Background
Autoimmune Diseases
Autoimmune diseases are conditions that are said to be caused by alterations in genes within the human genome (Quintero-Ronderos, Montoya-Ortiz, 2012). Autoimmune diseases have a direct effect on specific target organs or multiple organ systems (Anaya et al., 2016). It is as if the body is attacking itself in order to get rid of an infection (NIAID), antibodies and immune cells mistakenly target healthy tissues instead (NIH). Autoimmune diseases are also a subtype of immune-mediated diseases (Wilson et al., 2016).
Epigenetics, the study of changes in gene expression (Anaya et al., 2016) may be a leading cause of autoimmunity within the human body (Quintero-Ronderos, Montoya-Ortiz, 2012). Many autoimmune diseases cause inflammatory responses within the body (Quintero-Ronderos, Montoya-Ortiz, 2012). Epigenetic modifications within the gastrointestinal tract are critical in the process of developmental regulation (Häsler et al., 2013). Epigenetic alterations during the developmental process can lead to inflammation, thus leading to IBD’s like CD (Häsler et al., 2013). Within CD, there are 50 methylation sites that have been found to be epigenetically modified (Häsler et al., 2013). DNA methylation is important to the cause of CD since it interacts with the environment and genome (Loddo & Romano 2015). It also acts as a mediator of genetic risk that has an effect on the cells (Gutierrez-Arcelus et al., 2016). Variation in DNA methylation causes disease and complex disorders (Loddo & Romano 2015). Exposure to certain environmental factors has shown to trigger diseases (Gutierrez-Arcelus et al., 2016). Gene expression within CD is altered due to changes in the chromatin structure (Loddo & Romano 2015).
According to Dinarello, inflammation is caused by the T-cell being associated with pathogenesis as a dysfunctional cell; and in order to treat autoimmune diseases, immunotherapies that target T-cell function and antibodies that deplete T and B-cells are used. It has been found that autoimmune diseases are linked through, Interleukin-1, a pro-inflammatory cytokine, found amongst all tissues within the body (Dinarello, van der Meer, 2013).
There are about 80 different autoimmune disorders and about 3-5% of the population is affected by these disorders (Kochi, 2016). A few examples of autoimmune diseases are type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease (NIH). The first symptoms of autoimmune diseases usually come in the form of fatigue, muscles aches, and a low fever (MedlinePlus). Inflammation is also a common sign of autoimmune disease (NIH). Oxidative stress, as shown in Figure 1, within the cellular pathways is caused by environmental
and lifestyle factors. These factors include smoking, UV light, viral infections, and even medications (Anaya et al., 2016). The environmental factors that have this effect activate the
mammalian target of rapamycin (mTOR) pathway which acts as an inhibitor of DNA methyltransferase 1 (DNMT1) (Anaya et al., 2016). Oxidative stress brought into the CD4+
cells cause a decrease in protein kinase C (PKC), causing a functional loss of PKC and reduction of the phosphorylation of extracellular signal-regulated kinase (ERK) (Anaya et al., 2016). (Anaya et al., 2016). Once ERK is phosphorylated, DNMT1 expression becomes reduced and CD4+ cells become autoreactive after the occurrence of DNA hypomethylation (Anaya et al., 2016). After CD4+ T-cells become autoreactive, overstimulation of antibody production takes place (Anaya et al., 2016). This antibody production is caused by B-cells and kill macrophages to induce apoptosis (Anaya et al., 2016).
The pathogenesis of autoimmune diseases involves the role of cytokines (Moudgil & Choubey, 2011). It has recently been found that autoimmune pathogenesis depends on the cross-regulation of T helper (Th)1 and Th2 to create a cytokine balance (Moudgil & Choubey, 2011). Th1 and Th2 cells produce different cytokines, as well as other T cells, as seen in figure 2. As it says in Figure 2, cytokine responses that are either reduced or increased will eventually lead to inflammation within the body and for specific autoimmune diseases (Moudgil & Choubey, 2011). The shape in the middle of figure 2 refers to the types of properties that become apparent during varying stages of autoimmune diseases. Th1 cells serve to activate as macrophages when inflammation at a specific location is occurring (Jäger & Kuchroo, 2010).
