Inside the Autoimmune War by Mallika Tripathy

Mallika Tripathy

Table of Contents

About the Author ………………………………………………………………………………………………………………….. 2

Chapter 1: Introduction ………………………………………………………………………………………………………... 3 Chapter 2: The Immune System …………………………………………………………………………………………. 5 Chapter 3: The Immune System …………………………………………………………………………………………. 8 Chapter 4: The Human Gut Microbiome ………………………………………………………………………….. 10 Chapter 5: Microbiota and Disease ………………………………………………………………………………….. 14 Chapter 6: Autoimmune Diseases ……………………………………………………………………………………. 18 Chapter 7: Autoimmune Disease Risk Factors ……………………………………………………………….. 28 Chapter 8: Autoimmune Disease Complications ……………………………………………………………. 30 Chapter 9: Living with an Autoimmune Disease ……………………………………………………………. 32 Chapter 10: Autoimmune Diseases and COVID-19 ………………………………………………………. 34 What Worked for Me …………………………………………………………………………………………………………. 36 Author’s Note ……………………………………………………………………………………………………………………… 39

References ………………………………………………………………………………………………………………………….. 42

About the Author

Mallika Tripathy University of Houston Class of 2021 Mallika Tripathy is a junior majoring in Honors Biomedical Sciences and minoring in Medicine & Society, Chemistry, and Health at the University of Houston. Her future goals include going to medical school after which she hopes to enter the pediatric field. Outside of school, she enjoys spending time with friends and family, trying new foods, dancing, making jewelry, teaching, and meeting new people. Having been diagnosed with psoriasis six years ago, Mallika became extremely curious about the mechanisms behind this disease and many other immune-mediated conditions. She took notes on her symptoms, what caused her psoriasis to flare up, and how long each episode would last. Her research on how her disease manifested motivated her to learn more about how autoimmunity works. Noticing how many students have little to no knowledge on autoimmune diseases, she decided to write a book to inform those around her. Determined to raise more awareness on these conditions, she hopes to use this platform as a way to share, encourage, and educate.

Chapter 1: Introduction Autoimmunity refers to an immune disturbance against one’s own immune system. This definition is paradoxical given the purpose of our immune system: to provide us with immunity against foreign antigens that could otherwise threaten our wellbeing. Autoimmune diseases are commonly known to be linked to certain malfunctions in the immune system. While autoimmune diseases can be detrimental to our daily functions, a lot remains unknown about them. Most believe that genetics, epigenetics or environmental factors, lifestyle choices, particularly stress, nutrient deficiencies, sleep disorders; certain medications, and past infections can be linked to the disease process. However, growing interest is being projected towards gut bacteria. Ultimately, these illnesses arise through either hyperactivity or underactivity of the immune system. Often times, individuals get Band-Aid treatments for commonly known diseases due to the lack of knowledge surrounding the pathophysiology that manifests into these autoimmune diseases. In recent years, there has been a renewed focus on understanding the specific mechanisms underlying the causations of these diseases. A somewhat popular risk factor being explored is gut bacteria and its relation to autoimmunity. This evolving area of science involves studying how the unique gut microbiome in individuals’ bodies influences the immune cell responses. Specifically, our gut microbiome consists of several bacteria (beneficial bacteria, the commensals), viruses, and fungi that aid in

digestion and disease prevention. These are normally in harmonious balance, but alterations or imbalances can lead to abnormal immune responses.1 Over the course of our lives, starting from our time in the womb, the environment within our gut is subject to changes associated with maternal exposure to illnesses, tobacco/alcohol use, type of birth, stress, environmental factors and dietary habits. These changes are extremely detrimental to our health. First, they lower gut microbiome diversity, increasing the relative concentration of unhealthy bacteria and lowering that of the healthy bacteria. Second, they have been linked to leaky gut syndrome, a condition in which the gut barrier becomes extremely permeable and bacteria is able to travel through blood to other parts of the body and trigger an immune response. Third, they cause an immune disturbance by increasing the number of Th1 or Th2 lymphocytes, and subsequently increasing the number of pro-inflammatory cytokines due to Th1 dominance or increase in antibodies from Th2 dominance. Significant research on autoimmune diseases has shown that there is a multifaceted interaction between genetics, lifestyle, environment, gut microbiota, and the immune cells - which play a major role in autoimmune disease onset. Our immune cells are designed to prevent the onset of diseases brought on by foreign invaders or linked to an imbalance in our bodily systems. However, as will be explored in further detail later, problems arising within our gut microbiome can lead to attack on our own healthy tissues and cells. Unfortunately, this mistake leads to years of suffering for patients who often find it difficult to resolve their ailments. This is the primary reason for a lack of research on treatments encompassing autoimmune diseases, one of the leading causes of chronic, debilitating disease states in the United States. In the upcoming chapters, the definition of autoimmune diseases, risk factors involved, examples of diseases, gut microbiota and its link to autoimmune diseases, studies with their findings, and prevention techniques will all be explored. While there are no cures for autoimmune diseases yet, understanding the role a healthy gut environment plays in preventing our bodies from being in a chronic disease state is imperative.

Chapter 2: The Immune System The immune system is one of the most complex, yet crucial systems in our bodies. Its purpose is simple: to initiate attacks against invaders that shield the body from disaster. However, the mechanisms and parts involved in carrying out these attacks are not as simple. Our immune systems contain cells such as lymphocytes, which include T-cells, B-cells, and NK cells (natural killer cells), neutrophils, monocytes, macrophages, along with proteins and antibodies wired in a manner to enforce protection of the host organism. It is a system that is maintained by immune cells throughout the body that move through the blood or by vessel transport. When a foreign substance, known as an antigen invades the body, antibodies, or proteins in the blood, bind to them. These antibodies could be acute phase IgM antibodies or the chronic/past exposure IgG antibodies.2 There are two types of immune system responses that are mediated by different cells. The innate immune system involves cells that are able to conduct their response efficiently, as they are natural responses that don’t require any learning. This system involves cells such as neutrophils, monocytes, NK cells, and complement proteins. The adaptive immune system, on the other hand, includes T-cells and B-cells. These cells need to learn how to attack certain cells, and thus develop memory and adaptation ability.2 The innate immune system acts as the first responder in operation get-rid-of-the-invader, which eventually causes the adaptive system to respond within

