Autoimmune disease

Autoimmune diseases affect over 3% to 8% of individuals worldwide, with 78% to 85% of cases in women (1). Their prevalence is also steadily rising, potentially due to increased exposure to contributing environmental factors (2). 

Although there are more than 80 autoimmune diseases that vary significantly and manifest differently, the loss of immune tolerance towards self-antigens characterizes all autoimmune diseases (5). As a pathophysiological state, autoimmunity is driven by the exact mechanisms that influence the normal immune response to foreign threats, involving innate and adaptive immune responses (3).

Researchers posit that autoimmune diseases undergo various phases, including susceptibility or pre-disease, initiation, transition, propagation, and resolution, resulting from defects in the regulatory mechanisms of the immune system (4). The susceptibility or pre-disease phase explains how a person’s predisposition to developing the autoimmune disease may be due to inherited or acquired defects in pathways that result in loss of immunological self-tolerance at central and peripheral levels. In the initiation phase, environmental factors interacting with susceptibility genes trigger an immune response against self. The transition phase is where dysfunction in immune response results in the manifestation of identifiable clinical symptoms (5). The propagation phase is also known as the self-amplifying phase, where progressive inflammation and tissue damage ensue due to the dysregulated immune response to self-antigens. The resolution phase is followed by a partial restoration of balance to the effector T cells and regulatory T cells during which there may be cycles of clinical remission and relapse or symptomatic flares caused by the struggle between effector and regulation responses (4).

Autoimmune diseases are classified based on the extent of the involvement of body components into organ-specific autoimmune diseases like type 1 diabetes, multiple sclerosis, Graves’ disease, inflammatory bowel diseases, and coeliac disease, and systemic autoimmune diseases, including systemic lupus erythematosus, scleroderma, rheumatoid arthritis, and Sjögren’s syndrome (5).

The development and propagation of autoimmune diseases are multifactorial, with the complex activity and interaction of multiple genetic and environmental factors playing contributory roles. These genetic contributors to autoimmune diseases are complex, and more is yet to be discovered. It’s understood that the polymorphisms of multiple immune-related genes contribute to the predisposition to autoimmunity.

Human leukocyte antigen (HLA) has been recognized as the genetic factor most strongly associated with autoimmune disease susceptibility. Similarly, CTLA4 polymorphisms are linked to a higher likelihood of type 1 diabetes, Graves’ disease, rheumatoid arthritis, and other autoimmune diseases, and IL2RA polymorphisms are associated with multiple sclerosis. