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The Unlikely Transplant - Why the fetus isn't foreign

There are certain things which cannot be, or rather, are yet to be explained by science.

Some things keep scientists awake and push them harder to strive for explanations. But medical science has come a long way (some of our recent articles have tried to throw some light on the the latest leaps we have made!).

But, if you asked me to pick one area of advancement that has truly changed medicine, it would be the field of organ transplantation – a field that is simultaneously morbid and incredibly cool. Since the first transplantation of a kidney in the year 1954, many medical protocols and surgical procedures have been perfected for a successful organ transplant. While a successful transplant gives surgeons an understandably immeasurable high, a graft rejection can make them hit rock bottom. And that prompted researchers to dwell into the field of transplant immunology, to explain the immunological basis of transplant rejection and hopefully prevent this devastating complication from tearing apart lives. 

When a foreign body enters the human body, the immune system recognises it to be alien and tries to repeal and reject it. So it is easy to understand why a kidney from a genetically unrelated donor stands the risk of being rejected by the recipient’s immune system. However the law of rejection is being conveniently evaded in another branch of medicine, enabling a foreign body to comfortably survive without being rejected. Yes! I’m talking about the foetus. How is a foetus able to survive in the uterus, despite being half – foreign owing to the paternally gained genetic material? How are surrogate mothers able to carry a fully foreign foetus without rejecting it?

Before we answer these questions, let us first try to understand the mechanism of transplant rejection. The master behind the whole process is a widely polymorphic complex called the Major Histocompatibility Complex (MHC).

The MHC in humans is called Human leukocyte antigen (HLA) coded on chromosome number 6. It is basically the central processing unit of the immune system. Whenever a foreign cell enters the body, the MHC molecule breaks it down, processes it, and displays the foreign peptides for recognition by the T lymphocytes which ultimately help to eliminate it from the body. On the basis of chemical structure and function, the HLA gene products are divided into 3 classes.

Class 1 products are HLA-A, HLA-B and HLA-C. Class 1 MHC is present on all nucleated cells of the body and they process intracellular foreign peptides, like a virus. Whatever is processed by the class 1 MHC is attacked by cytotoxic CD8 T lymphocytes only. HLA-D is a product of class 2 genes and this is present on specific group of cells called the Antigen presenting cells (APC) like the Dendritic cells and the macrophages. Class 2 MHC processes extracellular foreign peptides, like those derived from a bacteria. Whatever is processed by class 2 MHC is always and only presented to the CD4 helper T lypmphocytes which then eliminate the foreign peptide with the help of B lymphocytes. And then there’s class 3 genes which code for the components of the complement system. They do not play a role in graft rejection reactions so let us not dwell into them now.

 

 
hla.jpg
 

Still seems a bit complex? Well, here’s something to visualise it all!

 
 Mechanism of action of MHC 1

Mechanism of action of MHC 1

 Mechanism of action of MHC 2

Mechanism of action of MHC 2

 

Now what makes the system more unique is the fact that there are several alleles, 3500 to be exact, coding these systems. During fertilisation, 50 % of these alleles are derived from the maternal genetic material and 50 % from the paternal side. This selection process is not organised, not systematic but in fact a completely random process. Except in genetically identical twins, of course. However the randomness of it is a double edged sword. It explains how the immune system is able to process and eliminate a wide variety of bacteria and viruses, but it also means that no 2 individuals will have the same set or same combination of alleles coding their HLA genes.

 It’s consequence?

When an organ from a genetically non identical individual (allograft donor) is placed in the host, the host’s immune system now recognises the MHC molecules on the graft to be foreign and eliminates or rejects the graft by the mechanisms explained before.

Now coming back to the more intriguing question – how is the foetus able to overcome all these complex systems set in place? The answer to that is still being widely researched under the broad heading – “Immune tolerance in pregnancy”. There’s an ocean of information and upcoming theories to explain this question which is beyond the ambit of one article. However the most widely accepted theory is this. The placental trophoblast cells which are present at the feto-maternal junction do not express MHC class 1 and Class 2 molecules. And their mere absence prevents the maternal immune system from recognising the fetus as a foreign body!

Another explanation is a biochemical phenomenon rather than an immunological one. Studies have found that the trophoblast cells contain an enzyme called Indoleamine 2,3-dioxygenase. This enzyme metabolises the essential amino acid, tryptophan, in the maternal T lymphocytes and depletion of the amino acid renders T lymphocytes inactive.

However, these mechanisms of immune tolerance in pregnancy come at a price. Though it lets the foetus survive, the apparent immunocompromised state of pregnancy makes pregnant women more susceptible to infections.

Our understanding of the immune system has enabled us to answer the question this far. But trying to answer why these MHCs are absent in the placenta would be like trying to answer why the alphabet is arranged from A to Z and not in reverse! And while Some might still pursue to find answers, sometimes we might have to just accept that this is how nature works!

Author: Soundarya V (Facebook)

Sources and citations

Guleria, I., and M. H. Sayegh. Maternal Acceptance of the Fetus: True Human Tolerance. The Journal of Immunology, vol. 178, no. 6, May 2007, pp. 3345?3351., doi:10.4049/jimmunol.178.6.3345.

Kumar, Vinay, et al. Chapter 4 - Diseases of the Immune System.? Robbins and Cotran Pathologic Basis of Disease, 9th ed., Elsevier, 2015, pp. 102?136.