Crohn’s Disease
Crohn’s disease (CD) is a type of chronic, autoimmune, inflammatory bowel disease (IBD) caused by either genetics or environmental factors (Kamdar et al., 2016). Pathogens have also been found to be a factor in the cause of the condition. (Robertson et al., 2016). Those with Crohn’s disease have an increased amount of mucosa-associated adherent-invasive E.coli, which increases the secretion of TNF (Torres et al., 2017), tumor necrosis factor alpha. mucosa-associated adherent-invasive E. coli reduces the amount of Faecalibacterium prausnitzii, a commensal bacterium that has anti-inflammatory properties is reduced (Torres et al., 2017). According to MedlinePlus, inflammation in CD occurs within the ileum, which is located in the lower part of the small intestine. Crohn’s disease can lead to bowel damage and disability since it is a progressive disease (Torres et al., 2017).
The Crohn’s & Colitis Foundation (CCFA) has stated that the general symptoms and signs that indicate the presence of CD are a fever, loss of appetite, weight loss, fatigue, night sweats, and loss of a normal menstrual cycle for women. A common scenario that occurs when a person is experiencing CD for the first time is abdominal pain in the right lower quadrant, chronic diarrhea, and weight loss (Torres et al., 2017). In patients that are experiencing the condition for the first time with the colon, anorexia, rectal bleeding, bloody diarrhea, and fatigue are the common symptoms (Torres et al., 2017). Depending on the severity of the condition, symptoms may range from mild to severe (CCFA). There are three main goals with treating CD, as according to the CCFA; achieving remission-meaning that there are no symptoms present, maintaining remission, and improving a patient’s quality of life-making yourself and others more aware about the condition.
Loddo and Romano have stated that about 15% of patients with CD have at least one family member with some type of inflammatory bowel disease. CD affects more than 2.5 million individuals, specifically in the Western part of the world (Boyapati et al., 2015). The condition does not affect one gender more than the other (Torres et al., 2017), CD affects both men and women equally (CCFA). CD is found to develop more between the ages of 20-29 (NIDDK) the condition is also most commonly reported in northern Europe, the United Kingdom, and North America (Ha and Khalil, 2015). According to the CCFA, there are several types of CD that are determined by the symptoms that a patient experiences, which vary, some more severe than others. Ileocolitis, the most common form; ileitis, which only affects the ileum; gastroduodenal, affects the stomach; jejunoileitis, causes patchy areas of inflammation; and granulomatous colitis, which affects only the colon (CFFA).
The likelihood of getting CD is higher for those who live in developed countries and urban areas (Torres et al., 2017). Interestingly, those of Jewish descent have a higher risk of getting CD than those in non-Jewish, African American, and Asian populations, who have the lowest risk of getting the disease (Torres et al., 2017). As these low risked countries have started adopting a western lifestyle, the incidence of CD has actually increased (Torres et al., 2017). Factors such as smoking and various oral medications have increased the risk of the condition (Torres et al., 2017). More specifically, Torres et al. have stated that exposure to antibiotics during childhood has been able to increase the risk of CD. Figure 3 shows the environmental exposure or triggers that lead to CD (Boyapati et al., 2015). There are various environmental factors and lifestyles that lead to epigenetic mutations, which increases the risk of getting CD, but there are three main triggers that actually lead to Crohn’s disease: genetics, gut immune response, and the microbiota (Boyapati et al., 2015). Since many people suffering from CD face similar and sometimes different side-effects, depending on the severity of the condition, specialized and customized treatments are made (Boyapati et al., 2015). Customized treatments include the dosage amounts of medication, amount of time a medication should be taken, and the formulation (CCFA). These treatments are also trials, giving researchers more understanding on the genetic and molecular pathways involved in CD (Boyapati et al., 2015).
