Genes and Germs: The Battle that Defines Us

(Originally published by C2ST, August 11, 2015)

As we go about our days, it’s easy to forget the cells, molecules, and organs silently ticking, keeping us alive and hopefully well. One of the most intricate of these biological teams is our immune system.

Within it, there are two major subdivisions: the innate and the adaptive systems. Innate immunity is more ancient, dating back to plants and even primitive multicellular organisms. It responds to common traits of microscopic foreign invaders, such as a protective cell wall or double-stranded RNA, which our cells lack. Adaptive immunity is a more recent innovation, first cropping up in jawless fish and sharks. Equipped with immunological memory, adaptive responses are based on previous encounters with intruders.
In June’s edition of C2ST’s Speakeasy, Dr. Sean McConnell showed the audience that our immune system is a Renaissance man, with a hand in processes including transplants, cancer, and pregnancy. Appreciating the underlying cellular and molecular machinery puts these phenomena in new light, showing that processes that seem different can have commonalities on an unseen level.
The relationship beneath it all: T cell and MHC
One very important cellular interaction is behind all the phenomena Dr. McConnell highlighted. This interface allows an immune cell to survey the contents of the body’s cells and mount a response if it detects anything fishy.
Specifically, a protein called the major histocompatibility complex (MHC) on the surface of all our cells allows the immune system to screen the contents of cells. The MHC takes proteins inside our cells, chops them into smaller pieces, and displays them outside the cell.
The T cell, one class of immune cell, has a protein on its surface that then recognizes these protein bits. The protein studding each T cell is slightly different, and only recognizes a small percentage of the protein pieces. Together, all of our T cells recognize a wide variety. Depending on whether the protein bit is identified as one of our own or foreign, the T cell will either leave the displaying cell alone or destroy it.
Transplants: A game of MHC matching
When we look at an organ – heart, lung, liver – with the naked eye, one person’s might look very similar to another’s. We might expect transplantation to be a matter of successfully surgically attaching it to the relevant tubing nearby, or some other macroscopic process.
In fact, the success of transplants depends on matching the MHC protein on the surface of all our cells. With so much variability in this protruding protein and the immune signals that it transmits, MHC is to blame for the difficulty of finding matching organs.
The immune system can be finicky with grafts on another level as well. Even when the right match between MHC’s has been made, sometimes the immune system still needs to be told to calm down. The drug cyclosporine, for example, can do this job by decreasing the replication of certain immune cells.
While many transplants involve an organ, bone marrow transplants are unique because the patient is effectively receiving a new immune system. If this incoming immune system attacks the host, this may result in mild symptoms like a skin rash. However, in order for the transplant to succeed, the new cells cannot strike the host’s organs. Ideally, this form of transplant may wipe out the host’s cancer, but the challenge is to limit its attack to only the cancer.
Cancer: Going under the radar
Cancer-causing mutations can change the bits of protein on the surface of cells to the point where they no longer resemble those from our own healthy cells. In theory, this should mean that the immune system sees the cancer as foreign cells and eradicates it.
However, cancer cells can evade the immune system in several ways. A type of dog cancer down-regulates MHC, meaning it decreases the number of MHC molecules on the surface of tumor cells. Since MHC molecules are the tags that immune cells respond to, this puts the tumor under the radar.
Tumors that hide from the immune system in this way, such as the cancer that plagues Tasmanian devils (called facial tumor disease), might be possible to treat by harnessing the immune system. By giving the body a signal that turns the immune system on, it could be encouraged to target the cancer.
Treatments that leverage the immune system in this way are called immunotherapy. An immunotherapy exists for human melanoma. This tumor makes a molecule that interacts with T cells to tell the immune system to leave it alone. The immunotherapy blocks the interaction between this molecule and the T cell.
Pregnancy: a delicate balance
You’ve probably never thought of a pregnancy as similar to a safeguarded transplant, but in immune terms, this is precisely what it is. The fetus has DNA from both mom and dad, so in theory the mother housing it should reject this tissue that inherited dad’s DNA, detecting it as foreign. However, when the fetus engrafts in the uterus, it sends signals to the immune system to leave it be. Specifically, the layer of cells outside the embryo (that later become the placenta) invades the uterus and increases blood flow to the fetus to supply nutrients, but tells the immune system to stay back.

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