a few days. While the innate immune system is fully functioning right from birth, the adaptive immune system is not optimally working until the individual has adequate exposure to the environment. Every part of the immune system is vital to our well-beings since each component serves a distinct purpose. Both B-cells and T-cells, two major players of the immune system, begin development in the bone marrow from a progenitor hematopoietic stem cell. T-cells develop from immature lymphocytes and attack infected cells. There are three types: helper T-cells that aid in the production of antibodies, regulatory T-cells that prevent continued action after the pathogens have been removed, and killer T-cells that bind to target cells and destroy them. B-cells produce antibodies, or immunoglobulins, that once produced have the potential to travel to blood and tissues. Natural killer (NK) cells kill infected cells by injecting them with toxic chemicals. Neutrophils phagocytose pathogens and then release chemicals that lead to their death. Monocytes mature into macrophages as they enter tissues where they act in the same manner as neutrophils when they interact with harmful material. Finally, cytokines enable communication between local and distant targets to monitor the presence of toxins.2 Several organs are imperative to the function of a system that is so widespread throughout the body and is not localized to a specific organ. The organs of the immune system include the thymus, liver, bone marrow, tonsils, lymph nodes, spleen, and blood. The bone marrow and thymus, commonly known as the lymphoid organs, are in charge of monitoring the production and maturation of lymphocytes. The lymph nodes, spleen, and tonsils are where immune system cells are able to directly interact with foreign cells. The bone marrow is the production site of several immune system cells. From here, defense cells are able to reach the bloodstream and enter organs and tissues. The thymus is the site of maturation for lymphocytes, which entails an understanding of what belongs to the individual and what is foreign. Lymph nodes act as filters with immune system cells that check for pathogens and produce antibodies for specific antigens. The spleen is the production site of blood and immune system cells prior to

birth, and removes erythrocytes and platelets after birth. Finally, the tonsils, which are often times removed in children, are located near the throat, and can lead to rapid alerts to the immune system of a foreign invader.3

Health Direct. (2019, May). The Immune System. Retrieved from https://www.healthdirect.gov.au/immune-system.

All of the above components work towards the common goal of our immune systems: to prevent our bodies from being exposed to infections. In order to do so, it must be able to recognize foreign invaders and act efficiently towards their removal. In the case of autoimmune diseases, the supposedly clear distinction between healthy and unhealthy becomes very muddy. When the immune system uses its highly integrated network to kill its own harmless cells and tissues, the body lacks harmony, which can lead to an autoimmune disturbance or disease state.

Chapter 3: The Human Gut The gastrointestinal tract must serve as an internal gate: it accepts the “good” stuff, including nutrients, vitamins, and water, and rejects the “bad” stuff, such as harmful pathogens, toxins. The “gut barrier” is known to be composed of a single layer of intestinal epithelial cells that secrete proinflammatory molecules, mucus, and antimicrobial proteins to protect our bodies. These epithelial cells are very selective in regulating what can pass through. The immune system of the gut located in the mucosa consists of many immune system-promoting components, including Peyer’s patches, the lamina propria, and several lymphocytes.4 Tight junctions, the most selective type of cell-to-cell junction, are prominently found in the intestinal epithelium and they function to regulate permeability. Intestinal permeability can be measured through zonulin levels in the stool. A change in the presence or function of tight junctions causes an increase in the permeability of the intestinal epithelial cells, leading to movement of unwanted pathogens into the bloodstream to circulate throughout the body. For example, Helicobacter pylori, commonly known as H. pylori affects the GI tract by negatively impacting the strength of cell-to-cell adhesions and causing a loss of cell polarity. When cell polarity is no longer present, receptors within the membranes can diffuse to the other side, leading to a loss of function upon binding to various receptors as well as the movement of nutrients in a manner that can promote bacterial

growth.5 Pathogens within the GI tract are especially harmful to the body when they are able to reach the lamina propria.

Wikimedia. (2014, March 2nd). Layers of the Alimentary Canal. Retrieved from commons.wikimedia.org.

In studies done on mice, rapid inflammation was noted whenever leaky gut epithelium was present; an increase in intracellular & transcellular permeability allows for bacteria and other intestinal components to travel and reach sites where they aren’t supposed to be found, causing inflammation. This inflammation ultimately manifests into diseases such as Inflammatory Bowel Disease (IBD). Interestingly, for those with IBD, there has been a decrease in the quantity of healthy gut bacteria and diversity of

the gut microbiome population, a reason for increased gut permeability.

Chapter 4: The Human Gut Microbiome The human gastrointestinal tract, commonly referred to as the gut, consists of the mouth, esophagus, stomach, small and large intestines. The less known components of our gut include bacteria, fungi, and viruses. These influence how we protect our bodies from toxins and help digest foods to better absorb nutrients and vitamins. The greatest number of bacteria reside in our mouths, and are less populated in the stomach, duodenum, and jejunum.6 Recent studies have found a total of almost 10 million genes related to gut bacteria with a lot of variation between individuals. The health-promoting bacteria were found to belong to the phyla Bacteroides and Firmicutes.4 Additionally, another study proved that gut microbiota stayed constant within an individual’s body for the most part, with very little variation over time.6 The greatest variation happens to occur in the early years of life.4 These gut bacteria not only aid our bodies in metabolism but are also integral to our immune systems. Research has noted an interesting trend: unhealthy gut microbiota, usually involving some sort of imbalance, causes inflammation which can then lead to an abnormal, chronic disease state associated with either Th1 or Th2 dominance. To emphasize the importance of the gut environment, research has shown that an individual’s immune system is greatly influenced by the body’s exposure to gut bacteria. The epithelial cells of the intestine display an immune response by producing

protective peptides, cytokines, and white blood cells after receptors recognize and bind to the bacteria. Problems related to bacterial exposure at an early age leads to immune system malfunctions that cause abnormal responses.7 Specifically, the human gut microbiome mainly consists of obligate anaerobes, rather than facultative and tolerant anaerobes, and aerobes. At birth, the intestines of a baby have gut bacteria that are low in diversity and quantity. However, a rapid increase in both quantity and diversity is noted during and after delivery. Specifically, natural birth, or the type of delivery by which a baby is delivered through the birth canal, enables the child to gain exposure to the microbiota of the mother’s vagina. Ultimately, the mother’s vaginal bacteria directly influences the bacteria in the child’s GI tract. Research on the gut microbiota of children delivered by cesarean section demonstrated that there was a significant difference in gut microbiota levels after a month of birth, but these numbers equalized after around six months. The gut bacteria that begins colonizing a baby’s gut shows profound similarity to that of their mother’s, and is consistent throughout life.7 There are two main mechanisms through which diseases and unhealthy behaviors affect existing gut microbiota. First, through eating habits; when researchers observed the impact of dietary changes on infants, they noticed that diet had a direct correlation to the type of gut bacteria present. Those who were breastfed had more Bifidobacteria spp., while those who were formula-fed had more Bacteroides spp., Clostridium coccoides, and Lactobacillus.4 More studies have been conducted using mice models since that have shown how even a short-term diet change can lead to the observation of different gut bacteria with varying gene expression. Interestingly, phenolic acids, flavonoids, fibers, carbohydrates, and clean drinking water with the appropriate pH, are all linked to generating balance in the gut. On the other hand, iron obtained through red meat and smoking increase the iron present in our bodies and allow for the overgrowth of bacteria, making the gastrointestinal tract more permeable.8 This gut permeability, also known as leaky gut syndrome, is extremely detrimental since it enables the bacteria to move to distant organs and lead to

autoimmune diseases, as evident in Kruegel’s study. Another way unhealthy gut bacteria can manifest is through the exposure to antibiotics. These have been found to reduce the diversity in the gut microbiome, which makes it more difficult to prevent future diseases. Antibiotics not only kill the harmful targeted bacteria but also destroy the healthy commensal or beneficial bacteria causing an imbalance in the gut.4

Sorini, C., & Falcone, M. (2013). The multifaceted interaction of diet, the immune system, and autoimmune disease. Retrieved from https://www.semanticscholar.org.

While diet and consumption of antibiotics during times of bacterial infection are common ways for imbalances in gut microbiota composition to occur, there are other ways this can occur. These include the temperature of the environment, pH of the intestines, presence of bile acids, drug use, and gastrointestinal secretions. The varying degrees at which individuals are exposed to these factors determines the proportion in which the different bacteria exist.

Ultimately, gut microbiota can cause disease. The level of diversity of organisms in our bodies has many benefits, but also some harms; some species of bacteria have been linked to the secretion of inflammatory molecules (called cytokines) from T-cells, leading directly to inflammation. Dysbiosis, or changing gut microbiome composition conditions, leads to several pathologies as discussed above. Many of these diseases are linked directly to our immune systems and culminate in autoimmune diseases. The three mechanisms by which gut bacteria can influence health are as follows: they can reduce the permeability of the intestinal layer, trigger an increase of lymphocytes, and lower gut microbiome diversity, leading to an imbalance between the types of bacteria present in the gut.

Chapter 5: Microbiota and Disease Ultimately, it is now established that gut microbiota can cause disease. The diversity of organisms in our bodies has many benefits, but relative predominance of bad bacteria can cause harm; some species of bacteria have been linked to the secretion of inflammatory molecules (called cytokines) from T-cells, leading directly to inflammation. Dysbiosis, or changing gut microbiome composition, leads to several pathologies. Many of these diseases are linked directly to our immune systems and culminate in autoimmune diseases. The three mechanisms by which gut bacteria can influence health are as follows: they can increase the permeability of the intestinal layer, trigger an increase of lymphocytes, and lower gut microbiome diversity, leading to an imbalance between the types of bacteria present in the gut. The “gut barrier” is known to be composed of a single layer of intestinal epithelial cells that are able to secrete proinflammatory molecules, mucus, and antimicrobial proteins to protect our bodies. These epithelial cells are very selective in regulating what can pass through and the level of bacterial proliferation. The immune system of the gut located in the mucosa consists of many immune system promoting components including Peyer’s patches, the lamina propria, and several lymphocytes.4 Researchers have found that the immune system of the gut is unable to carry out its normal functions when the gut microbiota is low in diversity.8

Dendritic cells located in the mucosal immune system allow for T cells to become helper T cells by differentiation. They can differentiate into Th1 cells, Th2 cells, and Th17 cells, all of which promote immunity. Healthy gut bacteria produce short-chain fatty acids that monitor these differentiation processes. These are necessary to prevent the onset of disease and inflammation.4 In other words, this differentiation process can be altered negatively by a decrease in healthy gut bacteria. In a recent study, a knockout mice strain was used to observe the effect of diet on disease. The conditions affecting the mice included a lack of proteins in the diet, which led to a changed gut microbiome environment and increased inflammation.4 Studies have also shown that both healthy and unhealthy individuals do have E. coli and B. fragilis, two species of bacteria that are disease-causing, but unhealthy individuals have a greater amount, leading to a variety of inflammatory bowel diseases (autoimmune diseases).6 Another important discovery was made using gram-negative bacteria which contain lipopolysaccharides (LPS). These are known to cause pro-inflammatory cytokines to be released upon association with macrophages, by which they led to inflammation, obesity, and diabetes in the studied mouse model.6 They can be found in foods we consume daily. Studies on the link between gut microbiota and autoimmune disease specifically are very limited. Some research has been done on autoimmune diseases such as Type 1 diabetes and multiple sclerosis. For Type 1 diabetes, bacteria in the gut has been shown to be linked to diet starting at an early age. Antigens such as casein and bovine serum albumin found in cow’s milk have been linked to an increased risk of developing Type 1 diabetes, as mice with this disease had more antibodies against these antigens. From this study, researchers concluded that Type 1 diabetes results from the shaping of the immune system at a young age and is linked to increased permeability of the gut barrier, more of an immune response, and different gut bacteria when compared to individuals without the disorder. Interestingly, infants who had a higher risk of developing diabetes due to genetic predisposition were noted to have low gut microbiota diversity and overgrowth of certain bacterial strains.4 Another autoimmune