According to Man et al., microbiota play an important role in host nutrition and gut development. Microbiota also contributes to the immunological homeostasis of healthy gastrointestinal tracts (Man et al., 2011). Changes in the microbiota lead to adverse effects on the health of the host leading to dysbiosis, an imbalance between protective and harmful bacteria (Man et al., 2011). Because of this imbalance, inflammation may occur, leading to chronic intestinal inflammation (Man et al., 2011). Studies that have been done showed that patients with Crohn’s disease had a decrease in Gram-positive bacterium and an increase in Gram-negative proteobacterium (Man et al., 2011). Figure 4 presents a schematic of the possible pathways that lead to Crohn’s disease and the factors that lead to microbiota alterations (Man et al., 2011). Alterations in the microbiota cause the gastrointestinal tract to develop susceptibility to infection (Man et al., 2011). Infection within the gastrointestinal tract can lead to thinning of the mucus layer (Man et al., 2011) This then, in turn, results in inflammation since the bacteria has traveled to the submucosa after the intestinal epithelium has been broken down (Man et al., 2011). Crohn’s disease, according to Huang and Chen, can have innate immune abnormalities that will eventually lead to adaptive immune disorders. In the innate intestinal immune system, there are certain components involved in defense; the intestinal mucosal epithelial barrier, natural immune cells, and innate immune molecules, (Huang, Chen, 2016). Adaptive immunity works alongside innate immunity to present antigens for T-cells and provide activation signals (Huang, Chen, 2016). In CD, macrophage levels increase, which plays a major role in the pathogenesis (Huang, Chen, 2016). It has been found that certain cytokines are responsible for the driving force of inflammation in Crohn’s disease (Strober, Fuss 2011). These pro-inflammatory cytokines include IL-12, IL-17, IL-18, IL-21, IL-23, and IL-32 (Nemeth et al., 2017).
Current Treatments for Crohn’s Disease
Diagnosing CD involves an endoscopy and colonoscopy (Torres et., al 2017). Currently, there is no exact cure for CD, but there are medications and treatments that help reduce the symptoms of the condition. Some of these medications also aid in putting a patient through remission. Flare-ups are a common occurrence with CD, especially if environmental factors are taken into consideration. Because of the limited treatment, those with CD suffer from a high risk of recurrence for the condition (Singh et al., 2012). Currently available treatments for CD include aminosalicylates, corticosteroids, immunomodulators, and biological therapies (NIDDK).
Depending on the severity of CD, bowel rest or surgery may be the best treatment for a patient (NIDDK). Aminosalicylates are usually prescribed to patients who have just been diagnosed with CD and are only experience mild symptoms (NIDDK). Aminosalicylates are medications that lower inflammation due to containing 5-aminosalicylic acid (NIDDK). Corticosteroids, more commonly known as steroids, not only lower inflammation but lower the immune system (NIDDK). Corticosteroids are prescribed when a patient is experiencing moderate to severe CD symptoms (NIDDK). According to Torres et al., about 28% of patients become steroid dependent, meaning that certain medications have no effect when maintaining remission.
Immunomodulators, like corticosteroids, lower both inflammation and the immune system (NIDDK). This type of medicine starts taking effect in about several weeks to 3 months (NIDDK). Immunomodulators also lower the need for having surgery, which is usually the last resort, depending on the severity (Torres et al., 2017). There are many side effects to the medication treatment, especially depending on the dosage prescribed (CFFA). CD only has so many treatments, the cost of medication tends to become more expensive, each year, especially because there is a lack of generic brand medication, which is usually the more affordable choice. Table 1 shows the types of medications used for Crohn’s disease and the location where the medication targets within the gastrointestinal tract. These medications are used for specific target areas because depending on the severity of the condition, more areas may be more affected than others. Also, the location of inflammation indicates the type of IBD a patient has, CD or ulcerative colitis (UC). Mesalamine is a type of medication that goes under the same category as aminosalicylates, which acts like aspirin (CFFA).
