2015-07-04 09:19:59
Most of the antibodies produced initially are not very effective in defending ourselves
I still remember that yesterday, that first popular article that I wrote, back in 1998 of the last century, which dealt with the wonderful mechanism of the generation, through the method of “shuffling” genes, of antibody molecules. Let us remember that antibodies are defense proteins produced by a special class of white blood cells, called B lymphocytes.
Antibodies are extraordinary molecules for several reasons. The most important thing is that, despite having a common structure, they are capable of binding and neutralizing practically any substance that is or may be found in the future in Nature. Yes, yes, even substances that do not exist today, such as new drugs that will be synthesized in the next decade, may be susceptible to generating antibodies that will mediate allergic reactions to said drugs.
The generation of a gigantic variety of antibodies allows the immune system to defeat both present and future disease threats. As I explained in my first article, the way B lymphocytes achieve this molecular feat is by randomly combining a series of DNA fragments. In the same way that with a Spanish deck of 40 cards an enormous variety of sets of three or four cards can be obtained, randomly joining two to four DNA fragments from a set of between 70 and 80 genetic fragments results in the generation of a formidable repertoire of antibody genes. Since the binding of gene fragments is carried out in each B lymphocyte in a random manner, and since there are hundreds of billions of B lymphocytes, antibodies are generated capable of binding to any molecular structure that can be imagined.
Not all possible antibodies are produced at all times. For a B lymphocyte to begin producing large amounts of a particular antibody against a substance, normally present in a virus or bacteria, it must first detect it, which it achieves through the antibody molecules it carries in its membrane, and which moment they are not secreted into the blood. Only upon detection of a potentially harmful substance, B lymphocytes are activated and begin to produce antibodies in large quantities and release them into the blood.
However, if B lymphocytes are capable of generating antibodies against any molecule, this does not mean that all antibodies generated are capable of binding strongly to the substance they detect. Most of them will only bind weakly (in scientific language, with low affinity), that is, they will have little tendency to neutralize the foreign substance. This problem means that most of the antibodies initially produced are not very effective in defending us against attacks by microorganisms or parasites. It is, therefore, imperative to increase their effectiveness, which can only be done by increasing their affinity, that is, the strength with which they bind to foreign molecules. Can B lymphocytes achieve this?
If you can.
Directed mutations
To understand how they achieve this, it is necessary to focus on the fact that antibodies bind to foreign molecules due to interactions, complementary chemical bonds, between specific amino acids among the thousands that form them and specific areas of the molecules they detect. This means that the strength of the interaction with the foreign substance depends on the chemical nature of the amino acids found in the binding zone of the antibody. There are, as we know, twenty different amino acids that have different chemical properties: positive or negative charge, affinity for water, etc. Well, if we change one or more amino acids in the binding area of the antibody, leaving the others fixed, we will be able to modify the binding strength of the antibody, increasing or decreasing it.
This is what B lymphocytes do that have detected a substance. They generate random mutations in the areas of the DNA that modify the information about the amino acids in the area where the antibody binds to said substance, and only in those areas. The B lymphocytes that detect the substance more strongly after the mutations receive survival and stimulus signals that allow them to divide more quickly and produce greater quantities of antibody, which, in addition, will be of greater affinity than the initial one, that is, more efficient. B lymphocytes whose mutations do not improve affinity die.
An enzyme called AID participates in the generation of these mutations. Regulating the amount of this enzyme is very important, since if there is too little, the affinity of the antibodies cannot be improved, but if there is too much, mutations can occur that cause cancer. How this regulation was carried out was not completely known.
Now, scientists from several research centers in Canada publish the finding that a protein, called eEF1A, participates in keeping the AID enzyme in the cell cytoplasm and reducing the amount that reaches the nucleus, where the DNA that must help mutate is located. . Thus, eEF1A participates in achieving the correct amount of AID that acts in the nucleus and prevents it from “getting out of hand.”
These results, published in the Journal of Experimental Medicine, may help improve certain immunodeficiency states, or even improve the effectiveness of some vaccines that are not yet completely effective, such as the vaccine against the HIV virus, which causes AIDS.
References:
http://jorlab.blogspot.com.es/2008/01/la-naturaleza-baraja-los-genes-para.html?q=baraja
Methot SP, et al. Consecutive interactions with HSP90 and eEF1A underlie a functional maturation and storage pathway of AID in the cytoplasm. J. Exp Med. 2015 Apr. 6;212(4):581-96. doi: 10.1084/jem.20141157. Epub 2015 Mar 30.
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