disease with ongoing research is multiple sclerosis which causes nerve damage and is an incurable chronic disease. Patients with this detrimental disease have been found to have an imbalance in gut bacteria with an increased proportion of bacteria that have an inclination to cause inflammation, and also the inability to differentiate T cells, which is crucial to normal immune function.6 Dr. Martin Kriegel, a professor at Yale School of Medicine, conducted a study in the small intestines of mice where he noticed gut bacteria (Enterococcus gallinarum) travel from the gut to the liver, spleen, and lymph nodes due to a leaky gut barrier. In these organs, they caused inflammation by producing antibodies. These antibodies would trigger the pathway in which tissues and cells mistake healthy tissues and cells for unhealthy ones, leading to the exact progression of diseases characterized by autoimmune diseases. After this portion of the study was completed, the liver cells of healthy patients were compared to those of unhealthy patients, and only the unhealthy patients had the bacteria present.9 Gut bacteria has been found to have four forms of extensive impact on the body that are not mutually exclusive: increased gut barrier permeability, pro-inflammatory response, gut diversity imbalance, and reduced ability to maintain normal functioning of the gut immune system. Essentially, the case of gut microbiota and disease is multifaceted. Gut bacteria can lead to disease, and changes in diet and the state of disease can cause changes in gut bacteria. Eating foods with lower than recommended amounts of fiber (normal recommendation being around 35-40 grams/day) and nutrients, processed foods, sugar/sweets, and life stresses alter our gut microbiome leading to increased gut permeability and autoimmune disturbances.10 When looking at autoimmune diseases, the mechanism by which gut bacteria causes misinterpretations between what is healthy and what is a pathogen becomes extremely important.

Clark, A., & Mach, N. (2016). The Interplay between Vitamin D, Vitamin D Receptors, Gut Microbiota, and Immune Response. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179549/.

This figure illustrates how a leaky gut can be caused by a variety of environmental factors, including stress, lifestyle, toxin exposure, vitamin deficiency, and many more. These increase the likelihood of an autoimmune disease by reducing the effect of tight junctions in the intestinal epithelia to allow bacteria to travel into the bloodstream. Here, antibodies detect this bacteria from the host system’s gut as foreign and begin to attack it. This process is simply the immune system working to defend the body, but results in inflammation and a variety of other symptoms depending on the organ(s) it travels to. In other words, this progresses into a variety of autoimmune diseases.

Chapter 6: Autoimmune Diseases There are two types of immunity: innate and acquired. Our innate immunity refers to the immunity we are born with. This mechanism involves white blood cells solely attacking foreign bodies. The second type of immunity is one we develop as we age. Acquired immunity depends on what we are exposed to as we grow up, and thus uses antibodies that have the ability to recognize antigens. Acquired immunity directly plays a role in an individual’s development of autoimmune diseases.11 Some common pathophysiologies associated with these diseases include primarily, inflammation in the body, causing symptoms such as fatigue, trouble concentrating or brain fog, muscle and joint pains, gut issues, hair loss, weight gain, skin rashes, digestive issues, and fevers.12 Additionally, there are more than a total of eighty autoimmune diseases known to researchers and doctors. Some of these include Graves’ disease, multiple sclerosis, lupus, vitiligo, and anemia.13 Autoimmune diseases are especially deadly because some can be systemic, which means that they can start in one part of the body but cause symptoms in other body parts too, as they continue to involve other bodily systems.9 The most problematic issue surrounding these diseases is that there is no known cure. Treatment available today focuses on suppressing the symptoms and modifying the immune disturbance. However, a pioneering area of

research deals with a possible causal factor being linked to gut bacterial disturbance or imbalance. Below will be a brief description of various autoimmune diseases - understanding each one can elucidate the mechanism common to these conditions. a. Rheumatoid arthritis Rheumatoid arthritis (RA) is the most common form of systemic inflammatory arthritis. It occurs when there is proliferation of synovial cells in joints causing an inflamed synovial membrane and a pannus to form. This pannus formation may cause cartilage to be destroyed. The pannus contains T-cells, macrophages, B-cells, and fibroblasts. Within the synovial fluid, pro-inflammatory cytokines, such as IL1, IL6, and TNF⍺, induce inflammation. Specifically, in RA, autoantibodies attach to the linings of joints and attack the joints, leading to symptoms of inflammation, swelling, and pain. RA affects the metacarpophalangeal (MCP) joints, specifically involving the wrists, hands, elbows, shoulders, knees, and ankles. Without treatment, RA can lead to joint deformities and fusion of bones at the joints (ankylosis). Patients with RA also present with fever, skin nodules, and inflammation of various organs because it is a systemic disease. A defining symptom is morning stiffness. Risk factors include older age, genetic predisposition, as indicated by monozygotic twin studies, smoking habits, and female sex. In terms of diagnostic tests, rheumatoid factor is not specific for RA, but anti-citrullinated protein antibody has been associated with RA pathogenesis. Two other biomarkers are high C-reactive protein levels and erythrocyte sedimentation rates. The primary therapeutic agent for RA is a disease-modifying antirheumatic drug, or DMARD. Other options include TNF inhibitors, peptides, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids, but the latter two are more promising as short-term therapy options.

University of Washington. (2019). Rheumatoid Arthritis Pathology. Retrieved from http://www.pathologyoutlines.com/topic/jointsra.html.

b. Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a systemic illness, which means that many organs are involved as evident by the variety of symptoms patients have. SLE is characterized by autoantibodies attacking nucleic acids, such as DNA, and their binding proteins, such as chromatin ribonucleoproteins (RNPs). Once these autoantibodies associate with their targets, the autoantigens, they form circulating immune complexes (CICs). Once these CICs accumulate in target organs, an inflammatory response commences. Interestingly, neutrophils from patients with SLE have abnormal phenotype and function, including increased apoptosis, faulty phagocytosis, and increased low density granulocytes (LDGs) that contribute to inflammation. The most common symptoms include a low-grade fever, photosensitivity, ulcers, muscle aches, arthritis, fatigue, loss of appetite, a “butterfly rash”, inflammation, poor circulation, and lupus nephritis. Lupus nephritis leads to chronic renal failure, and is known as the most common cause of morbidity and mortality in SLE. It mostly affects African American and Hispanic females, and is largely based on genetic predisposition. Diagnostic biomarkers include anti-dsDNA and ANA (antinuclear antibody), which can be detected

using ELISA. Treatments include immunosuppressive drugs, such as corticosteroids or steroids.

