Continuing what has apparently become a series of explaining poorly understood illnesses, this week we’re going to talk about autoimmune disease. This is still an area of study that isn’t understood terribly well, so it can be hard to talk about. But with our previous discussions about the immune system for Covid and vaccination, this might provide further insight.
Self vs Non-Self Proteins or Molecules
Yes, those are the technical terms. Self refers to any proteins or molecules that are normally found in the body’s tissues while non-self refers to proteins or molecules that are foreign to the body. The acquired immune system is supposed to remove and destroy any dangerous non-self molecules while leaving self molecules untouched.
I’ve touched on the basics of the innate and acquired immune system before, and I encourage you to click over and refresh your understanding before going on.
Now, let’s go into a bit more detail. As stated before, your innate immune system is the first line of defense against pathogens such as bacteria and viruses, but they can rarely fight off an infection on their own. So certain cells in the innate immune system (called dendritic cells) will “eat” these pathogens, tear them apart, and mount pieces of these germs (called antigens) on their cell membranes. These dendritic cells will activate the acquired immune system by traveling to the nearest lymph node, which houses thousands of naive T and B cells. Each of these T and B cells has a unique protein on its surface that is able to bind very tightly to a very specific protein or molecule. The dendritic cell tests the antigen it’s carrying with every naive T cell it comes across until it finds one that can latch on strongly to the antigen. This naive cell will then mature, reproduce rapidly to create a line of identical cells, and will attack anything that has this antigen. B cells manufacture antibodies, proteins which latch onto antigens in order to disable pathogens and make them easier for other immune cells to track. Killer T cells identify antigens on body cells, usually meaning the cell is infected or cancerous, and kills them. Helper T cells identify the presence of antigens in the body and secrete molecules that rally other immune cells to attack. Once the infection has been defeated, a few mature T and B cells will live in the lymph nodes for the rest of one’s life, allowing the body to respond quickly to the same infection again.
The problem with this setup is that it’s possible for T and B cells that attack the body’s own tissue to develop and become activated. When T and B cells are created, the gene which encodes for their binding protein is randomly altered to create a unique target antigen for each cell. There is nothing to prevent this random binding protein being one that attaches itself to insulin or hemoglobin or something else important. So how does the body avoid this?
To use a metaphor, the acquired immune system creates millions of soldiers, each highly trained in killing one very specific opponent. This opponent might be an actual enemy of the body, or it could be something from the body itself. To filter out these self-attacking soldiers, there is a multi-staged training process. First, each soldier is tested on if they can obey the innate immune system and only attack when they’re told to. Next, each remaining soldier is shown normal body proteins and tested on whether they attack. Last, a few of these body-attacking soldiers are retrained to defend their former targets, so that any future soldiers that attack these targets will have to get through them. To go into a bit more detail;
T and B cells (collectively called lymphocytes) go through a complex maturation process before they’re allowed to migrate to the lymph nodes and await activation. Taking place in the thymus for T cells and the bone marrow for B cells (notice the naming convention?), each new lymphocyte is checked that it won’t activate unless it’s shown certain proteins. Put simply, this means that T cells will need a dendritic cell to activate it and B cells will need a T cell to activate it. This ensures that lymphocytes won’t activate without the express permission of the innate immune system, which itself only activates for legitimate infections. Lymphocytes that don’t recognize these “ID” proteins are culled.
The next stage of the maturation process directly filters out self-active cells. Special cells in the thymus and bone marrow produce trace amounts of almost every protein found circulating in the blood, with any immature T and B cells that bind to these proteins being immediately killed. Only about 2% of these cells survive the maturation process, but these survivors will be highly unlikely to react to self. Mature lymphocytes that pass both tests will migrate to the lymph nodes where they have a natural lifespan of about nine years or until they are activated.
A few helper T cells that are self-attacking aren’t killed however. Those that meet a few very specific conditions will instead be reprogrammed to defend their antigens. These T regulatory cells (Tregs) will patrol the bloodstream and whenever they detect their antigen, they’ll secrete hormones that stop other immune cells from attacking. This means that if self-attacking T cells are ever created by accident, these Treg cells can already be prepared to shut down these attackers before they can cause damage.
Autoimmunity
This system for preventing the immune system becoming self-active may be robust and multilayered, but it’s not foolproof. Tens of millions of naive lymphocytes are produced every day, so there’s always some chance of a self-active cell accidentally passing inspection. There’s some chance that a self-active T cell won’t need a dendritic cell to activate it. And there’s some chance that the tissue type this T cell will attack won’t have an existing line of Treg cells defending it or that this line of Treg cells won’t be sufficient. If a line of lymphocytes were to evade all these safeguards, one could wind up with an autoimmune disease. Killer T cells from this cell line could attack healthy tissue because they mistake it for infected cells. This can result in certain cells being permanently killed off, such as with Type I Diabetes or Addison’s Disease. Tissues that can heal might have significant damage and scarring that compromise their ability to function, such as with Multiple Sclerosis. Or there could simply be chronic inflammation that results in tissue damage or a loss of function, such as with Rheumatoid Arthritis or IBD. This immune response to something inside the body can also cause the immune system to be consistently or permanently upregulated, causing symptoms ranging from fatigue to rashes to low-grade fever. Many of the symptoms of lupus and psoriasis are caused by this immune hyperactivity. In virtually all cases, these illnesses are chronic as the immune response is lifelong.
