The Genetic Story of Autoimmune Disease
Autoimmune diseases (AD’s) are a family of more than 80 chronic and often disabling illnesses characterized by immune system dysfunction (Ramos, Shedlock, & Langefeld, 2015). The dysfunction can lead to loss of tolerance to self-antigens, increased levels of autoantibodies, inflammatory mediator cells and chronic inflammation. AD’s are also relatively common, affecting 5 to 9% of the population, and are considered a personal and public health burden (Mariani, 2004). The genetic component of autoimmune diseases is revealed by the increased risk of developing an autoimmune disease carried by twins and siblings of affected individuals (Mariani, 2004). According to Ramon et. al, immune and inﬂammatory responses can be highly sensitive to environmental change. As a result, evolutionary adaptation to speciﬁc environments might have driven selection on immune-related genetic variants (Ramos et al., 2015). Interestingly, alleles selected for protection against infection can increase the risk for autoimmune and allergic diseases. “It is thought that the adaptation to pathogen pressure through functional variation in immune-related genes conferred a speciﬁc selective advantage for host survival, including protection from pathogens and tolerance to microbiota” (Ramos et al., 2015). For example systemic lupus erythematosus (SLE) may be associated with an immune response to Plasmodium falciparum, the parasite responsible for the most severe form of malaria. It is suggested that that the higher frequency of human FCGR2B polymorphisms predisposing to SLE in Asians and Africans. It is also postulated that the polymorphisms are maintained because these variants reduce susceptibility to malaria (Ramos et al., 2015). Unfortunately, theses “positive selections” can also have negative consequences in the case of AD.
Over 130 genome-wide association studies have established AD-associated alleles, and the evidence that the genetic variants are under selection is growing (Ramos et al., 2015). “Multiple lines of evidence suggest some degree of common genetic etiology in ADs, including clustering of multiple ADs in families and in individuals, and the number of conﬁrmed genetic regions predisposing to several ADs” (Ramos et al., 2015). Interestingly, the genetic heritability of ADs is extremely variable, from very high in Crohn’s disease to almost negligible in SLE. Interaction with common epigenetic and environmental risk factors, along with specific and multiple different pleiotropic (producing or having multiple effects from a single gene) effects, may result in the clinical manifestations of AD. Most ADs exhibit marked gender and ethnic disparities and unequally affect women. “African Americans are at higher risk than European Americans for systemic lupus erythematosus and scleroderma (systemic sclerosis), which they tend to develop earlier in life and experience more severe disease, but are at lower risk for type 1 diabetes, thyroiditis and multiple sclerosis” (Ramos et al., 2015).
I found the role of natural selection and evolution of autoimmune disease interesting, particularly the role it plays in protecting from pathogenic infections. “Balancing selection favors genetic diversity by retaining variation in the population as a result of heterozygote advantage and frequency dependent advantage” (Ramos et al., 2015). An example of balancing selection is with the HLA region. The high levels of polymorphisms in the HLA-region are thought to be the results of pathogens driving selection balance. ( Note-heterozygote advantage describes the case in which the heterozygous genotype has a higher relative fitness than either the homozygous dominant or homozygous recessive genotype ). The heterozygote advantage against multiple pathogens is thought to contribute to the HLA diversity, which confers resistance to multiple pathogens, but also may explain the persistence of alleles conferring susceptibility to AD (Ramos et al., 2015).
Over 40 regions with evidence for selection are associated with at least one autoimmune disease. Close to half of these regions are shared among AD’s, including the HLA region, PTPN22, TNFSF4, ARHGAP31-CD80, TNIP1 and TYK2. Over the years, various researchers provided evidence suggesting some MHC class II allotypes are associated with certain conditions, examples listed below (Mandal, n.d.):
1. HLA DR2 with SLE, MS and type 1 diabetes
2. HLA DR3 with myasthenia gravis, SLE, type 1 diabetes and Sjögren’s syndrome.
3. HLA DR4 is associated with Type 1 diabetes, pemphigus vulgaris and rheumatoid arthritis.
4. HLA DQ2/DQ8 with Celiac Disease. However not all DQ2 carriers will develop CD. Also homozygous patients seem to have a more severe presentation of the disease.
Correlations between autoimmune conditions and MHC class I molecules are less common, but one notable example is the association between ankylosing spondylitis and HLA B27 (Mandal, n.d.)
Also, the HLA region is demonstrating to contribute to half of the genetic susceptibility to RA, particularly in disease presentations characterized by the presence of anti-citrullinated antibodies (Ceccarelli, Agmon-Levin, & Perricone, 2017). RA seems to be most strongly associated with HLA-DRB1 alleles, with a higher susceptibility and more severe presentation for individuals carrying a homozygous pair of alleles (Bodis, Toth, & Schwarting, 2018). Next to HLA genes, other variants seem to be implicated in RA susceptibility such as the PTPN22, TRAF1-C5, PADI4, and STAT4 genes. The genetic factors can contribute to disease phenotype in terms of extent of erosive damage.
It should be pointed out that although the theory that AD risk alleles are positively selected due to their protective effects against infections, the authors indicate that these observations are limiting. Other population level phenomena, such as bottlenecks, migration, admixture, and random genetic drift are also likely to contribute to this complexity of gene effects (Ramos et al., 2015). “Given the complex history of selective pressures acting on humans, unequal selective pressures and a diverse spectrum of plausible evolutionary models are expected to be exerted on susceptibility loci for ADs” (Ramos et al., 2015). Human pathogen coevolution is ongoing, and new pathogens will continue to emerge. Therefore pathogen driven host specific adaptations are expected and will have long standing relationships with humans, particularly those that involve the human microbiome. “Regardless of the agent of selection and the reasons for the emergence of both common and rare AD-causing alleles, incorporating population genetics to understand human genetic diversity will lead to a better understanding of the causes of health disparities, identiﬁcation of functional variants and discovery of cellular mechanisms and contribute to the development of new therapies” (Ramos et al., 2015)
Mandal, A. (n.d.) Autoimmunity Genetic Factors. Retrieved (2018, June 18) from https://www.news-medical.net/health/Autoimmunity-Genetic-Factors.aspx (Links to an external site.)
Bodis, G., Toth, V., & Schwarting, A. (2018). Role of Human Leukocyte Antigens (HLA) in Autoimmune Diseases. Methods Mol Biol, 1802, 11-29. doi:10.1007/978-1-4939-8546-3_2
Ceccarelli, F., Agmon-Levin, N., & Perricone, C. (2017). Genetic Factors of Autoimmune Diseases 2017. J Immunol Res, 2017, 2789242. doi:10.1155/2017/2789242
Mariani, S. M. (2004). Genes and autoimmune diseases – a complex inheritance. MedGenMed, 6(4), 18.
Ramos, P. S., Shedlock, A. M., & Langefeld, C. D. (2015). Genetics of autoimmune diseases: insights from population genetics. J Hum Genet, 60(11), 657-664. doi:10.1038/jhg.2015.94