Interleukin-1 Family
Interleukin-1 (IL-1) is a pro-inflammatory cytokine that damages tissues and causes a lot of pain (Dinarello et al., 2012). There are two types of IL-1 genes, ILIA and ILIB which encode for IL-1 and IL-1 (Dinarello et al., 2012). IL-1 and IL-1 are inflammasome products that trigger the adaptive immunity pathways (Lopalco et al., 2015). When IL-1 is bound to the receptor, IL-1 triggers chemokines and cytokines, which leads to inflammation (Dinarello et al., 2012). IL-1 damages tissues by causing inflammation within the body’s tissues (Dinarello et al., 2012). IL-1 is actually a cytokine family that consists of several other members besides IL-1 and IL-1 (Dinarello & Netea, 2013). Table 2 shows a list of pro-inflammatory cytokines within the IL-1 family. These are the types of cytokines that signal for inflammation within the body. Of the 11 cytokines, there are 2 antagonists that try to inhibit inflammatory activation: IL-1Ra, an antagonist for 1L-1alpha and IL-1beta, and IL-36Ra, which is an antagonist for IL-36alpha, IL-36beta, and IL-36gamma (Dinarello, 2011).
In one study, patients treated with IL-1 to help increase bone marrow function have begun experiencing an array of side-effects such as fever, loss of appetite, fatigue, muscle and joint pain, and gastrointestinal disturbances (Dinarello et al., 2012). This study has found that IL-1 causes more pain than actually helping. It has been found that blocking IL-1 can be used for a variety of autoimmune conditions such as rheumatoid arthritis and psoriasis (Dinarello et al., 2012).
According to Dinarello et al., targeting IL-1 had begun back in 1993. During this time, a recombinant of form of the interleukin-1 receptor antagonist (IL-1Ra) called anakinra was introduced (Dinarello et al., 2012). Another study conducted by Vounotrypidis et al. had shown that mice lacking the receptor antagonist were more likely to develop spontaneous instances of inflammation.
Figure 5 shows the signal and signaling inhibition by Interleukin-1 receptors. Each of the cytokines has specific receptors that they bind to. Each member of the IL-1 family has a Toll-1L-1-receptor (T1R) domain (Dinarell0, 2011). Part A shows that the cytokine and receptor are able to form a complex, initiating the signal to recruit the MyD88 adapter protein (Dinarello, 2011). Part B shows that there is no complex formed due to the signal being inhibited and failure to recruit the protein (Dinarello, 2011). Part C shows that the antagonist is able to bind to the receptor but is unable to create a complex therefore there is no inhibition of IL-1 (Dinarello, 2011). Part D simply lacks a TIR domain in the cytoplasm, therefore a complex cannot be formed, thus a signal cannot be released (Dinarello, 2011). The TIR domain is needed and present within the IL-1 receptors to perform inflammation inhibition (Dinarello, 2011). Part E shows an altered TIR domain and because of this alteration, the signaling has been inhibited (Dinarello, 2011). Part F shows that the three cytokines are able to bind to receptor and form a complex, thus showing that inflammation can occur (Dinarello, 2011). Part G shows that no signal occurs because the antagonist is unable to bind to the receptor (Dinarello, 2011). Hügel et al. had stated that the IL-1 antagonist may function as a switch in the phenotype that causes the inflammation.
How Are They Connected?
Crohn’s disease is related to autoimmune disease because it belongs to the category of inflammatory bowel disease, which is one of the common diseases caused by autoimmunity. CD and various autoimmune diseases involve immunity responses (Bolge et al., 2017). Studies have shown that all autoimmune diseases share the same inflammatory pathways, meaning those already diagnosed with an autoimmune disease have a much higher risk of developing another (Bolge et al., 2017). Autoimmune diseases are rare cases, but the prevalence of having an autoimmune disease has increased over the years in the United States (Bloge et al., 2017). Since the treatment of blocking interleukin-1 has been used to treat inflammation for a few autoimmune diseases such as rheumatoid arthritis and psoriasis, it may be possible to use the same treatment for CD, which could also be a cure. Inhibition of the IL-1 family has been found to lessen the amount of inflammation caused by other autoimmune diseases. Completely eliminating inflammation within the gastrointestinal tract is the main goal of finding an actual cure for CD.
Thesis Statement
Although Crohn’s disease has an increasing prevalence all over the world, many people are still not aware of the disease. The condition has an impact on many people and their daily lives not only psychologically and physiologically, but economically as well. Crohn’s disease has many side effects and the effectiveness of medication may have a delayed response. There is no single sure reason as to what causes this condition, but there are a few factors that have been found to trigger an autoimmune response leading to Crohn’s disease. Treatments for Crohn’s disease are very limited and there is no exact cure for the condition. Crohn’s disease should be correlated with other autoimmune diseases since many side effects of various autoimmune diseases and Crohn’s disease are very similar. It is possible that other treatments for other autoimmune diseases can be used as treatments for Crohn’s disease. I hypothesize that Crohn’s disease can be treated with therapies used for other autoimmune diseases, more specifically by blocking the Interleukin-1 family, which may be the answer to treating Crohn’s disease with very little side-effects.