What exactly triggers an autoimmune response in any given person is still very poorly understood. The immune system is an incredibly complex system and the exact trigger might be different between different people. But some common hypotheses are:
Stress, both physical and mental, has been linked with autoimmune disease. While multiple studies have found that autoimmune disorders are more common with those with stress disorders, such as PTSD, the exact link isn’t understood. It is possible that the chronic inflammation caused by stress disorders leads to immune system hypervigilance, making the activation of self-active cells more likely and their regulation harder.
Exposure to certain toxins and foreign substances have been linked to increased prevalence of autoimmune disorders. This could be because they cause chronic inflammation or because they are molecularly similar to proteins found in the body, so an immune response to the toxin also affects tissue. Substances linked to autoimmune disorders include chemicals in cigarette smoke, silica dust, and numerous chemicals linked with occupational exposure.
Certain bacteria and viruses are believed to be potential triggers for autoimmunity as immune responses to them also affect body tissues. This is an ongoing area of research, as what pathogens cause this response, how long exposure needs to last, and how long this response occurs are all still being studied. There has been speculation that Covid-19 might cause autoimmune reactions in certain patients, but it will be a while before enough data can be collected to say anything with certainty.
Certain genes are directly linked to a higher prevalence for autoimmune diseases. These genes are those that encode for proteins critical to the lymphocyte maturation process or for lymphocyte activation. Certain mutations to these important proteins can break them, removing layers to the defenses against autoimmunity. Now, these gene variants don’t result in a higher propensity of a specific autoimmune disorder, but for a higher propensity for autoimmune disorders in general. If one has a family member with significant autoimmune disorders, their risks for developing any autoimmune disorder could be higher.
Genes have also been discovered that correlate with specific autoimmune diseases, but how exactly these genes connect to these disorders isn’t well understood. (We often don’t know how a certain gene contributes to a certain condition, just that patients with certain genes are statistically more likely to have certain conditions) It has been proposed that these gene variants affect how particular body proteins are expressed during the maturation process. For example, a certain gene might make it harder for insulin to be expressed in the thymus. This means that T cells that react to insulin won’t be filtered out, making it more likely that Type I diabetes will occur.
Treatment
Since some T and B cells will live in the lymph nodes indefinitely, autoimmune disorders are chronic conditions. Thus, treatment usually consists of symptom management, typically with anti-inflammatory and immunosuppressive drugs such as corticosteroids.* Treatment might also include artificially-produced hormones to replace the ones lost due to autoimmunity, such as insulin for diabetics. Healthy diet and other lifestyle choices are also beneficial, as it can promote basic immune system health. Even if self-active lymphocytes are present in the body, a healthy immune system can keep these cells in some degree of check with Treg cells and by properly regulating the strength of immune responses.
But research is ongoing into how to treat these conditions in a more permanent manner. In recent years, a topic of research has been artificially creating Treg cells. By studying the complex intermolecular mechanisms by which the body reprograms T cells into Treg cells, scientists hope to be able to isolate self-active T cells from a patient, turn them into Treg cells, and reintroduce them to the body in order to downregulate an autoimmune response. This research is promising, albeit ongoing. Another area of research is examining ways to isolate affected tissue from the immune system. For example, one could implant a diabetic patient with a kind of “cage” that contains insulin-producing cells. These cells could restore healthy insulin production while the “cage” protects them from attacks by self-active T cells. Trials in mice have been extremely effective though human trials have yet to be attempted.
If this post was at all confusing to read, that’s quite understandable, as I found it rather difficult to research and write. The human immune system is one of the most complex parts of the body. It must mount multiple lines of defense against a wide selection of danger from both outside and within while also not causing too much collateral damage to the body it’s protecting. And while complex systems are often more robust, they can also have more points of failure. Luckily, autoimmune disorders are another field of medicine that benefits from the explosion of computing power and data-analysis in the field of biology. Large scale data collection and supercomputing makes it possible to identify the thousands of genes and proteins that make up the mechanisms of the immune system and to trace how they all interact with each other. There is still a lot of work to do in the mapping of this intricate system, but the research won’t stop until it has been mapped.
*It should be noted that corticosteroids are not the same as anabolic steroids. The word steroid simply refers to any organic molecule with a particular structure, specifically four carbon rings. Many hormones and signalling molecules are steroids, including cortisol (a hormone that downregulates the immune system) and sex hormones including testosterone. Steroid drugs are artificially generated steroid molecules for either purpose.
For More Details
https://www.breakthroughs.com/biology-explained/get-know-t-team-immune-systems-special-defenders (Image 1)
Comments