The Enemy Inside: Rhumatoid arthritis and Autoimmunity

RA Ulnar Deviation

This week’s question comes from Cory, who asks, “I have been reading your blog posts, they are so great. I would love it you wrote one on autoimmune diseases, specifically Rheumatoid Arthritis. I have RA and the lack of information about it is astounding. The number of times I have been told that I have the same thing as Shaq (who has osteoarthritis) is unreal.” Well, Cory, I agree that there is widespread misinformation and misunderstanding about autoimmune diseases, including RA. Even worse, people tend to associate these diseases solely with the elderly, which could not be further from the truth. Let’s explore how autoimmunity works, highlight RA as an example. and efforts to treat it and other autoimmune diseases.

Autoimmunity, as you might infer from the name, is a type of disease where the immune system starts attacking the body’s own tissues. It can occur in just about every tissue the body has, though some types are much rarer than others. As we explored briefly in a previous blog, the body’s cells have surface markers that declare them as “self,” or part of the organism. When the body normally produces immune cells, it has mechanisms in place to prevent self-attacking cells from maturing and becoming part of the immune system. This is known as immunological tolerance The thymus is the organ where T-cells (hence the “T”) mature and autoimmune T cells are found and normally destroyed. B cells, which do not have a particular organ to mature within, undergo a process known as receptor editing during their maturation. Receptor editing tests the immature B cells against self antigens (identifying proteins) in the bone marrow and those that react strongly undergo apoptosis (cell death) to prevent autoimmunity under normal conditions. T cells undergo a similar process within the thymus. This process is not fool proof, as some low-levels of autoimmunity exist throughout the body, but on the whole that low level has minimal impact on normal functioning. So how, then, does this transition from normal to an autoimmune disease state occur?

The answer to this is unfortunately incredibly complicated and not well established in any one direction. I will do my best to summarize three of the prevailing theories, however this is going to be far from an exhaustive list. These are also not exclusive explanations; autoimmunity may be caused by one or a combination of these or other factors.

  • Loss of immunological tolerance: As noted above, immunological tolerance is the process by which B and T cells are exposed during development to self antigens and self antigen-reacting cells are destroyed. When this process is disturbed, autoimmune cells can avoid destruction and enter circulation. This can also occur if a certain type of self antigen not normally presented in the thymus or bone marrow is newly introduced into the blood by trauma or surgery or is absent all together from these maturation areas by genetic mutation.
  • Reduced regulatory T cell activity: Regulatory T cells are responsible for down-throttling the activity of T cells. Its job is two fold: modulate T cell activity back to normal after a pathogen has been eliminated and maintain immunological tolerance. The exact mechanism for this process is unknown. It is theorized that the reduced activity can either stem from suppression (by the use of other signaling molecules that keep them away) or by loss of sensitivity to their regulatory signal. It is thought that these issues may be genetic in nature, stemming from mutations expressed within the thymus that affect T cell function around the body.
  • Cross-reactive antigens: Certain pathogens can present antigens that are similar enough to a particular tissue’s self antigen to prompt a response against both. For example, syphilis and Klebsiella infections can cause autoimmunity against the mitochondria (anti-cardiolipin) and spine (ankylosing spondylitis), respectively.

Now that we have an understanding of how these autoimmune cells can get out and attack, let’s explore rheumatoid arthritis (RA) specifically within the context of our understanding. RA involves autoimmunity against the articular (joint) cartilage and synovial membranes (where the lubricating fluid for the joint comes from). This disease causes progressive joint damage, scarring, and eventually fusion of the bones and complete loss of joint function. It is systemic, which means that it can effect any part of the body, though it is most commonly recognized by its effects on the hands. It also has a host of related effects on the blood vessels, neurological system, heart, kidneys, lungs, and eyes. RA has a particularly strong genetic component, though a significant component also can be attributed to smoking or particular viral infections.

The mechanism by which RA operates is not definitively proven, but it is thought to involve inappropriate B cell-T cell interaction. Under normal circumstances, T cells recruit B cells to the site of an infection by use of messaging molecules called cytokines. There are many different types of cytokines, each with a specific message. The one of particular value is called tumor necrosis factor-alpha, or TNF-a. TNF-a is secreted by, among other cell types, T cells to promote many of the symptoms of infection, such as local inflammation, fever, etc. Combined with interleukin-1 (Il-1) and interleukin-6 (Il-6), which are signaling molecules from T cells that prompt local B cell maturation, these represent the most basic model of interaction between B cells and T cells. TNF-a has been shown to be a major regulator of Il-1, with increased TNF-a contributing to increased systemic levels of Il-1. It is thought that inappropriately increased TNF-a and Il-1 are responsible for setting in motion the inflammatory processes associated with RA. This TNF-a and interleukin activity is also thought to possibly kick off activation of similar immunological processes across the body, far removed from the original site. This model might explain the diverse side reactions present in RA across a variety of tissues that can’t possibly be explained by a simple loss of immunological tolerance. Other interleukins have significant roles (specifically Il-6, Il-15, and Il-17), however the effects of TNF-a and Il-1 on the progression of RA have been fairly well established in the literature.

So, as you may have already concluded, TNF-a and Il-1 present ripe targets for attack to prevent the process at the source. Drugs against TNF-a currently represent the mainline treatment method for treating RA. Molecules called monoclonal antibodies, which are essentially B cell antibodies against a particular molecule, that specially target TNF-a were created to do just this. Other similar antibody-based fusion protein bio-technologies have also been developed, with similar effects. Unfortunately, attacking this widespread and multi-faceted molecule can have negative effects on the immune system. Because it is so important to normal immune function, suppression of TNF-a can lead to undesirable side effects such as cancer, increased rates of infections, and congestive heart failure. So these drugs represent a powerful weapon in the fight against RA and other autoimmune diseases, however the benefit must be weighed with their strong side effects.

It is possible that the future will involve stimulating the body’s own regulatory mechanisms to present development of autoimmune conditions without inhibiting immune response. Il-2 has been shown to naturally decrease TNF-a production, which represents a potentially fruitful route for future research. However, the activity of TNF-a is only one mechanism. Many other autoimmune diseases are unfortunately not quite so well understood and must be treated with strong drugs like corticosteroids to induce broad immune suppression. Less damaging drugs can be used to control symptoms (ex. retinoids such as acitretin to reduce skin lesions in psoriasis) in lieu of immuno-modulating (changing the immune system) therapies like steroids and monoclonal antibodies.

It is clear that the induction of autoimmune disease is incredibly complicated and involves a variety of very complex cellular signally pathways we are only beginning to understand. Due to this, it will likely be many years before we can begin to attack these diseases without collateral damage to the wider immune system. But, luckily for those who suffer from RA, these anti-TNF-a drugs represent a quantum leap forward in the battle and may herald a new era of drugs capable of even more effectively modulating an immune system gone wrong.

Hope this helps, Cory! Thank you for the question. As always, everyone and anyone is welcome to submit a question.

Till next time, namaste.



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