Cell and DNA

Can Genetics affect how well we accept Transplants?

What are the different types of transplant?

When most people think of transplantation, they are usually thinking of a ‘solid’ organ transplant.  This is the process of taking a working organ from someone who can either survive without it or who has died recently (but their organs are fine) and putting it inside someone else who needs it. Liver, kidney and heart transplants are examples of these.

Another transplant type that is talked about less often is the transplantation of bone marrow. You may have heard of stem cell transplants (there are several types). A bone marrow transplant is a type of stem cell transplant. This is because the marrow contains the cells that make up your blood and immune system. The medical community calls this type of transplant a ‘Haematopoietic Stem Cell Transplant’ or HSCT. Haematopoietic means ‘the forming of blood cells’.

Who needs a HSCT?

Most people who need a bone marrow transplant have either got a problem with their immune system or their red blood cells. Often people with leukaemia (too many white blood cells that often don’t work properly) need to have their bone marrow replaced so they can produce normal white blood cells. Other reasons for needing a HSCT could be due to a condition called aplastic anaemia (where your bone marrow doesn’t make new blood cells) or sickle cell anaemia (where the red blood cells that are produced are misshapen). There are many more reasons for needing a HSCT and it has become a very important procedure.

What are the common complications of HSCT?

A HSCT is a very advanced procedure that can have a lot of complications. The main reason it’s so difficult to replace bone marrow is due to the immune system. Before you can insert the new bone marrow stem cells, you have to make sure that all the old bone marrow has been removed. The reason for needing to do this is because the new immune system from the transplant can start to attack your body. This causes a condition known as graft vs host disease (GVHD) where essentially the new immune system can’t tell the difference between your body’s cells and infectious pathogens like bacteria and viruses. This is different from a transplant rejection which is the opposite (your body rejects the new immune system).

One of the most dangerous periods of a HSCT is when the old bone marrow has just been removed and the new bone marrow hasn’t been put in yet or started to develop the white blood cells needed to fight pathogens. At this point, you don’t have an immune system and a common cold could kill you. This is why doctors put these patients in a ‘clean room’, where there is a much lower risk of infection.

What role do genetics play in our immune system?

The reason we all look different to each other and family members can look similar is due to our genetic profiles. Our DNA has coding parts and non-coding parts. It’s the coding parts that we see, for instance the gene that codes for blue eyes or brown. However, the biggest and most frequent genetic differences between humans isn’t actually in the coding part of our DNA, it’s in the part that scientists used to call ‘junk DNA’ – the non-coding part.

Recently, the medical community is realising that junk DNA isn’t really as useless as previously thought and often evolves into functional coding DNA. Scientists believe that non-coding DNA has a purpose as we have kept it in our genome throughout evolution.

Recent discoveries have shown us how our different genetic makeup can affect our immune systems. Some people may have better genes to fight off infections but also have an overactive immune system that can make transplant rejection occur more frequently.

To make matters even more complicated, scientists have found a link between the bacteria in our gut and our genes. We all have different levels of bacteria in our digestive systems. Most of this is helpful bacteria that can help us digest food easier and even provide us with more nutrients. ‘Good bacteria’ is often referred to as mutualistic as we help it and it helps us. We also have ‘commensal’ bacteria is our digestive system that don’t hurt us or help us. Having said that, commensal bacteria can become dangerous if the delicate level of bacterial balance is disturbed.

One of the first drugs given to transplant patients are antibiotics. As we mentioned earlier, getting an infection with no immune system is life threatening and so doctors give these patients antibiotics just in case. The problem with this is that it can kill all bacteria (both good, commensal and bad), which causes the bacterial balance of your gut to go wrong. Ironically, sometimes getting rid of the good bacteria can make way for bad bacteria (if they are more antibiotic resistant) as there’s less competition. Studies have shown that bacteria that take this opportunity (also known as opportunistic infections) can cause GVHD, infections and organ failure.