U.S. National Library of Medicine. (2016). Systemic lupus erythematosus, National Institutes of Health (NIH). Retrieved from https://ghr.nlm.nih.gov/condition/systemic-lupus-erythematosus.

c. Inflammatory Bowel Disease Inflammatory Bowel Disease (IBD) involves three main dysfunctions. First, the development of dysbiosis that is linked to an increase in Proteobacteria and a decrease in bacteria that produce short-chain fatty acids. Second, the intestinal barrier becomes leaky because of down-regulation of E-cadherin in tight junctions, goblet cell abnormalities, and decreased secretion of antimicrobial products. Third, there is uncontrolled activation of T-cells that travel to the site of inflammation: the intestine. There are two main types of IBD. Crohn’s disease (CD) is a chronic relapsing inflammatory condition that can affect any portion of the GI tract, but mainly presents in the ileum. Ulcerative colitis (UC), on the other hand, is limited to the colon and rectum. These diseases have different symptoms in relation to the location of the digestive tract that is affected. Crohn’s disease is known to get worse as time goes on, and is

characterized by patchy transmural inflammation. Specifically, inflammation leads to a thickening of the bowel wall and a narrowed lumen (stricturing). Symptoms of CD include diarrhea, abdominal pain, fever, rectal bleeding, and growth failure. With CD, individuals may face bowel obstruction, fistula formation (abnormal channels of communication between loops of bowel, bladder, and skin, or colon and vagina, or colon and perineum), or perforation, in addition to inflammation. Symptoms of UC are fairly similar to those of CD, but the main difference is bloody diarrhea.

Celgene. (2015). Ulcerative Colitis and Crohn’s Sing Different Tunes. Retrieved from https://www.celgene.com/ulcerative-colitis-chrons-different-strategies/.

For these patients, IBD is not the only autoimmune disease they face. Many other diseases coexist with IBD. Some diagnostic methods utilized in IBD diagnosis include a tablet endoscopy/pill-cam that is swallowed and acts as a video recorder that captures an image of the small bowel. Additionally, faecal calprotectin is a biomarker used to understand inflammatory activity. Those with CD tend to have a higher quantity of ASCA antibodies, while those with UC have more p-ANCA antibodies. In terms of treatment for IBD, those with milder symptoms take aminosalicylates, those with moderate symptoms take immunomodulators, such as prednisone, and corticosteroids,

and those with severe symptoms might have to get surgery and/or receive anti-TNF⍺ antibodies.

Mayo Clinic. (2019). The Intestinal Mucosa in the Normal Bowel and IBD, National Institutes of Health (NIH). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386158/figure/F2/.

d. Multiple sclerosis

Multiple sclerosis (MS) is characterized by attack and subsequent damage of myelin, oligodendrocytes, and neurons. It specifically affects the central nervous system (CNS), leading to communication difficulties between the brain and every other part of the body. While patients may experience different symptoms, the most common symptoms include sensory loss, bladder, bowel, and/or sexual dysfunction, loss of vision, fatigue, cognitive difficulties, numbness, pain, and depression. MS is distinctly characterized by relapses in which patients face neurological disabilities from time to time which are followed by bouts of no symptoms. Genetic predisposition is a likely risk factor, and certain environmental factors like low D3 levels due to a lack of exposure to sunlight, infections, an inadequate diet devoid of nutrients, and smoking all play a role.

Mayo Clinic. (2019). Multiple sclerosis. Retrieved from https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269.

Patients with MS notice their condition becoming progressively worse, specifically in terms of their movement. Different types of MS involve varying levels of intensity in onset. Diagnostic measures include high levels of IgG antibodies and myelin proteins in the cerebrospinal fluid and MRIs that display cerebral plaques. Treatments currently include beta-interferon and corticosteroids. e. Type 1 diabetes mellitus Type 1 diabetes mellitus is also referred to as juvenile diabetes or insulin-dependent diabetes. This occurs when T-cells invade the islets of Langerhans population in the pancreas and destroy the beta cells that produce insulin. Insulin is a hormone that enables glucose to enter cells and subsequently, produce energy. Several complications may occur as a result of type 1 diabetes including cardiovascular disease, neuropathy, nephropathy, foot damage, and a higher susceptibility to infections. Symptoms of Type 1 diabetes mellitus include a frequent need to urinate, extreme thirst and hunger, weight loss, and skin/vaginal infections. For diagnosis, doctors check A1C levels over the course of the past two to three months, as well as cholesterol and triglyceride levels to determine heart disease risk. In order to check the extent of damage as a result of Type 1 diabetes, patients are recommended to get eye exams, blood and urine tests, as

well as a foot exam. For those diagnosed with Type 1 diabetes, insulin injections must be done each day, a healthy diet is emphasized, and blood sugar levels must constantly be monitored to ensure the levels don’t drop too low. LDL cholesterol levels must also be monitored frequently as diabetic patients tend to have higher levels of this bad cholesterol.

Biochemistry Notes. (2012). Type 1 Diabetes Mellitus and Its Etiology. Retrieved from http://edusanjalbiochemist.blogspot.com/2012/11/type-1-diabetes-mellitus-and-its.html.

f. Psoriasis Psoriasis is a disease marked by the rapid turnover of epidermal cells that primarily involves the skin and joint movement. It is primarily genetic in transmission with stress and unknown environmental factors named as causes too. It results in red patches, white silvery scales, and dry plaques. It can affect individuals of any age, and mainly affects the scalp, palms, soles, and extensor surfaces of joints. Interestingly, those with psoriasis have a high chance of developing other autoimmune diseases, specifically rheumatoid arthritis, Crohn’s disease, and ulcerative colitis. Diagnosis is made through a physical exam; doctors can observe the surface of the skin and ask about symptoms the patient is feeling. Treatment with anti-IL-22 antibodies has been shown to prevent development. Additionally, individuals may use steroids, coal tar products, petroleum jelly, Vitamin A, and ultraviolet therapy.

