The Emergence of Autoimmune Diseases and Associated Disparities in Global Research
In the last few decades, autoimmune diseases (AD) have been increasing in prevalence around the world, especially in Western and developing countries [1]. The common disease pathogenesis is an immune-mediated attack on the body’s own organs, seen in notable ADs such as type 1 diabetes, multiple sclerosis, inflammatory bowel diseases, systemic lupus erythematosus, and autoimmune thyroiditis [2]. Although the reasons behind the increasing prevalence of ADs are not entirely known, there are some hypotheses and trends that could help to explain this phenomenon. Even so, there are gaps in current AD research on a global scale that prevent us from making conclusions surrounding AD causes and risk factors.
Original illustration created by Cassandra Seal.
One popular theory behind the increasing incidence of ADs is the “hygiene hypothesis” [3]. According to this hypothesis, industrialized countries have experienced a decrease in infectious diseases and consequently a simultaneous increase in autoimmune and allergic diseases. Public health interventions to limit the spread of infectious diseases such as water and food sterilization, milk pasteurization, childhood vaccinations, and the wide use of antibiotics are common features of developed nations that could explain the emergence of ADs [3,4]. Comparably, countries with lower health standards have populations that experience chronic infections but have notably not seen a rise in ADs [3].
Yet, if individuals from countries with low AD incidence migrate to a country with high AD incidence, this immigrant population acquires the same disease incidence as the host population within the first generation of offspring, suggesting that the change in the environment plays a role in AD incidence [3]. It is worth noting that the hygiene hypothesis does not implicate a causal link between AD incidence and the socio-economic status of a country, but rather a strong correlation between the two. As causal links between migration, economic development, and AD incidence have not been found, molecular mechanisms have instead been used to explain susceptibility to AD. Based on the hygiene hypothesis, a higher incidence of infectious disease is correlated with lower AD incidence, thus implicating the potential role of infectious diseases in inducing protection against autoimmune disorders. Infectious diseases have since been found to alter immunoregulatory mechanisms in the body [3]. These mechanisms could in turn be altered by lifestyle changes, including changes to our environment, diet, and microbiota (our naturally occurring gut bacteria), either as a result of lifestyle changes or migration. The overall consequence is an alteration in our susceptibility to developing an autoimmune disease.
An alternative theory to explain the incidence of ADs implicates air pollution [5]. Air pollution initiates several autoimmune responses in airway tissues that promote systemic inflammation. Sources of air pollution include industrialization, vehicle exhausts, natural disasters, and fuel combustion that can produce particulate matter (PM) of different sizes that can influence AD incidence and severity. Elevated PM levels are especially implicated in increased risk for systemic lupus erythematosus (SLE), multiple sclerosis (MS), and Type 1 diabetes (T1DM) by increasing inflammation. Air pollution has also been associated with epigenetic modifications in T1DM that could be inherited and affect diabetes age-onset which is taking place earlier in life in some European countries, namely in Finland [3,5]. Even so, environmental changes due to industrialization are not the only risk factors for AD onset as genetic components are also known to play a role [2]. Thus, this is not a causal theory behind AD incidence however it does help researchers prioritize the study of factors that could cause autoimmune disease. The actual prevalence of ADs could also help scientists narrow down these factors.
Epidemiological studies have shown that AD prevalence is increasing in most countries, although there are different leading ADs [2]. The prevalence of asthma is increasing in both developed and developing countries; greater than 15% in the United Kingdom, Australia, and New Zealand compared to 10% in Peru, Brazil, and Costa Rica [3]. Multiple sclerosis (MS) prevalence is also increasing; MS prevalence is highest in European and Western countries followed by West Asian countries, particularly Iran and Jordan [6]. South Asia and East Asia have also reported increasing MS incidence over the last decade although the prevalence is still the lowest in the continent. It should be noted that many of the epidemiological studies on MS prevalence in Asia are outdated and some countries in this region have less income and reduced access to diagnostic technology like MRI machines, thus the actual MS incidence could be misreported [6]. There is also a limited number of global epidemiological studies on specific ADs due to limited research in some regions, particularly in Africa [7]. While systemic lupus erythematosus (SLE) has been studied to a greater extent in individuals with African ancestry, the studies have been limited to comparative studies of African-Americans, and individuals residing in major cities in Morocco and South Africa [7,8,9]. The implication is that there are underlying factors for the lack of evidence regarding autoimmune disease incidence and prevalence in Africa, thus raising the question of the context behind AD research in the region.
