Thursday, February 09, 2006

Evolution of the Immune system: MHC part I

Unlike what some advocates of a certain particularly credulous political movement would say, there is in fact a wealth of detail and research being carried out on the evolution of numerous systems. One of these is the immune system that is found in vertebrates and particularly prominent among the mammalian lineage. Although research is carrying on in many different areas of the immune system, one of the most fundamental areas of research is to determine how the immune system determines what is a friend and what is a foe. The basic group of molecules responsible for this determination is called the Major Histocompatibility Complex (MHC) and these make up the most important part of the Aquired Immune System (AIS). Here I shall describe some (and I emphasise that this is just the tip of the iceberg) of the research being conducted into the origins and continuing evolution of these molecules.

The immune system of vertebrates is basically responsible for organising molecular weapons that destroy pathogens attempting to attack the host. This process is exceedingly complicated and starts with the recognition of invading organisms by cells such as dendritic cells and macrophages. On the surface of these sentries are molecules that recognise PAMPs (Pathogen Associated Molecular Patterns), which include structures such as bacterial LPS (Lipopolysaccharide) and peptidoglycan (a bacterial cell wall structure). These sentries can then pick the invader up and degrade it intracellularly to present the invader to other cells. Alternatively, most other cells in the body can recognise pathogens as intracellular organisms like viruses proteins are degraded. These are then presented on the surface of the cell for the immune system to survey.

Importantly this raises the question of how the immune system recognises what is ultimately a friendly cell and one that is infected. After all, when the immune system gets it wrong and attacks self tissue things quickly spire out of control. To solve this dilemma, cells of the immune system are 'trained' as to what is friendly and what isn't by special molecules called the major histocompatibility complex or MHC. These molecules are what macrophages and dendritic cells mount the peptides they produce on after degrading invaders. Similarly, cells that have degraded viral proteins or similar also display the chopped up protein on MHC on the surface of the cell for the immune system to survey. Additionally, they also display chopped up proteins that have been produced by friendly cells and these are critical in 'tolerising' the immune system so it knows what friendly proteins should look like. Although this is important as well, I won't be discussing this particular part of the immune system in this post so we'll leave that particular story as is for the moment.

There are two general classes of these MHC molecules that are important in the immune system performing the same sort of function. The first is MHC class I that is produced by all cells with the exception of sperm and certain neurons. This is the MHC molecule that mounts proteins that have been degraded by cells generally and displays both microbial and 'self' antigens. As it's responsible for sensing what is happening inside a cell these molecules are mostly involved in cell mediated immune response against intracellular parasites. A second class of MHC, conveniently called class II, is produced by the aforementioned macrophages and dentritic cells upon degrading invaders they have found.

With this critical function in immunity it raises interesting questions as to how the MHC came to evolve and then become incorporated into a proto-immune system. The first obvious question that needs to be considered is what the original function of the proto-MHC molecules were. As it turns out, some clues as to the origin of the MHC is revealed in some of the simplest chordates alive today. In a paper in Nature(1), Anthony W. De Tomaso et al, investigated a primitive chordate called Botryllus schlosseri, which has an unusual mechanism for ensuring sexual diversity. These animals produce a small tadpole like larvae that moves around eventually settling to form an immotile colony.

Although seemingly unexceptional, when two seperate colonies of this organism meet they can have a widely different reaction. In one particular scenario the colonies may fuse together, while in another they reject the other colony and remain unfused. This results from the fact these colonies form structures at their periphery called ampullae, which are sites where a kind of MHC like molecule interacts with the other colony they have encountered. The molecule, called FuHC (Fusion/Histocompatibility) has hundreds of different alleles, similar to that of vertebrate MHC molecules and if similar to the other colonies FuHC alleles causes the ampullae fuse so the colonies share a single blood supply. If the FuHC alleles are not in common, then the ampullae go into a 'rejection' mode, destroying themselves preventing vascular fusion.

In this scenario, FuHC is acting as a mechanism not for immunity but for maintaining a more diverse range of genes among Botryllus schlosseri. When two colonies of Botryllus schlosseri fuse very often one of the colonies gametic expression becomes the norm and the other fails to be able to spread its genes. Naturally, the effect on the organisms would be to lower the amount of diversity in their gene pool if this occured more often. The FuHC system as a result plays an interesting role in maintaining the diversity of the organisms gene pool and preventing them all from reducing the diversity of their gene pool. Perhaps most tantalising, is the possibility of discovering potential effector cells similiar in function with vertebrate Natural Killer (NK) cells that are responsible for the destruction of cells at the ampullae that do not match.

Although the FuHC story gives an interesting insight into the possible origins of the MHC in vertebrates, it's unlikely to be a direct homologue. This is due to the fact FuHC is structurally different to the vertebrate MHC, in that its immunoglobulin domains do not directly correspond. In any event, this molecule gives key insight into the possible functions of a proto-MHC molecule that are still shared today.

The discovery of the MHC was one of those numerous 'fortuitous' things in science, where looking for the solution to one problem led to the discovery of something entirely different. These molecules were discovered while looking for the mechanisms that determined graft rejection, as it turned out individuals with different MHC molecules to the graft would end up having their immune system attack it. This is because the hosts immune system sees the grafts MHC molecules (among other things) as non-self and goes on the attack. Genetic mapping revealed that these genes were all clustered in the same genetic context with three general regions (The MHC I region, the MHC II region and the MHC III region, which is ironically in the middle of the MHC I and MHC II regions).

So in this scenario I have (hopefully) shed some light on the possibly origins of the vertebrate MHC from a simple molecule that serves to differentiate cells to aid in sexual diversification. Tommorow, we shall continue investigating the wealth of evidence for the evolution of these molecules, with an important discussion as to the mechanisms that acted to produce the human immune system: namely gene duplication and a process called co-option. Additionally, I'll also discuss the means that selection acts to keep the genetic diversity of MHC in humans so unusually high.


De Tomaso A.W., S.V. Nyholm, K.J. Palmeri, K.J. Ishizuka, W.B. Ludington, K. Mitchel and I.L. Weissman (2005). Isolation and characterization of a protochordate histocompatibility locus. Nature, 438:454-459.

Also used (extensively used in tommorows post):

Danchin E., V. Vitiello, A. Vienne, O. Richard, P. Gouret, M.F. McDermott and P. Pontarotti (2004). The major histocompatibility complex origins. Immunological reviews, 198:216-232.

Piertney S.B. and M.K. Oliver (2006). The evolutionary ecology of the major histocompatibility complex. Heredity, 96:7-21.