Introduction
The word immune comes from the Latin root “immunis” which means “exempt from.” Immunity is defined in Meriam-Webster as “the ability of an organism to resist a particular infection or toxin by the action of specific antibodies or sensitized white blood cells” (Meriam-Webster, 2018). Putting these together, autoimmunity is immunity in which your body is not exempt from itself, the body is incapable of distinguishing “self” from “non-self,” and cause many different diseases. One such disease is rheumatoid arthritis. Rheumatoid arthritis is an autoimmune disease that is present in about 1% of the population thought to have heritable causes (Hemminki et al., 2009). Rheumatoid arthritis is characterized by inflammation of synovial fluid and hyperplasia (which both cause swelling), production of autoantibodies, destruction of both cartilage and bone, as well as other disorders involving the cardiovascular, pulmonary, and skeletal disorders (McInnes and Schett, 2011). While typically it is believed to be a “syndrome of the elderly” it can be found in children as young as 10 (Weyand, Fulbright, and Goronzy, 2003). Rheumatoid arthritis is an autoimmune disease in which Thelper (Th) cells do not recognize “self.” This paper discusses the intended function of the immune system, how autoimmunity differs from the normal function in rheumatoid arthritis, and the role of the Th cell in both instances.
History of Autoimmunity
The discovery of microbial diseases contributed to the discovery of the immune system which acts to fight off infectious diseases. Antibodies work to destroy bacteria through the mechanism of complement-mediated lysis which begged the question: does the immune system ever malfunction? Does disease occur if antibodies attack a host antigen? World War I had many scientists away from the lab, during which time a German bacteriologist named Paul Ehrlich published “Horror Autotoxicus” meaning the horror of self-toxicity and was accepted as proof that autoimmunity does not exist; effectively prolonging the discovery of autoimmune diseases by 40 years. It wasn’t until 1957 in which the discovery of autoantibodies of thyroglobulin in the research of Graves’ disease that autoimmunity was proven to exist (Adams, 1996). While much research has occurred since the late 1950s, a lot is still unknown about autoimmune diseases and how they function.
The Immune System in Healthy Physiological Conditions
In order to understand autoimmunity, we must begin with what the ideal picture of immunity looks like. The immune system is rather large and complex, involving numerous molecules and players. The first is a virus. A virus is an infective agent that contains protein-encased nucleic acids that utilize host cells for multiplication of itself. With that, a viral antigen in a protein that is encoded by a viral genome. Next are macrophages which are large, phagocytic cells. They are stationary but can be mobilized as white blood cells (WBC) when an infection is encountered. Then we have the T cells- thymus secreted lymphocytes, of which there are a few different types. Helper T cells (Th) cells are T cells that activate a range of other immune cells via the release of T cell cytokines. A cytokine is a cell that can affect another cell, also called an interleukin, and works to suppress or regulate the immune response. Memory T cell (Tm) is a T cell that has already encountered and responded appropriately to an antigen. There are also B cells, similar to T cells in that they are also lymphocytes, but these are not processed by a thymus gland but do produce antibodies. Antibodies are proteins in the blood that are produced in the response to a specific antigen by chemically combining with substances that the body recognizes as foreign. All of these can be found in plasma, the colorless part of blood and lymph.
In a healthy individual, the immune system takes roughly eight steps when generating an immune response under normal physiological systems. It begins when the body detects that a virus has infected the body which in turn, causes cells to display viral antigens. This recruits a macrophage to engulf the virus and display the viral antigen which then activates Th cells. The role of a Th cell is to activate cytotoxic T and B cells. Following, B cells form plasma cells which are responsible for making antibodies that attach to the virus and any infected body cells to signal for their destruction. The cytotoxic T cells then destroy the virus and all infected body cells which are eventually excreted through the digestive tract (Adams, 1996). But this is only half of a very large picture.
Figure 1. The immune system function under healthy physiological conditions. There are roughly eight steps to an immune response under healthy physiological conditions. This figure is included to assist in visualizing the immune system, a topic not yet covered in ZOOL 312. (Negus, 2011).
