The disease I have decided to research is Systemic lupus erythematosus (SLE). SLE is categorized as a chronic autoimmune disorder that causes inflammation in connective tissues such as cartilage and the lining of blood vessels. Since SLE causes chronic inflammation in connective tissues it can attack multiple organs and cause full body side effects such as fatigue, joint pain, skin rashes, kidney disease (lupus nephritis) and neurological and cardio problems. Lupus affects each diagnosed patient differently with minor symptoms to full blown organ failure. There is not a defined understanding as to why patients develop and express different symptoms at varying levels of intensity; however, it is understood that there is a genetic link which “triggers” this downstream effect of chronic inflammation in patients. This “trigger” is often a result from damaged cells not being able to properly heal or recover once this damage has occurred; with some of the most prominent examples being environmental causes like UV damage (sun burns or radiation), viruses like the Epstein-Barr virus and even certain drugs. Once this “trigger” is pulled, it cannot be stopped, and patients will ultimately develop lupus symptoms over the course of their life. Depending on the severity of the damage and how much inflammation is “activated” patients can develop the symptoms of lupus in a short span of a few months to never even developing noticeable physical symptoms. It is also important to note that with this genetic link and “trigger”, patients are born essentially born with lupus; however, as described above environmental factors help determine if a patient will ever develop lupus-like symptoms.
Lupus is a relatively old disease, with the first documented case recorded by Hippocrates in the year 400 BCE, it was medically classified and characterized in 1948 by Dr. Malcolm McCallum with the discovery of the LE cell. The term lupus itself comes from the Latin meaning of wolf because of the “wolf-like bite” the iconic lupus facial (malar) rash resembles. Lupus was originally described as a skin disease that caused “painful lesions and skin ulcers on affected patients” and the term Lupus vulgaris was prominently used throughout history to describe this disease. This changed with Dr. Malcolm McCallum found this unique cell found in lupus patients was later called the “LE cell” for Lupus Erythematosus. This LE cell is the end result of either phagocytosis of free nuclear material or an actual autolysis of one or more lobes of the nucleus. This cell also is practically always a mature neutrophilic polymorphonuclear leukocyte, meaning that this cell was a result of polymorphisms throughout the cell. What makes this cell so unique is that the LE cell could be present when no other symptoms were shown in patients, suggesting that there is this genetic component and patients are “born with lupus” or that there has to be some immune response that activates these lupus-like symptoms.
McCallum also went on to research how non-LE marrow incubated with LE serum can produce LE cells, resulting in the conclusion that there is a “triggering” effect of SLE. This was further proved through research concluded in 1957 that there was a factor in serum of some cases of SLE that reacted with DNA. This reaction of DNA lead to the eventual discovery of antihistone antibodies and the importance of antibodies and their roles in SLE. This finally led to the modern-day discovery of antinuclear antibodies (ANA) playing a role in SLE and new forms of testing such as the “lupus band test” and Murine Model testing to help determine genetic predispositions to SLE and affected cells in lupus patients.
As briefly described above, lupus is defined as an autoimmune disorder in which the innate and adaptive immune systems create an inappropriate immune response to nucleic acid-containing cellular particles and produce these ANAs, which is found in all lupus patients. However, ANAs are incredibly common in the general population but not all people who have ANAs develop SLE. This leads to the conclusion that there are other mechanisms that promote this progression of autoimmunity into SLE, including different polymorphisms of genes that induce responses in the innate immune system. It has been found that a large number of SLE-associated single-nucleotide polymorphisms are found in genes that encode proteins involved in the induction of or response to type I IFNs. It was also discovered that genetic variants of IRF5 and IRF7, which are involved in signaling through endosomal TLRs, are examples of variants that can be mapped to molecular pathways responsible for innate immune activation. It was further researched that TLRs, TLR7 and TLR9, have specific genetic mutations that can trigger this disease. Both of these TLRs interact specifically with the MYD88 gene that provides instructions for making a protein involved in signaling within immune cells. This is a critical piece of information because this Myd88 acts as an adapter that connects proteins to stimulate signaling molecules that turn on a group of interacting proteins known as nuclear factor-kappa-B which regulate inflammatory reactions and protects cells from apoptosis. These polymorphisms actually cause malfunctioning of this Myd88 which result in this ultimate downstream regulation and overactivity of inflammatory reactions and cell apoptosis, causing lupus symptoms to emerge.