Epigenetic alterations lead to autoimmunity and Crohn’s disease
Epigenetic alterations cause inflammatory bowel disease, such as CD (DeFilippis et al., 2016)
Since Crohn’s disease is caused by various environmental factors, the study of Crohn’s disease is taken at a molecular level. According to DeFilippis et al., Crohn’s disease may have an evolutionary adaptation to environmental microbes, which shows how genes respond to the bacterial infection. Crohn’s disease shows that genes overlap with each other, leading to an evolutionary adaptation to environmental microbes as a response to infection (DeFilippis et al., 2016). There are genetic pathways that are shared with about 30 Crohn’s disease-specific loci and genes that lead to Mendelian susceptibility to mycobacterial diseases (DeFilippis et al., 2016). Signaling through the JAK/STAT pathway has a role in Crohn’s disease since the pathway is involved in cell growth, differentiation, and immune system regulation (DeFilippis et al., 2016). Inflammation that occurs within Crohn’s disease is due to an abnormal decrease in the transforming growth factor TGF-beta1, an immunosuppressive cytokine (DeFilippis et al., 2016).
DNA methylation causes inflammation in Crohn’s disease (Karatzas et al., 2014)
Even though there is no exact cause for Crohn’s disease, epigenetic factors like DNA methylation are suggested to be involved in the pathogenesis of CD (Karatzas et al., 2014). It has been found in previous studies that chronic inflammation has a correlation to increased methylation (Karatzas et al., 2014). Genomic DNA samples were taken from blood and intestinal biopsies were taken from 12 adults with CD (Karatzas et al., 2014). The patients were categorized based on the type of CD they had-meaning the point location of inflammation (Karatzas et al., 2014). Methylation PCR analysis was used to profile the promoter methylation status of genes that are involved in both inflammation and autoimmunity (Karatzas et al., 2014). After Methylation PCR was performed, qRT-PCR was done to examine the expression of selected methylated genes, shown in the x-axis of Figure 6 (Karatzas et al., 2014). The y-axis refers to the amount of DNA methylation expression. These methylated genes were taken from the RNA extracted from the blood samples (Karatzas et al., 2014). Figure 6 shows the mRNA expression levels of the methylated genes for patients with CD and the control samples. Bars that show high relative expression refer to hypermethylated genes (Karatzas et al., 2014). There are genes that show slightly higher levels of methylation, but they do not show enough expression to be hypermethylated (Karatzas et al., 2014). Overall, the genes of patients with Crohn’s disease show that DNA methylation increases with inflammation (Karatzas et al., 2014). These results determined the levels of DNA methylation that occur in CD, depending on the severity, and how active the condition is showing that there are certain genes responsible for the pathogenesis of CD (Karatzas et al., 2014). Although extracting blood samples has proven to be successful, it still raises a concern due to the heterogeneity of cells being expressed (Karatzas et al., 2014).
