The ability of the immune system to reject transplanted organs seems a bit unfortunate when the organs are required for a life saving function. This makes you think, why is it so important that our body is able to know what is self?
To understand the rejection process I need to give you some information on how self/ non self recognition occurs. You may have heard about tissue types and tissue matching, this is as an important process in organ donation to prevent avoid organ rejection. When someone does a 'tissue match' they analyse the properties of a family of molecules that are encoded by a region of the genome called The Major Histocompatibility Complex. These molecules play important functional roles on the surface of cells. A particular family of these surface molecules have a special groove in their structure which can be used to sample the internal and external protein environment of cells. Sampled bits of proteins called peptides (like small sections of a necklace) are held in this groove and offered up to be screened by survelliance cells of the the immune system. If we call these surface molecules that have this function,'presenting molecules', this will make things easier to explain.
Humans like many other animals have a lot of diversity in their presenting molecules, inheriting and expressing one full set from their mother and the other from their father. This is the diversity that causes issues with organ transplants because it is not common to find identical presenting molecules on both the donor and recipient's tissues. Even a few mismatched molecules that are recognised as 'foreign' can excite an immune response sufficient to cause damage to the donor tissue. The foreign presenting molecules are also chopped up and used as stimulatory peptides, adding more fuel to the rejection process. The difficulty in getting a perfect match with all the different presenting molecules is the main reason why organ recipients are given immune suppression to increase chances of a successful transplant.
This raises the critical question, why are the presenting molecules so diverse?
It has been the dogma that this diversity is important as it imparts individuals with greater 'fitness' due to protection from infection by pathogens. We need a variety of presenting molecules to give us a better likelihood of binding the peptides from chopped up bits of viruses and bacteria. If pathogen derived peptides are not presented up for surveillance the pathogen could evade a protective immune response. This has important implications since individuals with presenting molecules that lack the ability to present a large repertoire of bacterial/viral/fungal peptides may be more susceptible to infection. As a scientist in an immunology lab it is not uncommon to have your presenting molecules typed. I know that I have inherited a very good presenting molecule that enables protection from TB, a mycobacterial infection and it is pretty useful for certain flu peptides as well. Overall this diversity is good to give us a wide variety of presenting molecules to cover all possible bases so that even when a rare opportunistic infection occurs the immune system can respond. This property of the immune system is not good for transplants but very good for survival against infection.
So does this answer the question, organ rejection is simply a co-incidental effect occurring as a consequence of diversity selected for protection against pathogens. It would seem fantastical to think that this diversity was selected due to threat of invasion of cells from another individual. Sitting on a sofa next to my husband am I risk of invasion from the cells of his body? Although most cells in our body lack the replicative qualities to infect another individual, transformed cells such as cancer cells may have a greater infective potential. There are rare cases where tumours have been known to be passed to surgeons that are operating on an individual suffering from cancer. More commonly cancer cells are passed to recipients receiving an organ donation. The cancer cells piggy backing a ride into the donor and because the recipient is immuno-suppressed they are able to grow in the recipient because their immune system has been disabled.
Well until recently, the idea that tumours could be infectious in healthy individuals was thought to be rather far fetched, until some recent research involving the Tasmanian devil came to light. This Marsupial from Tasmania is a rather aggressive creature that has recently become endangered due to a facial tumour disease. What became evident is that the devils were catching the tumours from other affected individuals. This transfer of cells was possible due to the rather aggressive behaviour which includes face biting during disputes over food and mates. This infectious cancer known as devil facial tumour disease has spread virulently thought the Tasmanian devil population This phenomenon is threatening their survival as a species because the animal typically starves to death three months after infection because the tumors interfere with feeding.
Studies on the genetic makeup of the Tasmanain devil and analysis of their presenting molecules revealed a really interesting finding. These devils had been through an evolutionary 'bottleneck' and are highly related. This has the consequence that these creatures also have very similar presenting molecules. It was proposed the lack of presenting molecule diversity was a significant contributing factor that prevented the devils's immune system from ridding themselves from the 'infectious' tumour. The key reason for susceptibility was the tumour wasn't being recognised as foreign tissue. This isn't the only example of infectious tumours,there is also evidence from other species such as wolves and dogs which succumb to infectious tumours contracted during mating and coincidently also have limited presenting cell diversity. In this case, the infection is transient and the animals recover from the disease.
Maybe an infectious threat from foreign tissue was a selecting pressure that also contributed to diversity in presenting molecules over evolutionary time, Not such a way out idea after all?
One thing to note, not all animal of limited diversity succumb to tumour 'infection'. Cheetahs are highly related due to a similar 'bottle neck' effect but show no evidence of this phenomenon. There are obviously other factors to consider. Another caveat in is this theory is that more recent studies revealed that the Tasmian devil tumours do seem to have extra infectious characteristics, since skin grafts from other devils are rejected effectively by the host devil. Nethertheless, this phenomenon looks very interesting. Could these characteristics be acquired in human cells and a wave of infectious cancer become a threat to humans? Well the chances of this happening seem very low but the use of immuno-supressive agents and the spread of viruses that result in immunodeficiency, might provide a larger pool of individuals who could act as vectors from which a tumour with infectious potential might develop. Please don't lose any sleep over this though!
Just to finish off, it is worth mentioning that knowledge of self and the diversity of our presenting molecules may have had other evolutionary pressures. Recent studies shown that presenting molecules can influence mate choice, but that's another story.
Foot notes:
First, don't confuse this infectious tumour phenomenon with tumours that occur as a result of infection by pathogens, eg human HPV infection that causes cervical cancer, here the tumours arise from our own transformed tissue resulting from an infectious virus.
Secondly, there are additional surface molecules that play a role in immune responses, that are called minor histocompability antigens which have an alternative way of orchestrating immune responses and also contribute significantly to organ rejection.
No comments:
Post a Comment