The balance of your gut’s bacteria is mostly determined by your environment, but recently it’s been discovered that your genetics can also play a role in the bacterial balance. Your immune system (which genes play a major role in) can control how many nutrients are available and the secretion of certain antibodies (see this article on antibodies), which in turn affects the chemical and physical makeup of the bacteria in your digestive system.

Even more shockingly, pathogenic or ‘bad’ bacteria can also play a role in what proteins your body expresses and can attempt to change cell pathways to allow themselves to spread leading to a bigger infection. Recent discoveries have shown that even commensal bacteria can do this. This is why the correct balance of bacteria in the gut is so important to lower the risk of GVHD.

A diagram showing how bone marrow transplants can affect the bacteria in your digestive system. Dysbiosis is another word for the wrong levels of bacteria.

So what does this all mean?

For patients that need a bone marrow transplant, more focus needs to be made on the gut, as this may play an important role on how well they accept the new transplant.

This article tells us that, with this new information, we should consider treatments that help our gut bacteria stay balanced. These can include probiotics, diet changes, bioengineered bacteria, more precise antibiotics or a faecal transplant (yes poop contains a lot of good bacteria too!). With the introduction of artificial intelligence, techniques could be developed where clinical information and bacterial balances are compared with each other to come up with a strategy for addressing infections in HSCT patients.

 

Reference: https://www.frontiersin.org/articles/10.3389/fmicb.2018.02317/full

Journal: Frontiers in Microbiology, Volume 9, Article 2317, 02 October 2018

Authors: J. Luis Espinoza, Yohei Wadasaki and Akiyoshi Takami

Copyright: Open Access

 

 

 

Antibodies

Autoimmune Diseases – when our body attacks itself

How does immunity work?

When we feel ill, our body is usually fighting off germs (the medical community call them pathogens). Our body does this in many different ways. Our immune system is mostly made up of white blood cells. These cells can kill pathogens by eating them, injecting them with materials that kill them or by tagging them with antibodies. These antibodies act like little flags that notify the other white blood cells that there is a pathogen in the blood and essentially marks them as targets.

What is autoimmunity?

These antibodies are great for letting other white blood cells know where the dangers are in the body, but sometimes our antibodies can get confused and end up tagging normal parts of our own body! This is how type 1 diabetes occurs. Our cells start to attack the pancreas until it doesn’t work anymore causing our blood sugar to become unregulated. When our antibodies start to attack our own body, we call them auto-antibodies. Autoimmunity is currently treated by reducing our immune system’s strength (immunosuppressant therapy).

Whilst we know what happens during autoimmunity, we largely don’t know what causes our antibodies to turn against us. Having said that, recent research has given us a clue as to what might be causing some autoimmune diseases.

Macrophage – a white blood cell that ‘eats’ pathogens

What are commensal microbes?

Commensal microbes are essentially the ‘good’ bacteria that you find in yogurts and health drinks. These help you with digestion and can actually boost your immune system.

So what was discovered?

Blood was taken from people who have a known autoimmune disease and their antibodies were tested. It was found that these patients had antibodies that were programmed to target the good commensal bacteria. It was also found that the antibodies that attacked the good bacteria also cross reacted with human tissue and then ended up attacking healthy cells.

What does this mean/where to from here?

This research has shown that one of the causes of autoimmune diseases may be due to a bad relationship between certain people’s immune system and the ‘good’ bacteria. Getting rid of the specific type of ‘good’ bacteria that causes the body to make autoantibodies may be a new type of therapy to consider for some autoimmune diseases.

 

Reference: https://www.frontiersin.org/articles/10.3389/fmed.2018.00153/full

Journal: Frontiers in Medicine, Volume 5,  May 2018

Authors: Peilin Zhang, Lawrence M. Minardi,  J. Todd Kuenstner, Steven M. Zekan and Rusty Kruzelock

Copyright: Open Access