Genetics play a major role in autoimmune disease and Crohn’s disease
There is a genetic overlap between Crohn’s disease and other autoimmune diseases
(Lees et al., 2011)
Genetics is one of the causes for the development of Crohn’s disease. According to Lees et al., defective processing of intracellular bacteria is the most common theme within CD pathogenesis (Lees et al., 2011). This is due to the fact that from the large gene discovery, that there are Crohn’s disease-specific genes: NOD2, ATF1gL1, and IRGM (Lees et al., 2011). This had brought attention to innate immunity on microbial recognition and autophagy (Lees et al., 2011). In CD, NOD2 is associated with a phenotype specific for ileal disease. It has been found from GWA studies that there are certain areas that have an overlap between Crohn’s disease and various autoimmune diseases such as ankylosing spondylitis, psoriasis, systemic lupus erythematosus (SLE), and type 1 diabetes mellitus (Lees et al., 2011). There are 23 genes that are shared by two or more diseases (Lees et al., 2011). Most of the genes had been found to be involved with T-cell differentiation, immune cell signaling, and the innate immune response (Lees et al., 2011). NOD2, with the recruitment of ATG16L1, is able to initiate autophagy to the cell membrane (Lees et al., 2011). This autophagy then leads to the bacterial entry that results in inflammation (Lees et al., 2011). Within the Th17 signaling pathway, there are four that are solely specific to IBD’s: IL-12B, STAT3, JALK, and TYK2 (Lees et al., 2011). These components are in charge of maintaining intestinal immune homeostasis. Figure 7 shows the overlap of certain susceptible genes for Crohn’s disease and various autoimmune diseases (Lees et al., 2011). Many of these susceptible genes are responsible for chronic inflammation within the IL-23/Th17 signaling pathway. The overlap in this figure shows that it is possible for treatments for various autoimmune diseases can be used for CD as well. Because the inflammatory diseases have an overlap, common treatment approaches could be used, according to Lees et al. A recent treatment had proved to be successful, Anti-TNF therapy was used to treat CD, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, and psoriasis (Lees et al., 2011). The genetic overlap, shown in Figure 7, between susceptible loci give rise to more treatments for diseases involving inflammation, especially CD (Lees et al., 2011).
Inflammatory pathways connect Crohn’s with other autoimmune diseases
Pathways are shared between Crohn’s disease and other autoimmune diseases
(Halling et al., 2017)
Many autoimmune diseases, along with CD, share biological pathways within the body. Since these diseases share pathways, the likelihood of attaining other conditions is very high (Bolge, et. al., 2017). Genetics is one of the major factors that lead to Crohn’s disease. Autoimmune diseases are categorized under immune-mediated disease. Susceptible genes causing inflammatory responses within the body have been identified amongst various immune-mediated and autoimmune diseases (Halling et al., 2017). Because these susceptibility genes have been identified, there are overlaps between the pathogenic pathways and the pathogenesis of the inflammatory conditions, overall (Halling et al., 2017). The susceptible genes play a role in maintaining microbial homeostasis within the gut, but mutations may impair the function of innate and adaptive immune response (Halling et al., 2017). Mutations lead to an imbalance of pro-inflammatory and anti-inflammatory cytokines (Halling et al., 2017). This imbalance will have an effect on the regulation of Th1, Th2, and Th17 (Halling et al., 2017). According to Halling, since most autoimmune and immune-mediated diseases are mostly Th1 mediated, CD, thus has a connection to other autoimmune diseases.
The Interleukin-1 family
Interleukin-1 plays a role in inflammation of Crohn’s disease (Vounotrypidis et al., 2013)
Since Crohn’s disease has an overlap with other autoimmune diseases such as rheumatoid arthritis, interleukin-1 may play a major role in inflammation (Vounotrypidis et al., 2013). It is believed that the two conditions have different expression of the same disease due to the pathogenic and clinical features (Vounotrypidis et al., 2013). Symptoms of the inflammatory conditions also overlap (Vounotrypidis et al., 2013). Cytokine levels for IL-1 between the two diseases differ, as well as the antagonist (Vounotrypidis et al., 2013). For Crohn’s disease, the levels are higher because the colon promotes an immunostimulatory reaction that is induced by the beta gene of IL-1 (Vounotrypidis et al., 2013). In mice models, those without Crohn’s disease or arthritis were more likely to gain intestinal inflammation, due to an increase of IL-1 beta mRNA (Vounotrypidis et al., 2013). Vounotrypidis et al. proved that through inhibition of the IL-1 receptor, with a different autoimmune disease, inflammation can also be reduced for Crohn’s disease.
