cell isn't just spewing them all over the place, it's actually aiming at something. But how does it do that?

To put it simply, it mainly boils down to the organisation of organelles and molecules within the cell. The important ones to know here are MTOC (microtubule-organising centre, where microtubule skeleton proteins are produced), the Golgi apparatus and talin (a cytoskeletal protein). When the T-helper cell is activated by the B-cell, not only does it produce IL-4 and CD40 ligand, but it also begins to line up MTOC, the Golgi apparatus and talin so that the cytokines will travel through these and be released close to the point of contact between the two cells.

Class Switching

Yes, I know, I've spoken about class switching before. But stay with me, because I have some different things to say about it now.

Different cytokines can induce different transcription factors. For example, IFN-γ can induce STAT1. In combination with the CD40/CD40L pair, which induces NFκB in the B-cell, cytokine binding can result in class switching. You see, the transcription factors produced (STAT1 and NFκB) can bind to a promoter region upstream of a switch site, allowing class switching to occur. (If you don't remember switch sites or anything about class switching, please check out my earlier post on the topic.)

Here's a few cytokine-transcription factor-immunoglobulin class pathways that you need to know:

• IFN-γ -> STAT1 -> IgG
• IL-4 -> STAT6 -> IgE
• Cytokines in mucosal tissues, such as TGF-β -> IgA

Describe T-cell independent antigens

So far we've been talking about T-cell/thymus dependent (TD) antigens, which only activate a B-cell when presented to a T-helper cell on an MHC molecule. There are, however, thymus independent (TI) antigens, which do not require the help of a T-helper cell. There are two main types of TI antigens, so let's go over them one at a time:

TI Type 1

TI type 1 antigens are mitogens- that is, agents that induce proliferation, including lipopolysaccharide (LPS). These bind to mitogen receptors, such as LPS-binding TLR4. Sometimes, a BCR might also help to bind these antigens. Binding of TI Type 1 antigens can stimulate many B-cell clones, including those that do not have BCRs specific for the antigen. (B-cells that have specific antibodies, however, are more likely to be also activated by the TD antigen pathway, leading to upregulation of mitogen receptors, which in turn leads to preferential secretion of specific antibodies.) Most antibodies produced in response to these antigens are IgM, and usually no memory cells are formed.

TI Type 2

TI Type 2 receptors are generally larger things, like capsulated bacteria. They have repeating identical epitopes, which can cause BCRs to bind and cross-link. (PRRs and other mitogen receptors are not involved here.) Sometimes dendritic cells and macrophages might come along and help out by releasing other cytokines like BAFF, inducing class switching. (This is in contrast to binding by a Type 1 antigen, in which class switching generally does not occur.) Memory B-cells can be formed as a result of binding by Type 2 antigens.

And that's the last post covering the content of next week's midterm! Good luck!