Figure 2. Interaction between T cell and antigen presenting cell (APC). The T cell has a receptor known as the T cell receptor (TCR) that is capable of binding to the major histocompatibility complex (MHC) on the APC that holds the antigen of the toxin that initiated the response. This interaction highlights the area of “miscommunication” thought to cause autoimmune diseases. (Kahn Academy, 2018).
The immune system would constantly be working to fight off pathogens, working at full capacity all of the time, but the immune system has its own memory. Memory T (Tm) cells are able to recognize and destroy pathogens previously encountered at a more efficient rate. The leading mechanism proposed for self-tolerance is referred to as “recessive tolerance” which is often induced via a thymic deletion of autoreactive T cells. This has been shown to be incomplete and self-reactions can occur, even in healthy individuals. This is in contrast to “dominant tolerance” which is another mechanism proposed to maintain the peripheral self and is controlled by regulatory T cells (Dejaco et al., 2006). In short, even a small portion of a healthy individual’s T cells do not recognize “self.” This is where the pathology begins.
Defining Autoimmunity & Rheumatoid Arthritis
As of 2013, the study of how genetics and environment interact in the promotion of immune system dysregulation and the key players (cytokine mediators) involved have been studied extensively (Henriques et al., 2013). But it was not until the 1980s that the consideration of T lymphocytes as a role in the pathogenesis of rheumatoid arthritis (RA) was considered which quickly resulted in a surge of hypotheses that focused on T cell and its role in immunological pathologies (Fox, 1997). Fast-forward to 2005, research into the Th cell has provided invaluable insight into RA (Wilke et al., 2011). As stated earlier, there are many types of T cells, but there are subsets beneath these. Th17 cells were discovered as pro-inflammatory cells that are responsible for recruiting neutrophils and macrophages to infection sites (Tesmer et al., 2008). These cells are responsible for secretion of interleukin-17 (IL-17) which is a highly inflammatory cytokine that has a particular proclivity for stromal cells in a diverse set of tissues. These are what is believed to be the culprit of autoimmunity.
As stated previously, the healthy individual has recessive tolerance, but if this tolerance builds, it becomes dominant tolerance and a pathology. All immune responses, protective and harmful, are mediated by T and B cells, both of which have a large range of antigen recognition and specificity as well as provide long-lasting memory for the immune system (Sakaguchi et al., 2008). All of the delicate intricacies lead to a larger population of Tm cells that do not recall fighting what Th cells do not recognize as “self,” and the body attacks normal, healthy tissue. This leads to the hyperplasia and cartilage and bone destruction (McInnes and Schett, 2011).
Autoimmunity and Subsequent Effects on the Body
Rheumatoid arthritis is often considered an “invisible disease” as one does not see external “deformities” that are typically expected when the term disease is used. However, many people with RA that is not being treated or who are experiencing a “flare up,” or particularly aggressive symptoms, can be seen with red and/or swollen joints. But as one can imagine, the body contains an extremely large population of T cells that do not recognize “self” and go around attacking the entire body, not just the joints. According to the arthritis foundation many other symptoms can be experienced if diagnosed with RA including; nodules and rashes on the skin, Thinning of the bones, dryness and inflammation of the eyes, dryness of the mouth, inflammation and nodules in the lungs, atherosclerosis, heart attack, stroke, pericarditis, anemia, blood clots, pinches or compressed nerves, etc. (Dunkin, 2015).
The majority of RA patients are prescribed non-steroidal anti-inflammatory drugs (NSAIDs) which can help with pain. Biologics are often also prescribed to stop inflammation at the cellular level, typically injections the patient takes on a regular basis. There are several ways in which to attempt to get RA into remission (showing no symptoms). Many therapeutic strategies have been identified, targeting Th17 cells including: inhibition of amplification, neutralization of its cytokines, and inhibition of transcription factors; though no cure currently exists (Maddur et al., 2012). Recent advances in medical research have played with the idea that using gene editing technologies one can edit out this disease, this being highly controversial. There are other studies that are working on the hypothesis that one can “reprogram” cells to negate the possibility of self-toxicity.