The interleukin-1 treatment used for other autoimmune diseases can be a possible treatment for CD (Dinarello & van der Meer 2013)
Interleukin-1 (IL-1) is a cytokine that is responsible for local and systemic inflammation within the body (Dinarello & van der Meer, 2013). IL-1 plays a pathological role within the body for certain diseases and causes more inflammation (Dinarello & van der Meer, 2013). A naturally occurring antagonist, interleukin-1 receptor antagonist (IL-1Ra), present within the body blocks the IL-1 receptor in order to stop inflammation from occurring within tissues (Dinarello & van der Meer, 2013). Dinarello and van der Meer had figured this out through an experiment with mice. Mice who were IL-1Ra deficient had resulted in going through spontaneous flare-ups, similar to that in rheumatoid arthritis. This research done by Dinarello and van der Meer shows that inhibiting IL-1 will be able to stop inflammation that occurs with Crohn’s disease (Dinarello & van der Meer, 2013). There are two types of Interleukin-1 genes, IL-1 and IL- (Dinarello & van der Meer, 2013). According to Dinarello and van der Meer, IL-1 is naturally occurring in the bodies of those who are healthy while IL- is a product of blood monocytes, tissue macrophages, and dendritic cells. IL- can be self-inducing or can be induced by other IL’s, 1L-18 or IL-1 (Dinarello & van der Meer, 2013). This induction leads to inflammation within the body (Dinarello & van der Meer, 2013).
Safety issues when considering IL-1 blockade as a possible treatment
(Dinarello et al., 2012)
In another research study conducted by Dinarello et al., blocking IL-1 had been able to reduce disease severity in various inflammation-mediated diseases. Reversal of the inflammatory effects had been effective, which made it seem that blocking IL-1 could be a possible treatment for CD (Dinarello et al., 2012). IL-1Ra, also known as anakinra, is said to have an outstanding safety record (Dinarello et al., 2012). Many people suffering from other types of autoimmune disease, such as rheumatoid arthritis, have used the treatment for over 10 years (Dinarello et al., 2012). The only drawback from using anakinra as a means of blocking IL-1 is that patients using the treatment are more susceptible to bacterial infections over the course of treatment (Dinarello et al., 2012). According to Dinarello, studies have yet to use inhibition of the IL-1 family to treat Crohn’s disease since with the condition, comes an increase of IL-1 levels within the body. Despite the issue about bacterial infections becoming more prevalent in the case of using anakinra, the treatment may be the answer to lowering inflammation within the gastrointestinal tract with very little side-effects, in comparison to the commonly used medications that do come with them.
Social Impact: Current treatments for Crohn’s disease cause an economic strain
Crohn’s disease is very limited in treatments and many of the medications lack generic brands, making the cost of medication ever more expensive. Generic brands tend to be cheaper, but since Crohn’s disease is not a disease that so many people are aware of, there are mostly brand name medications which are more expensive. Limited treatments also mean that not much research has been done. It is important that people become more aware of this condition because it can benefit those who are looking for treatments. These medications are paid for monthly, which does tend to be costly, especially annually. Table 3 shows the types of medication used for Crohn’s disease and their prices. The red prices refer to the cost of the brand name medication, while the prices in black show the price for the generic brands. From Table 3, it is clear to see that there are currently only three brands of medication that have generic brands, showing why medication is so expensive.
Crohn’s disease is a life-long disease without any cure. It is important that a cure is found so that cost of the condition would be much more affordable. As someone who actually has Crohn’s disease, I believe that it is important that more treatments, more specifically a cure, can be found. Medicine is expensive, and the fact that there is a lack of generic brand medicine puts an even bigger strain, economically. Although the demographic for this condition is small, over the past few years it has grown to be a problem. It has been found that Crohn’s disease is a condition that affects certain demographics more than others. According to the CDC, the condition is more prevalent in people of Caucasian and Jewish descent in comparison to other ethnic groups.
Crohn’s disease is a painful disease, especially the more severe it is, and it takes a toll on those suffering from extreme symptoms. Because of the symptoms that come with Crohn’s disease, I feel like those who have the condition have to be more careful during the day. Also, current medications also have many side effects that also affect the daily lives of people suffering from Crohn’s. Many of these medications are steroids, which actually maintain the inflammation (CCFA). A lot of these medications also have negative effects on the immune system. Suppressing inflammation, unfortunately, also results in the suppressing of the immune system (CCFA). With a cure, those suffering would not need to worry so much about their condition and could continue on with their daily lives normally.