g. Graves’ disease Graves’ disease is when antibodies are produced that cause the thyroid gland to release excess amounts of throid into the blood, leading to hyperthyroidism. An overactive thyroid causes symptoms such as enlarged, puffy eyes, weight loss, heat sensitivity, hand tremors, and anxiety. This is commonly seen in women under the age of 40. Severity and disease manifestations largely depend on the age of the patient. For example, severe ophthalmopathy is more common in older men and women than younger individuals. For therapy, patients are advised to stop smoking, use antithyroid drugs, radioactive iodine, or undergo surgical thyroidectomy. Primarily, it is important to regulate iodine levels, which is a common area of therapy. h. Hashimoto’s thyroiditis Hashimoto’s disease occurs when inflammation of the thyroid gland causes thyroid hormone production to be impaired with declining function and hypothyroidism. Most individuals that are affected by Hashimoto’s thyroiditis are middle-aged women. Symptoms include weight gain, constipation, cold sensitivity, depression, muscle aches, dry skin, and irregular/heavy menstrual cycles. A biomarker for the disease is thyroid peroxidase (TPO) antibodies found in the blood, but this usually happens later on during the progression of the disease. Other diagnostic markers include goiter, elevated TSH, and possibly low T4 levels. Treatments are only given to patients who have normal TSH and Free T4 levels. Those with mild hypothyroidism may be given medications on a case-by-case basis. Patients who have severe hypothyroidism must have thyroid hormone replacement therapy. For many, this therapy is lifelong. i.

Myasthenia gravis

Myasthenia gravis is an autoimmune disease caused by antibodies attacking nicotinic acetylcholine receptors to affect muscle movement. Thus, patients normally display muscle weakness that worsens with greater exertion. In terms of disease progression, most individuals first present with droopy eyelid due to ocular muscle issues, which

then proceeds to affect other muscles. This causes symptoms such as drooping mouth, difficulty swallowing, double vision, and speech issues. Additionally, some individuals have breathing difficulties. Myasthenia gravis is fairly uncommon, affecting approximately 20 out of every 100,000 individuals in the US. Treatment options include steroids, blood transfusions, cholinesterase inhibitor therapy, and muscle strengtheners. j.

Guillain-Barre syndrome

Guillain-Barre syndrome involves antibodies attacking nerves for muscles in the legs as well as the upper body. This is a rare condition in the US population. This condition can be caused by a bacterial or viral infection. Symptoms include weakness and tingling that moves from the lower extremities upwards, and may cause paralysis. For those with the condition, immunoglobulin and physical therapy may prove beneficial.

Chapter 7: Autoimmune Disease Risk Factors Autoimmune diseases affect certain individuals more than others. One of the risk factors that predispose some and not others include gender. Women are seventy-five percent more likely to develop an autoimmune disease than men. While there are no clear reasons suggested for this, some propose that women have enhanced immune systems which might be a susceptibility factor. Additionally, some researchers state that hormone levels may contribute to onset. Specifically, studies have found that women have a higher risk of autoimmune diseases starting from their childbearing years. Ethnicity and family history also play a role. African Americans, American Indians, and Latinos are more likely to develop certain autoimmune diseases, such as lupus. On the other hand, Caucasians who have family members with autoimmune disorders are more likely to develop one as it is largely inherited and genetic in nature. Interestingly, one is likely to get the same disorder as their relative or one that is closely related to that disorder. Additionally, environmental exposures play a major role. Certain medications, metals, sunlight, chemicals, and viral/bacterial infections have been associated with autoimmune disease onset. Gut dysbiosis and diet (food additives, genetically modified

foods, etc.) are major environmental risks. Studies show that genetic predisposition accounts for thirty percent of autoimmune disease onset, while seventy percent develop these diseases because of environmental factors.

National Institute of Environmental Health Sciences. (2020). Autoimmune Diseases. Retrieved from https://www.niehs.nih.gov/health/topics/conditions/autoimmune/index.cfm.

Chapter 8: Autoimmune Disease Complications Unfortunately, autoimmune diseases can lead to health problems that are not directly a result of the autoimmune disease. Specifically, having an autoimmune disease weakens the immune system in a way that can increase an individual’s susceptibility to other diseases. First, studies suggest that patients have an increased risk of cardiovascular disease. With autoimmune diseases, increased inflammation is always present. Interestingly, research suggests that atherosclerosis, the chronic condition that leads to severe cardiovascular diseases, shares a common pathway with autoimmune diseases. When the metabolism of lipoproteins is negatively altered, the immune system is activated to cause proliferation of smooth-muscle cells to lead to the narrowing of arteries. The inflammation also leads to weakening of the heart muscle, which increases the likelihood of disease. Endothelial dysfunction, the first step in the atherosclerosis mechanism, is also a risk factor for autoimmune diseases. To ensure minimal risk, individuals with any autoimmune disease should eat a healthy diet, exercise, and monitor their blood pressure as well as get frequent blood tests. Second, patients with autoimmune diseases can have a very high risk of suffering from a pulmonary embolism. Specifically for those patients who are

hospitalized or more sedentary, there is a high chance that a blood clot can form in the lung and travel up to the lungs. To prevent this from happening, it is recommended that individuals, specifically those with Multiple sclerosis, wear compression leggings and use blood thinners. Third, autoimmune diseases can increase the chance of developing cancers. Since the immune systems in these patients are compromised and because there is inflammation, cells can continue to divide and grow without any mechanism stopping it. There is also an increased risk of cell mutations. Largely because of the absence of control for these cell proliferation mechanisms, tumors can be a result. Fourth, those with an autoimmune disease have an increased risk of developing one or more other autoimmune diseases. There are many different types of autoimmune diseases that exist and they largely coexist within the same individual, unfortunately. Finally, individuals with autoimmune diseases are likely to have symptoms of depression and anxiety. These symptoms can be attributed to the effects of autoimmune diseases that may leave patients in pain and/or self-conscious about their appearance. Additionally, there is a link between stress and autoimmune disease onset, so this may also lead to depression and anxiety seen in many of these patients. Interestingly, a study showed that those who have had an autoimmune disease are forty-five percent more likely to develop a mood disorder.14 This is likely because inflammation generates cytokines that alter brain cell communication. Often, it is the permeability in the blood brain barrier that causes autoimmune disturbance, which can then progress to an autoimmune disease. Therefore, it is well known that autoimmune diseases can attack the brain and nerve cells.

