So, this week was apparently proclaimed ‘Vaccine Awareness Week’ by the authority of fringe medicine practitioner Joseph Mercola and Barbara Loe Fisher (co-founder of the infamous National Vaccine Information Center).
This seems to be but a stunt from two rather prominent anti-vaccine activists, but, it gives us at She Thought, a nice opportunity to delve into the subject of vaccination, a subject dear to skeptical hearts and one made topical by both this year record pertussis epidemic (the highest incidence rate in 50 years) and the looming flu season… So, let me open what could become a week of vaccine frenzy with a short (maybe) run-down focusing for today on the mechanisms behind generating the humoral component of the specific immune response that vaccines target.
F*cking acquired humoral immunity –part 1, origin of the immunoglobulin.
Vaccines work by taking advantage of the natural mechanisms for acquired humoral immunity. Basically, our genome contains three loci of genes (two of these loci codes for what is called the light chain of the immunoglobulin while the third one codes for the heavy chain).
This heavy chain is composed of three main regions of interest: the V, the D and the J region (V stands for ‘variable’, D for ‘diverse’ and J for ‘joining’). Interestingly, each region contains multiple slightly different of the same segment (a bit like ACDC discography). For example, we have a bunch of ‘V’ segments following each others, and then a bunch of ‘D’ segments and finally a handful of J segments (in total, we have 65 copies of the V segment, 27 of the D and 6 of the J segment).
The light chains are pretty similarly organized but lack the D segment.
Now, there is a group of immune cells referred to as ‘lymphocytes’. During their maturation process they undergo what is called ‘somatic recombination’ and, simply put it consists of the elimination of all but one segment of each kind, hence generating a random sequences of this segments. In addition, random nucleotides are added in the process at the VDJ joint, thereby, increasing the diversity even further.
Thankfully, Wikipedia provided us with a nice little diagram of the process (cf. figure 1):
Figure 1: Somatic recombination, thanks to gustavocarra for Wikipedia common.
The immunoglobulin molecule is then assembled using two light and two heavy chains, assembled together by disulfide bonds (cf. figure 2) in such a way that the highly variable region created by the somatic recombination in each chain stick together in two regions called, quite unsurprisingly, ‘variable region’.
Figure 2: The structure of the immunoglobulin molecule.
This process is a veritable machine to create diversity. The recombination of random version of the multiple segments, itself, will produce about 3 million different possible combinations; introduce the additional layer of random nucleotide insertion and the number of possible variable regions jump to an astonishing estimated 1016…
Each cell will only produce one type of antibody with its own particular sequence, but, taken together, this amazing diversity insure that, whatever molecules are expressed by the pathogen entering the body at any given time, there will be a lymphocyte expressing just the right antibody to match it…
By the way, these molecules, that the pathogen expresses and the immune system ‘recognize’ are called ‘antigens’. Because pathogens express more than one type of antigen, the various antigens expressed, taken together, is referred to as the ‘antigenic profile’.
F*cking acquired humoral immunity –part 2, enter the antigen.
At this stage, the immunoglobulin produce stay stuck on the surface of the cell that produces them. That way it ‘recognizes’ the antigens it corresponds to. However, because these molecules are so specific, the odds of a circulating leukocyte to encounter its corresponding antigen are very low (it is estimated that, for one specific antigen, less than one in 10,000 or one in 100,000 lymphocyte will recognize it).
However, these lymphocytes also re-circulate between secondary lymphoid organs (spleen, lymph nodes and discrete location around the gut and respiratory track (GALT and BALT, respectively). When a cell of the non-specific immune system (which is not as picky and is quite likely to identify any given antigen) capture one such antigen, it migrates to the secondary lymphoid organ to present it to the lymphocytes. Because, as mentioned, lymphocytes congregate in these organs, the odds of finding one matching any given antigen are drastically increased.
Upon presentation of a matching antigen, B-cells are activated, they will maturate into plasma cells and some of them will start producing a first wave of antibodies, called IgM (cf. figure 3).
Other will form what is called ‘germinal center’ in which there will undergo somatic hypermutation, essentially, one more step of point mutations. This can either increase or decrease the strength of the binding to the presented antigen, the ones in which the strength of the binding is decreased enter programmed cell death, so this process allows for the production of cells with yet even more specificity to the antigen. Then, they will switch to a different class of antibody, called IgG (cf. figure 3). These are both smaller and more specific and constitute the main thrust of the specific immune response.
Another thing that takes place in the germinal center is a clonal expansion of the plasma cells. There the cells that, as we have said, had already been selected to be highly reactive to the infection taking place, greatly multiply in number. Among the cells produced are memory B-cells. These will then move in the bone marrow when they will where they will survive for several years (estimates for the duration of circulating plasma range from only a few days to a few weeks)…
Figure 3: The two main types of antibodies.
As we have seen, mounting the adaptive immune is a complex process and it is also quite slow. Generally, it takes between ten days and a few weeks (a couple of weeks in average) for the body to mount an effective specific immune response.
But after this, the body will have a stock of highly specific memory cells remaining so that, if the same antigen is encountered a second time, the immune response will be able to by-pass these steps and will start chucking out antibodies much faster…
This is particularly important as the first days of the infection are the most critical: the pathogen’s numbers are at their lowest but, because the body immune’s response is as it’s weakest; they are also increasing at their fastest rate.
By cutting this response time, the body is therefore able to counter the pathogen before it was able to establish an infectious beachhead…
What about vaccines?
You’ll notice that, when describing the mounting of the immune response in part two, I used the term antigen but never mentioned the actual pathogens it is normally attached to… That’s not an accident, because any molecules that trigger the immune system will be processed through this process. Whereas an actual pathogen or not, active or not, virulent or not, the basic mechanism behind the immune response will be the same.
There are subtleties, of course, as I mentioned, this is for what is called the ‘humoral’ response, there is whole other arm to the immune response (but it is simpler and we will go over that in later and hopefully shorter post) and I completely avoid mentioning the different compartments of the immune response (again, next post). But right now, it seems about enough information so, my friends, that’s all for today…