Epidemiological studies have shown that autoimmune disease prevalence is increasing in most countries
Studies of SLE in Africa have been driven by medical reports of historically high SLE prevalence among individuals in Nigeria, Zimbabwe, Senegal, and Egypt, thus AD research is prioritized for SLE specifically [8,9,10,11]. Many of these studies cite African ancestry as a potential factor in causing disease, however, there have been no conclusions made as not to generalize SLE incidence across a country, let alone a whole continent. Some studies have also noted conflicting data surrounding AD, specifically SLE, incidence rates [11]. This, coupled with the lack of general AD research, has raised a question as to why there is so much disparity in AD research in Africa.
One explanation is that there is poor access to healthcare, including diagnostic tools, treatments, and specialist physicians, that could lead to underdiagnosis of ADs and thereby an underestimation of the severity of AD prevalence in a country [11]. Alternatively, ADs may not be a pressing issue in several African countries due to the emergence or persistence of infectious diseases that are yet to be eradicated [12]. Outbreaks of Ebola virus, Zika virus, Yellow Fever and Chikungunya virus are endemic to some African countries, thus studies on infectious diseases in this region are still prioritized, however, there are some conflicts of interest in this situation given that infectious disease studies are supported by foundations outside of Africa [12]. External interventions by other countries may have a huge impact on research directions in Africa. A systematic review of authorship for publications in infectious disease research conducted in Africa found that most research was conducted with international collaborations with non-African partnerships, with few articles having Africans as first and last authors [13]. Altogether, the review suggests that African researchers are overshadowed in research publication by their international collaborators and there are concerns about equity for African researchers. This issue could extend to the research projects themselves, as the AD research field is relatively new and thus AD research is deprioritized.
The social context behind AD incidence and prevalence is also important. AD heterogeneity has been filtered by race, age and geographic location in the US [14]. Autoimmune diseases disproportionately impact women and specific racial groups in North America in every age group [2]. Epidemiological studies demonstrate that African Americans have the highest SLE incidence and prevalence, followed by Hispanics and Asians, and Caucasians have the lowest incidence [15]. There is a high SLE prevalence for African Americans in West North Central and South Atlantic regions, as well as higher MS rates in the South Atlantic and Pacific regions [14]. Interestingly, Native Americans experience higher rheumatoid arthritis (RA) rates in the same regions that African Americans are affected, including West North Central, Mountain, and Pacific regions. Native Americans also have earlier SLE diagnoses and greater disease severity, as well as lower Type 1 diabetes rates compared to Caucasians due to a genetic variant in the human leukocyte antigen (HLA). HLA variants have previously been implicated to account for differences in AD susceptibility between Caucasian and Asian populations [3]. Air pollution and toxic waste sites are also linked to the higher prevalence of primary biliary cirrhosis in Native Americans, thus AD prevalence for Native Americans and African Americans could be due to a specific interaction between the environment and genetics [14]. However, it is worth considering that the geographic environment in which Native Americans and African Americans reside is affected by historical context. Social and historical context is also important to consider when discussing disease emergence among minority populations.
Autoimmune diseases disproportionately impact women and specific racial groups in North America in every age group
Historically, nutritional deficiencies were to blame for the health conditions of Native Americans; poor diets led to diarrheal disease and also increased susceptibility to infectious disease [16]. However, access to food was directly impacted by colonization; government-supplied industrialized food chain products like canned and boxed foods negatively impacted the nutrition of the Native Americans living in reservations and the since-established traditional diet could be a risk factor for autoimmune disease [17]. Further, colonization brought Old World diseases, including measles, smallpox, and influenza, to the Native Americans resulting in lethal epidemics that killed many [18]. It was found that most survivors in the Native American population had a clear genetic difference in an HLA variant that could have saved them from infectious diseases, however, this difference in the genetic profile of the Native American population could have also resulted in their susceptibility to ADs today [18]. The importance of this finding is that it demonstrates that structural determinants of health, in addition to the environment and genetics, could account for AD incidence and prevalence among global populations. Yet, these factors have not been explored to great detail in AD research as of now.
Taken together, current research has provided some strong foundations to explain the increasing incidence and prevalence of autoimmune diseases. However, there are disparities in this emerging field of research that make it difficult to make conclusions about AD susceptibility among different populations. In order to better establish our knowledge of autoimmune diseases, it is important that further research be conducted around the world, particularly in Asia and Africa, so that we can understand the reasons behind AD incidence and prevalence. Ultimately, this will allow us to distinguish the causes and risks associated with ADs as well as establish the urgency to evaluate autoimmune diseases as a global health issue.
Suha (she/her) is a fourth year undergraduate student majoring in Neuroscience, Immunology, and Physiology. She is interested in developing creative ways to distribute health and science information to educate people from non-scientific backgrounds and is part of the 2021/2022 Juxtaposition Staff.
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