by Garrett Dunlap
graphics by Shreya Mantri

If you ever doubt how special you are, consider that one of the world’s most sophisticated security forces works non-stop to protect you and you alone. Once a threat to your safety is identified, a highly trained group of spies, intelligence networks, and assassins leap into action to quickly eliminate it and stay on the lookout for similar future threats.

This protector of peace is none other than your body’s immune system. But even a top-notch security system can occasionally make mistakes. Sometimes, the immune system mislabels normal proteins in the body as threats, leading to the potentially dangerous group of conditions known as autoimmune diseases. In addressing these conditions, mRNA vaccines have recently emerged as a promising potential therapeutic. So, how does this security force work normally, what happens when it receives bad intelligence, and how can mRNA vaccines help?

Meet the agents

Before learning about what happens when things go awry, let’s meet a few of the specialists involved in our immune defense: B cells, dendritic cells, and T cells (Figure 1). If the immune system’s motto is “search and destroy,” the search is conducted by B cells and dendritic cells. B cells have proteins known as antibodies that detect invading organisms, such as bacteria and fungi, as foreigners. 

The antibodies recognize antigens, which act like an invader’s unique fingerprint. Whether it is a piece of a virus’ coat or an internal part of a bacterium, the immune system concludes that this particular fingerprint doesn’t natively exist in the body. After an antibody recognizes one of these antigens, the B cells then turn into antibody factories. The produced antibodies latch on to the recognised parts of the invaders and signal to other immune cells, such as T cells, that the organism must be eliminated.

Dendritic cells, the intelligence agencies of the immune system, project long arms out to sample their environment, consume antigens, and then display them on their surface to communicate what invaders may be lurking around.

The dendritic cells then pass the information to T cells. Each T cell has a unique receptor corresponding to a specific antigen. When a T cell encounters a dendritic cell displaying the correct antigen, the T cell can turn into a highly efficient killer that eliminates invaders harboring that matching antigen. Further, B and T cells maintain a memory of the invasion that elicits an even faster response should the invader be detected again. While this network is generally very efficient and effective, the same system has the capacity to put the body that the immune system normally protects in its crosshairs.

A “self-less” decision: preventing the body from attacking itself

Normally, the immune system is able to differentiate between a foreign, “nonself” antigen, and a “self” antigen which acts as a fingerprint of the body’s own cells. In some cases, though, the immune system mistakes a “self” fingerprint as foreign and mounts a response against it. This occurrence, known as autoimmunity, can lead to damage of the body’s own tissues and the development of a range of conditions known as autoimmune diseases.

Autoimmunity can occur in a number of ways: following infection by a virus or bacteria, from certain genetic variants, often in interaction with risk factors such as smoking and environmental hazards, or even during the course of treatment for other diseases. Autoimmune diseases represent a massive array of conditions affecting nearly all parts of the body (Figure 2). Perhaps because of the diversity of the causes and the effects of autoimmune diseases, treatment options have been very limited. But mRNA vaccines were recently shown to be a promising new treatment avenue. 

mRNA vaccines: not just for pandemics

Historically, treatments for autoimmune diseases have been sparse and often focus on managing symptoms instead of curing the disease. Many of the standard treatments for autoimmune diseases can also have harmful side effects. Targeted treatments that solve the condition without harmful side effects must therefore be developed. Recently, a study turned to a promising technology for this effort: mRNA vaccines. 

The development of mRNA vaccines for Covid-19 has received significant press and attention. These vaccines employ mRNA, a molecule present in all cells that carries instructions from DNA to make proteins. Covid vaccines use mRNA to deliver information about a key coronavirus antigen to the many cells of our immune system. Once familiar with the Covid antigen, B and T cells can remember it, preparing them to eliminate the virus quickly and efficiently should we get exposed in the future. 

An mRNA vaccine for an autoimmune disease, on the other hand, would work to suppress the immune system. The vaccines would contain mRNA particles that deliver instructions for making “self” antigens commonly attacked in autoimmunity, acting as intel for dendritic cells to pick up. Dendritic cells present these “self” antigens to a specific variety of T cells called regulatory T cells, or Tregs. Tregs work as regulators instead of assassins, suppressing the attacker T cells and preventing them from becoming overactive and damaging the body.

To test whether mRNA vaccines can be used for treating autoimmune diseases, researchers focused on multiple sclerosis (MS). A “self” antigen associated with the development of MS belongs to a protein called MOG that forms a protective coating around the nerves of the brain and spinal cord. In cases of MS, the immune system mistakenly attacks MOG, destroying the protective coating and leading to a breakdown of the flow of information in the brain and spinal cord (Figure 3, left). The researchers gave an mRNA vaccine containing the information for the “self” antigen of MOG to mice with a disease that models human MS. Remarkably, disease progression was halted in vaccinated mice.

Examination of the brains and spinal cords of vaccinated mice revealed that the protective coating was largely still intact compared to unvaccinated mice (Figure 3, right). Further, researchers found fewer killer T cells and more Tregs in vaccinated mice, suggesting fewer assassins but more regulators that can dampen the immune response are deployed.

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Though this study seems promising for the future of autoimmune disease treatments, substantial future work will be needed to determine if the therapies work in humans. Further, although MOG seems to be associated with the onset of MS, it is not the only “self” antigen that can drive the disease. As a result, not all individuals with MS may benefit from this particular vaccine.  But the promising initial results for mRNA vaccines towards MS will likely inform similar work towards other autoimmune conditions. After all, the better information we receive, the better we can protect our bodies from damage. 

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Garrett Dunlap is a PhD candidate in the Biological and Biomedical Sciences program at Harvard Medical School. He can be found on Twitter at @dunlap_g.

Shreya Mantri is a PhD student in Biological and Biomedical Sciences at Harvard Medical School.

Cover Image: “Surveillance” by jonathan mcintosh is licensed under CC BY-SA 2.0

 For More Information:

• Check out this article describing various types of T cells, and how they work differently to benefit the immune system.
• Read more information about the initial results for the multiple sclerosis mRNA vaccine here.
• Want to learn more about how the immune system evolved? Read here about how a fish out of the prehistoric era is teaching us about the origins of our T and B cells.
• Nearly 80% of individuals with autoimmune diseases are women. Read this article in The Atlantic for more information about why women are disproportionately affected.

This article is part of our special edition on networks. To read more, check out our special edition homepage!