Self knowledge for the Immune system

Does my body need to know self?

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.

What is an individual?

Viewing the world as a human, I look out into the world and see myself as an individual, within a family and within a community and then as a member of the larger population of our world. A super organism of human and other life forms?

I would think of myself as a single organism. But where are the boundary lines? Biologically my body is made of millions of cells, living and dying thoughout my lifetime, I am full of bacteria and micro-organisms that are essential for my health and sometimes not so healthy existence. An organism may be either unicellular (a single cell) or, as in the case of humans, comprise many trillions of cells grouped into specialized tissues and organs. When we look further into the cell we see the nucleus, a specialised and contained region that contains the genetic material, the blueprint for cells and its multi cellular form.

This raises the question, Is an organism defined by the DNA contained within the nucleus?

Well not completely!

As a eucaryote organism, my cells also have DNA that resides outside the nucleus, the DNA is situated within small organelles called mitochondria that look spookily like little bacteria. The Mitochondria are the power generators of the cell, essential to our existence. Possibly the ancestors of the mitochondria were early cell invaders back in the mists of time, parasites, which then evolved a more symbiotic relationship with its host. Now millions of years later, the cell has become a permanent home for these 'bacteria' within our cells. Although still hosting some of its its unique coding DNA, evolution has occurred and now the nuclear DNA also codes for proteins that are required for the mitochondria's existence as well. The original parasitic mitochondrial ancestor would have been defined as an organism in its own right, but now the mitochondria has lost that identity. The distinction of an individual and an organism become harder to define when we look at some strange creatures that exist in our world.

Mixotrichia Paradoxia is one of these strange creatures that exists in symbiosis with four other organisms that provide critical structures or metabolic processes that Mixotrichia lacks. As a good analogy it is similar to thinking about your own body with the legs and arms provided by another creature. Looking down the electron microscope the Mixotrichia looked like may other singled organisms but the thing that give it away as being a little bit unusual was that it had BOTH cilia and flagella, apparently that is a no no in these kinds of cells. This encouraged scientists to look a bit harder, delving more thoroughly they realised that the flagella and cillia were actually separate organisms in their own right.

Mixotricha has four anterior flagella, that are used for steering, these are a paramecium. Movement is achieved by the beating movement of 250,000 hairlike stuctures which incredibly, were found to be helical bacteria, these are attached to the cell surface and provide the cell with cilia-like movements. Mixotricha also has rod-shaped bacteria arranged in an ordered pattern on the surface of the cell but no one knows what they do! Last but not least, Mixotrichia has spherical bacteria inside the cell which function like mitochondria.

So is Mixotrichia  and its symbionts, one individual, or many, one organism or many, a beautiful composite organism? This intriguing collection of creatures interacting symbiotically to define the the characteristics of Mixotricha paradoxia is a wonderful thing.

The definition of the boundaries of what is an organism becomes even more blurred, when you look at the larger scale and the perspective becomes even more interesting. Mixotricha paradoxia is an essential organism within the gut of the termite that allows it to obtain nutrients from wood and plant material, Mixotricha, allows the termite to exploit its barren environment, using poor food sources to sustain life. Most importantly, the termite relies on being a member of a larger community of termites in the termite mound, all working together as super organism to create the successful termite community.