ReadingThinkingAndWriting

The ability of a cell to sense its environment and receive information from other cells is central to the health and function of virtually every cell in the human body.  The information obtained by a cell at its surface will induce signals within the cytoplasm that end in a variety of effects including cell motility (movement), maturation, and even death.  Contrary to the static picture of cells, save neurons, from the biology texts of my youth, cells are dynamic and interactive. Further, this interactivity is critical not only to the health of the cell but the organism as well.  Errors in intracellular signaling have been shown to play a role in cancer as well as many other conditions. 

The primary implement for this environmental sensing and intercellular communication is the transmembrane receptor.  They are so named because they reside within the cell membrane and extend into the cytoplasm on one end and the extra cellular fluid on the other.  There are many different types of these receptors that can bind to a wide range of molecules (ligands).  They are classified into families with different binding specificities and signaling effects.  For example, chemotactic receptors induce the mechanisms of cellular motion.  Members of this receptor family can be found in many places including cells of the Innate and Adaptive Immune System.  The Neutrophil, the most important cell type in the Innate, possess several different chemotactic receptors in its membrane which drive changes in the cytoarchitecture.  In the video below, a Neutrophil can be seen pursuing a bacterium by following a chemical trail produced in its wake utilizing it’s chemotactic receptors.  Amazingly, this video was taken in real time.

All transmembrane receptors in the families I’ve encountered in my reading bind to specific patterns of amino acids within a peptide or complete protein or a combination of protein and sugar or fat.  This is referred to as the binding specificity of the receptor and it varies in strength (avidity) with minor variations in the amino acid sequence of the binding target. 

As far as I’ve read, a given receptor or receptor family is rarely unique to a one species.  All receptors of a given type will bind to a very similar, if not the exact same, amino acid pattern regardless of whether the receptor is on a human Neutrophil or a staphylococcus bacterium.  One interesting example is the family of so called Toll receptors which are highly important to immune system function.  These receptors are conserved throughout evolution and can be found in both vertebrates and invertebrates alike 1.  Another fact that makes the Toll receptors so interesting to me is that early on in the development of the fruit fly a toll receptor is critical for establishing the “top and bottom” orientation of the embryo.

The transmembrane receptors we are interested in here are called antigen receptors, further, in context of a B cell; Immunoglobulins.  Immunoglobulins stand out for two reasons.  First, they have two possible fates.  Once assembled, some Immunoglobulins will be transported to and embedded in the B cell membrane where they function as antigen receptors.  However, after assembly, they can also be secreted by the B cell as antibodies and enter the circulatory system.  Antibodies often encounter their binding targets, or ligands, in proteins found covering the surface of a pathogen such as a bacterium.  By binding in large numbers, the antibodies essentially coat, or opsonize the bacterium, thus marking the pathogen and making more efficient the action of cells in the innate immune system.  These cells, such as Neutrophils, have transmembrane receptors known as Fc receptors that bind to the ends of antibody molecules at what is known as their Constant Region.  This region is so named because it is always constructed by the same amino acid sequence. 

The second reason immunoglobulins stand out can be found at the other end of the antibody molecule opposite the Constant Region which is called the Variable Region.  In contrast to the Constant Region, and any region of any other receptor I’ve read about, the amino acid sequence that makes up this region is almost infinitely variable.  This is the region that makes immunoglobulins, whether secreted as antibodies or stuck in the membrane as antigen receptors, immensely useful in protecting the body from pathogen invaders.  This is because every amino acid sequence found in every possible invader, existing as well as yet to evolve, need not be encoded into the genome for transcription as the binding site sequence of an Immunoglobulin.   This would require more genes than there are in the entire genome; another process must be employed to produce the sequences of the Variable Regions.

Immunoglobulins are generated dynamically during the cell’s development, with virtually infinite potential for diversity in binding specificity.  Therefore, the receptors and antibodies of each new B cell will have specificity to a different peptide because each one bears receptors that are specific for a different sequence of amino acids.  The process responsible for this dynamic specificity is called Somatic Recombination, and I will present it over my next two posts.

Read my Health Science Disclaimer

1. Toll and Toll-like receptors in Drosophila
   H. Bilak, S. Tauszig-Delamasure and J.-L. Imler1
   UPR9022 CNRS, 15 rue Rene´ Descartes, 67084 Strasbourg Cedex, France
   http://www.biochemsoctrans.org/bst/031/0648/0310648.pdf

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.