Conclusion
Crohn’s disease can be treated with therapies used for other autoimmune diseases, more specifically by blocking the Interleukin-1 family, which may be the answer for treating Crohn’s disease with very little side-effects. Because CD and other autoimmune diseases are linked to each other by similar inflammatory pathways (Bolge et al., 2017) it is possible for CD to share treatments that are used for other autoimmune diseases (Dinarello et al., 2012). It was found that those who are already suffering from CD have a much higher risk of getting another autoimmune disease (Bolge, et al., 2017), showing that there really is a connection between autoimmune disease. Besides pathways, cytokines are similar in linking the diseases. Many autoimmune diseases along with CD share pro-inflammatory cytokines (Lees, et al., 2011).
Targeting specific receptors that cause inflammation may be a way to reduce the inflammatory effects of Crohn’s disease, but it may not be an actual cure that will get rid of the condition entirely. Evidence has shown that blocking the Interleukin-1 family may be a treatment that patients have been looking for. Medications temporarily treat the condition so that the patient can be in a phase of remission, which must be maintained, by continuing to take oral medications. With these medications comes many side-effects that vary depending on the severity of CD that a patient has (CFFA). Blocking the actual Interleukin-1 family can lead to long-term effects that other types of medications cannot do, also with very little side-effects.
One of the main problems with CD medication is that it causes a big financial strain, especially because of the lack of generic brand medication. Patients pay monthly for their brand name medication, and even more when calculated yearly. Because of this research is important, especially making people more aware of Crohn’s disease. With finding an actual cure, the financial burden could be less of a strain. I believe that further studies should be done especially because of there being no exact cure for the condition. The limited types of treatments may have a more positive effect on some, but not others because of the many side-effects that vary depending on the severity of Crohn’s disease. Lack of treatments causes a great economic strain annually mostly because the readily available medication is brand name, with very little options for generic, and more affordable, brands.
The lack of research for inhibiting the IL-1 family shows that the mechanisms for other autoimmune disease work differently than for Crohn’s disease. The various studies that were done by Dinarello et al. have shown that blocking the IL-1 family may be a possible candidate for treatment, but considering the lack research, it is an idea that should become more developed in the future. Even though the true cause of Crohn’s disease is still unknown, there are still other factors that lead to the pathogenesis. Epigenetics had been found to be one of the causes of CD. Figure 6 shows that DNA methylation increases the pathogenesis of CD through the hypermethylated expression of genes that had been found through PCR (Karatzas et al., 2014). Genetics had been found to be another cause of pathogenesis. Susceptibility genes also lead to inflammation of the body. Figure 7 depicts the overlapping of the susceptibility genes shared between CD and some autoimmune diseases (Lees et al., 2011). Because an overlap had been found Lees et al., 2011 had concluded that certain autoimmune disease and CD can share treatments to reduce inflammation.
There have been many studies done for inhibiting the IL-1 family to treat inflammation for various autoimmune diseases, except for Crohn’s disease, as proven by Dinarello et al. The idea has been brought to the surface, but no actual trials have been done to actually test if this type of treatment would be able to help inhibit inflammation in CD completely. The lack of knowledge in CD, especially the well-known cause for the condition, must change. Even though there are certain triggers and environmental factors that lead to the condition, there is still no exact cause as to how the disease develops. Studies for genetics has shown that susceptibility genes seem to be one of the causes of pathogenesis.
Since the exact cause for Crohn’s disease is still unknown, doing further research on genetics to see if there are more genes that are susceptible to Crohn’s disease may bring on the finding of treatments, especially because only a few have been found. Gene editing and actually testing IL-1 inhibition are a few ideas to consider for the future, especially because other autoimmune diseases have used the IL-1 inhibition treatment. The more knowledgeable and aware society becomes about this condition, then the more concern it will cause. Researchers will be willing to find an actual cure for the disease, and many answers could be answered. With finding a treatment that can actually lower and possibly completely gets rid of inflammation, many people suffering from CD would be elated, especially if the treatment is said to cause very little side-effects. As someone who actually has Crohn’s disease, I believe that finding a cure to completely eliminate inflammation is really something to consider. The first steps, though, include educating society and making those around more aware of the condition and why CD is so bad.