Chapter 9: Living with an Autoimmune Disease Living with an autoimmune disease is hard. It can be discouraging, painful, and taxing, both mentally and physically. But, there are ways to better control your autoimmune disease to prevent flare-ups and its worsening. Staying healthy is vital. Eating meals full of fruits, vegetables, protein, and grains is beneficial. To complement this, it is important to limit fat, cholesterol, salt, and sugar intake. Also, eating less amounts of foods with high fructose corn syrup and artificial food colorings can be beneficial. Getting physical activity is very therapeutic for those with muscle and joint pain, as in rheumatoid arthritis. The best way to decide which exercises to do on a regular basis is to talk to your physician - age, other health conditions, and symptoms can alter the specific exercise plan you should follow. Sleep is absolutely crucial. Giving your body rest can allow the immune system to stay strong. Additionally, sleep gives relief to body tissues and joints so they can repair and regenerate. Of course, sleep is also a direct mediator of how your mood and anxiety levels are the following day. Most importantly, though, it is important to manage stress. Some autoimmune diseases are caused partly by increased stress levels and many can be exacerbated because of stress. It is important to show some self-love and take care of yourself.

Some ways to reduce stress that can be followed daily are meditation, breathing exercises, yoga, fun activities, listening to calming music, and thinking of memories that bring happiness. Research has shown that lying down, closing your eyes, imagining your pain, and then imagining something destroying that pain.15 Below is a list for some top healthy living apps: 1. Yoga International 2. Yoga Download 3. Daily Yoga 4. Headspace 5. Calm 6. Aura 7. Enso

Chapter 10: Autoimmune Diseases and COVID-19 As mentioned previously, living with an autoimmune disease puts individuals at a greater risk for having other health conditions and may have worse health outcomes because of those. Currently, we are in the midst of a pandemic; unprecedented, yet a reality. As this invisible fighter has quickly spread through our borders and infected anyone in its path, we have continued to gain knowledge on its mechanism and capabilities. Unfortunately, these are the times our autoimmune diseases let us down more than ever. A novel virus has entered our environment, threatening our livelihoods. But, our bodies, with their weakened immune systems, fail us at the time we need them the most. It is a war: weakened immune system vs. powerful, unknown virus.

The question on several individuals’ minds has been this: am I more likely to get COVID-19 or have complications from the coronavirus because I have an autoimmune

disease? The answer is twofold. Individuals with autoimmune disorders are by no means more likely to contract COVID-19; this depends on who you’re around, if you’re following social distancing measures, etc. However, individuals with autoimmune diseases are more likely to develop complications and have a harder time recovering. Especially for those who take medications to prevent the symptoms of their disorders, they are at a very high risk because their immune system is suppressed and unable to fight infections. This is why it is all the more important for those with autoimmune diseases to practice CDC measures in place, to prevent exposure to coronavirus. It is also necessary to maintain the most optimal level of health as possible; this will boost the immune system to protect against any infections or negative effects. Individuals are recommended to exercise, eat healthy, manage stress through meditation and yoga, and get adequate sleep. Boost your immunity by consuming Vitamins C, A, D, Zinc. For reference, common symptoms of COVID-19 include fever, tiredness, dry cough, and difficulty breathing. However, some patients present with aches and pains, sore throat, headaches and diarrhea. Those with mild symptoms should self-isolate immediately for at least 14 days ; those with the most common symptoms should seek medical attention.16 CDC Self Checker: https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/index.html#cdc-chat-b ot-open

What Worked for Me Products/therapies that worked for improving my psoriasis condition: 1. Shampoo:

https://dermae.com/products/scalp-relief-shampoo?variant=26219318984 Amazon link: https://www.amazon.com/DERMA-Relief-Shampoo-Psorzema-Herbal/dp/B00VU68T6 U 2. Conditioner:

https://dermae.com/collections/hair-care/products/scalp-relief-conditioner?variant=262 19324424

Amazon link (both shampoo and conditioner): https://www.amazon.com/Relief-Conditioner-Pro-Vitamin-Vitamin-Botanicals/dp/B079 ZQC49K/ref=sr_1_2?dchild=1&keywords=DERMA+E+Scalp+Relief+conditioner+with+ Psorzema+Herbal+Blend%2C+8+oz&qid=1588294142&s=beauty&sr=1-2 3. 2-in-1 Shampoo/Conditioner:

https://www.amazon.com/JASON-Dandruff-Treatment-Shampoo-Conditioner/dp/B00 A8XPO6O 4. Sunlight Exposing skin affected by psoriasis to sunlight (UV rays) helped me a lot! In one summer vacation, the psoriasis on my leg was gone - of course, in conjunction with a healthy lifestyle! 5. Healthy eating (avoiding foods I’m allergic, even mildly sensitive, to) Getting the proper vitamins/minerals is crucial to a healthier lifestyle. This, along with physical exercise, is important to prevent more flare-ups. Specifically, I noticed that decreasing my consumption of sugar, foods with artificial colorings, and high-fructose corn syrup drastically improved my condition. 6. Positivity The key to living a healthy life! Even a smile can drastically change one’s mood - and you never know what someone else might be going through.

Author’s Note I remember my first flare-up of psoriasis. As my eighth grade teacher taught us about Spanish art and literature, I found myself distracted. The initial sensation of itching led me to feel an oddly raised area on my neck. Eager to go home that day, I rushed to my father, a family medicine physician, asking him about my new discovery. When he told me it looked like psoriasis, I began asking him loads of questions. What is an autoimmune disease? Can it be cured? Is this life-threatening? Why do I have it at such a young age? The questions circulated through my head; perhaps, the fact that I had a “condition” terrified 13-year-old me the most. Through my early teenage years, I didn’t care as much about my condition as I did about how it made me look. As any other growing female teenager, I cared about how I looked, always comparing myself to others. I became extremely self-conscious about my visible symptoms. A psoriasis patch on my neck was covered up with my hair, while a psoriasis patch on my leg was covered up with long pants. But, these cover-ups ultimately didn’t solve the problem. Well, there really was no solving-the-problem - something that I had to come in terms with about my autoimmune disease. But, there were preventative measures I could take to prevent more flare-ups and stop a penny-sized patch from becoming the size of a tennis ball. I soon became determined to find these methods of prevention and put them into use. Sometimes, I had success. Sometimes, I didn’t. But, I learned a lot from this. I began to understand how psoriasis looks, immediately diagnosing a small patch on my stomach upon its display. Now, that patch is gone. Instead of covering my skin, I began exposing it to sunlight, something that helped the patch on my leg. Through trial-and-error, I found shampoos and conditioners that worked to prevent the flaking of my scalp. I have developed a healthier lifestyle; I avoid gluten and dairy as much as possible and monitor my eating habits to a greater extent. While learning about these therapies, I often wondered how and why these methods worked. This drove me to conduct research and join a lab looking at biomarkers involved in various autoimmune disease pathologies. My initial research

