Tag: Immunity

Somatic Recombination Part 3: Odd Genes, Viral Action

by on Feb.13, 2011, under Immunology

It’s been my experience that when bacteria are discussed, it is usually in a negative light. This is despite the fact that there are ten times more bacterial cells in and on our bodies than human cells, and the co-location is actually mutually beneficial. Understandably, viruses get the same treatment, but with their potential sequestering for genetic therapies perhaps there will be a change. I have actually been thinking that viruses may have played a key role in early the evolution of life, but that is another story. This story, the one on somatic recombination, is a very complicated one, so you can review the first two parts, here, and here.  Note that I’m focusing on B cells, but the process is essentially the same in T Cells.

Given negative light in which viruses are seen, it seems ironic then that the mechanism by which a retrovirus integrates its genetic material into the infected cell is very similar to the mechanism by which our B and T cells produce the molecules needed to recognize and defeat bacterial and viral infections 1. Two proteins, named RAG1 and RAG2, which start off the process in our cells, have been shown to form what is known as a transposase. In retroviruses such as the one which causes AIDS, a transposase is used to splice the viral genetic material into that of the infected cell. RAG1 & 2 combined in a human cell can do the exact same thing2.

Even the genes which encode these proteins are extraordinary. Mammalian genes usually contain regions called introns which are non-coding and though transcribed, are edited out before the RNA is translated into a protein. However, the RAG genes, like most bacterial genes, contain none. This seems to me, at least, to be a very interesting evolutionary story. How did genes that don’t contain introns and code for proteins which form a transposase end up in our genome?  I’ll have to note this question for another post.

As I mentioned in my last post, the immunoglobulins that Recombination creates have a both a variable (V) regions and a constant (C) regions. They are made up of two identical pairs of protein strands, called chains, with each pair consisting of one light and one heavy (the heavy chains are the longer chains in the image to the right). It is the variable regions we are concerned with here and RAG 1 & 2 proteins join, and then incorporate a few other proteins to form what is known as VDJ recombinase to produce them. The recombinase is the lead actor in somatic recombination.

Before we continue to the process, the genes which code for the light and heavy chains are uncommon as well and therefore worth visiting. Ordinarily, the nucleotide sequence of a given gene is transcribed from the chromosome onto an RNA molecule that is then translated by a ribosome to produce the protein product. The location on a chromosome at which any given gene is located is known as the locus (loci, Pl.)

This is not the case, however, at the loci which encode the heavy and light chains of an Immunoglobulin. An examination of the light chain locus on chromosome 2 will reveal not a single gene but rather a large number of gene segments. Further, there are special sequences of nucleotides to be found surrounding those segments. First, up are the so-called Leader sequences which come into play after translation and mark an immunoglobulin for transport to the plasma membrane. Second are the even more interesting Recombination Signaling Sequences (RSSs) which are the markers to which the RAG 1 and RAG 2 complex binds.

As depicted in the diagram below, there are actually different types of gene segments within the locus which will be combined together in the process. The variable region generated by the VDJ recombinase will include one each of the V, D (heavy chain loci only), and J segments. The C segments code the constant regions and we’ve only found a handful so far. Estimates that I’ve read or heard for the number of V segments, on the other hand, range anywhere from forty to hundreds within a given locus.

The process of somatic recombination forming a Light Chain selects at random a V segment and a J segment and joins them together along with a C segment to form a single gene. The “D” in VDJ refers to the D, or Diversity, segments which exist only in Heavy Chain loci, in fact the proper spelling is V(D)J recombinase.  It is the process of joining the segments that produces the infinite potential for sequence recognition, not the segments themselves.  This process, Somatic Recombination,  is simple in concept, yet complex in execution and within, there is yet another twist which demonstrates the beauty as well as the danger in this amazing biological mechanism. In my next post, the process…

1.Janeway’s Immuno Biology
Seventh Edition
Garland Science

2. Nature. 1998 Aug 20;394(6695):744-51.
Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system.
Agrawal A, Eastman QM, Schatz DG.
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

