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.
First off, a huge thank you to everyone who has read, shared, submitted questions to, and commented on this thus far. I really appreciate the support I have received.
This week’s question comes from Aerin, who asked, “I’m allergic to cats. Does that mean I’d be allergic to tigers?” Well, after some detailed exploration of this topic, I found that the answer to this is “kind of.” Obviously, this is not a particularly impressive answer, so I will definitely explain what I mean in a little bit. But, before I get into that, this question brings up the larger question of how we get allergies in the first place. So I wish to begin with an overview of what allergies are and how they are produced in the body before then exploring Aerin’s question more in-depth.
Allergies are the body’s response to something foreign, called an allergen (or, more generally, an antigen). The dictionary defines allergens as things that cause allergies (shocker!). While not a particularly helpful definition, it is more telling that it seems on the surface. This broad definition demonstrates the wide variety of environmental elements to which the body can react. In theory, the body could produce an allergy response to just about anything, from avocados to pet dander to bee pollen to the detergent you use. Even foods you’re normally not allergic to may present allergens if they have been cross-bred or genetically altered. Some responses may be mild, others catastrophic.
Antibodies are protein structures secreted by immune cells called B cells that seek out specific epitopes (the part of the antigen that the antibody can bind to). B cells come in billions of varieties, producing a correspondingly wide array of antibodies to allow the body to recognize a large number of possible antigens and epitopes. There are five different types of antibiodies (or immunoglobulins, abbreviated Ig): IgA, IgD, IgG, IgM, and IgE. The particular one that concerns us here is IgE due to its role in the formation of the symptoms we most readily associate with allergies. More on that in a bit.
Once released by the B cells, antibodies themselves “tag” the antigen when they bind to said epitope, thus marking it for the body to destroy or at least attempt to eliminate. They can also be used to disable antigens in their own right (which is the foundation of monoclonal antibody therapy), but that is outside the scope of this discussion. These tags, if they successfully attach to an antigen, prompt the division of the successful B cell in preparation for the possibility of an antigenic invasion of some type as well as the stimulation of other immune cells to flock to the area. Once the reaction has subsided, the B cells created for this purpose largely die off, except for some, known as “memory B cells,” which stick around in the body in a state of ready alert to ward off any previously encountered threat. This is the basis of the “immunity” one gets from vaccines. Unfortunately, antibodies are not particularly selective in terms of their target. If the protein it seeks is found locally, antibodies can initiate a damaging response to the body itself. The exact mechanism of how this comes about is debated (B cells that damage the body aren’t supposed to survive), but this is thought to be the main source of autoimmune diseases like rheumatoid arthritis.
IgE itself is an important immunoglobulin because it is the only immunoglobulin that stimulates mast cells and basophils, cells that contain and release histamine. As you may have realized if you take Benedryl or Claratin (over the counter antihistamines), histamine is responsible for a vast majority of the physical symptoms felt during an allergic reaction, including runny nose, watery eyes, tightness in the chest, flushing of the skin, hives, and swelling. It causes the swelling by making the capillaries less water tight (increasing their “permeability”) as well as dilating (opening up) the blood vessels feeding them, which allows for immune cells in the blood to cross through more easily and in greater numbers in response to the antigen. This leakiness also allows fluid to flow from the capillary to the surrounding tissue, resulting in the characteristic swelling. If this release of fluid happens to an extreme degree, anaphylaxis can occur, causing throat swelling and shock (when blood pressure drops to dangerously low levels due to a loss of blood volume). Epinephrine, the medication contained in an Epi-Pen, acts to reverse the constriction of the lungs and dilation of blood vessels. This can quickly reverse the symptoms as the fluid drains back into the bloodstream.
So now that we have a general idea of how the allergy response works, let’s dive into Aerin’s question. As you may or may not know, “big” cats like tigers and lions are more distantly related to house cats than is commonly believed. Although house cats look very much like miniature, less ferocious versions of big cats, they are actually only related at the family level (Felidae). That means they aren’t just separate species, but in separate genera (Panthera for big cats and Felis for house cats) as well. This is a fair evolutionary spread, which contributes to the ambiguity of the question’s answer.
Just about the only conclusive journal article I could find that tackles this issue head on comes from the July 1990 issue of The Journal of Allergy and Clinical Immunology. In this article, the researchers investigated if the main house cat protein known to cause allergies in humans (Fel d I) is found in big cats as well by examining Fel d I-specific IgE response (as well as the more general IgG response) to big cat dander. Their results were mixed. Although they found the IgE reacted with the proteins found in the big cat dander, the amount of reaction was nowhere near that of Fel d I itself. The tiger dander specifically was found closely in line with the other big cats. Based on that data and the authors’ conclusions, it appears that tigers can prompt an IgE response in house cat-allergic people, however not with the same vigor. In other words, being allergic to house cats means you’ll likely feel something if you come in contact with big cat dander, but the severity will likely differ from the original allergy.
Thank you for the question, Aerin! Hope this response helps! If you want your question answered too, you can submit yours directly to me by selecting the “Submit Your Question” tab at the top of this page.
Till we meet again next week, “Live Long and Prosper.”
Thank you to MCAT studying and biology classes for endowing me with the knowledge to explain this without significant help. Who knew you’d actually be useful?