became the foundation of my interest in disease mechanisms. I found an endless opportunity of learning, which excited me. Perhaps, the most influential in my experience with psoriasis, was discovering that my freshman mentee also had psoriasis. Hearing her frustration with the medications, injections, and therapeutic treatments she had tried, I shared what worked for me. Of course, there was no guarantee these would work for her, but I also had to give everything a try before I found what worked for me - and, I still am looking for products that might work better. But, being able to be there for someone else my age who was going through something similar motivated me to put the research I spent years collecting, and write this book. Today, I still have psoriasis on my scalp. My black hair contrasts the white flakes, and has led several to point out my “dandruff.” But, I don’t try to cover this up anymore. I use products/therapies that work for me and take better control of my health, but I don’t cover it up like I used to. Instead, when they ask me about my “dandruff,” I tell them I have psoriasis, an autoimmune disease that I have been able to better control because of lifestyle changes. Autoimmune diseases can strike at any time, and it is important to inform others to do as much as they possibly can to promote health. To those with psoriasis, or any other autoimmune disease, I know that it can feel pointless and frustrating to deal with this. But, we have the ability to better our health and we should seize that opportunity. I hope this book educates and inspires all of you, regardless of whether or not you have an autoimmune disease. Be strong, confident, and there for others - I learned the importance of these throughout my years with psoriasis, and it made all the difference. Find the things that can help build your optimism - for me, learning about my condition allowed me to take better action to control it. I also began spending more time doing things I truly enjoyed - beading, dancing, singing, travelling. These served as means for relaxation and made me a more positive person overall. Whatever the condition, use your voice to empower others; interacting with my mentee fired up this desire in me to be there for others that were

also trying to navigate through their condition. Most of all, don’t be hard on yourself - nurture that body, mind, and soul God gave you, and you will see the benefits!

- Mallika Tripathy 41

References 1. 2. 3.

4. 5.

6. 7.

8. 9.

10.

11.

12.

13. 14. 15. 16.

Kesser, Chris. “What Is Autoimmune Disease?” What Is Autoimmune Disease?, 10 Sept. 2019, chriskresser.com/what-is-autoimmune-disease/. Immune Deficiency Foundation. “Immune Deficiency Foundation.” Autoimmunity | Immune Deficiency Foundation, 2013, primaryimmune.org/about-primary-immunodeficiencies/relevant-info/autoimmunity. Ji, Jianguang, et al. “Tonsillectomy Associated with an Increased Risk of Autoimmune Diseases: A National Cohort Study.” Journal of Autoimmunity, U.S. National Library of Medicine, Aug. 2016, www.ncbi.nlm.nih.gov/pubmed/27344241. Opazo, Maria C, et al. “Intestinal Microbiota Influences Non-Intestinal Related Autoimmune Diseases.” Frontiers in Microbiology, Frontiers Media S.A., 12 Mar. 2018, www.ncbi.nlm.nih.gov/pubmed/29593681. Konig, Maximilian F, et al. “Aggregatibacter Actinomycetemcomitans-Induced Hypercitrullination Links Periodontal Infection to Autoimmunity in Rheumatoid Arthritis.” Science Translational Medicine, U.S. National Library of Medicine, 14 Dec. 2016, www.ncbi.nlm.nih.gov/pubmed/27974664. Hakansson, Asa, and Goran Molin. “Gut Microbiota and Inflammation.” Nutrients, MDPI, June 2011, www.ncbi.nlm.nih.gov/pubmed/22254115. Bull, Matthew J, and Nigel T Plummer. “Part 1: The Human Gut Microbiome in Health and Disease.” Integrative Medicine (Encinitas, Calif.), InnoVision Professional Media, Dec. 2014, www.ncbi.nlm.nih.gov/pmc/articles/PMC4566439/. Zhang, Yu-Jie, et al. “Impacts of Gut Bacteria on Human Health and Diseases.” International Journal of Molecular Sciences, MDPI, 2 Apr. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4425030/. Kriegel, Martin. “Gut Microbe Drives Autoimmunity.” National Institutes of Health, U.S. Department of Health and Human Services, 10 Apr. 2018, www.nih.gov/news-events/nih-research-matters/gut-microbe-drives-autoimmunity. Palafox-Carlos, Hugo, et al. “The Role of Dietary Fiber in the Bioaccessibility and Bioavailability of Fruit and Vegetable Antioxidants.” Journal of Food Science, Blackwell Publishing Inc, 2011, www.ncbi.nlm.nih.gov/pubmed/21535705. NIAMS. “Arthritis and Rheumatic Diseases.” National Institute of Arthritis and Musculoskeletal and Skin Diseases, U.S. Department of Health and Human Services, 22 July 2019, www.niams.nih.gov/health-topics/arthritis-and-rheumatic-diseases. Orbai, Ana-Maria. “What Are Common Symptoms of Autoimmune Disease?” What Are Common Symptoms of Autoimmune Disease? | Johns Hopkins Medicine, 2018, www.hopkinsmedicine.org/health/wellness-and-prevention/what-are-common-symptoms-of-autoimmune-diseas e. ASCIA. “Autoimmune Diseases.” Australasian Society of Clinical Immunology and Allergy (ASCIA), 9 July 2019, www.allergy.org.au/patients/autoimmunity/autoimmune-diseases. Skerrett, Patrick J. “Infection, Autoimmune Disease Linked to Depression.” Harvard Health Blog, 17 June 2013, www.health.harvard.edu/blog/infection-autoimmune-disease-linked-to-depression-201306176397. OWH. “Autoimmune Diseases.” Womenshealth.gov, 1 Apr. 2019, www.womenshealth.gov/a-z-topics/autoimmune-diseases. CDC. “People Who Are at Higher Risk for Severe Illness.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 15 Apr. 2020, www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-higher-risk.html.