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Somatic Recombination, Part 1: Immunology; saving and speaking of life.

by on Dec.29, 2010, under Immunology

I would like to share with you some knowledge that very few people in the world have.  The topic is a very hearty one; Immunology, considered to be one of the most difficult in the health sciences.  However, the immune system is of critical importance not only in defeating pathogens such as bacteria and viruses, but also in clearing the body of damaged tissue and eliminating cancerous growths.  I will introduce some vocabulary for the simple reason that without it, this post would become very long, even for me.  It is said that a picture is worth a thousand words, well, in Immunology, some words are worth about the same.  The source of the information and my personal opinions presented in this post is my study of Janeway’s Immuno Biology.  I’m not a medical professional, and nothing I present in this post, or any other post I may make on a health science topic, should in any way be considered medical advice, the intent of the authors of any of the texts I reference, or an authoritative explanation.  This post is solely my understanding, theories, and interpretation of the material I’ve studied.

In a short series of posts, I will introduce an immune system process with the impressive title; Somatic Recombination, or, in this context,  V(D)J Recombination.  This process is significant for many reasons outside its critical and sole function; to build receptors.  These receptors, also called antibodies, or Immunoglobulins, are capable of recognizing bits and pieces of invading pathogens and other substances that might harm the body.  Of particular significance, the building process has potentially dangerous ends because it includes not only the cutting out and elimination of sections of an individuals DNA, but also the intentional introduction of mutations into the recombined DNA strands.  Also, the process, when viewed across many Immune System cells, is an example of selection.  It is not the same, of course, as natural selection occurring at a macroscopic level, but at the basic level, it does as it involves the survival and proliferation of those cells with receptors containing the sequence of amino acids that will best bind to a given antigen; the name given to the bits and pieces which stimulate our immune system into action.

Another interesting note about this process is that it is closely related to the process by which retroviruses insert their genetic information into the DNA of their host cells, i.e. human cells, which in turn can cause disease.  In fact, the RAG (Recombination-Activating Gene) protein which directs the process is arranged differently from other human genes suggesting that it was evolutionarily adapted into our genome making Somatic Recombination possible. 

I have often felt, during my studies that humans seem to be fabric into which is woven parts of many different molecules and organisms that probably coexisted in mutually beneficial societies; a social symbiosis.  I am of the opinion that this symbiosis is the key to the successful evolution of life rather than the necessary, but misinterpreted “survival of the fittest” notion to which evolution is so often tied.  Questioning Darwin… talk about delusions of grandeur on my part.

The Immune System, so far in my study, looks to me like a living model through which the evolution of life on Earth can be seen.  First, it was necessary for me to resist the compulsion to anthropomorphize.  The Macrophage, a staple cell of the Immune System, was so named because it was seen as a “big eater”.  I think this view is detrimental to a clear understanding and research path because we are essentially speaking of energetically favorable reactions not cells with a hankering for vittles.  When I remove this lens, I see the symbiotic relationship with mitochondria as possibly allowing the re-tasking of complex energy seeking molecules to protective capacities and the establishment of self at the cellular level.  I see that its not a matter of destroying non-self, there is actually more non-self inside us than self, it’s a matter of information dissemination, examination, and a resultant action.  To illustrate, consider that molecules called MHC which present pathogen derived peptides to T cells and elicit an immuno-protective response.  These MHC molecules, will present peptides from the individual’s own healthy proteins in the same manor if an infection is not present.  This presentation should, it would seem,  result in no action by the T cells, but considering auto-immune disorders of unknown pathogenesis, perhaps this is not always the case.  Pathogenesis is the origination and development of a disease.

This is just the very tip of a large and fascinating iceberg.  I hope my explanation of Somatic Recombination in antibody production serves well in sparking interest in a study which has saved countless lives and may yet shed light on the evolution of life  itself.

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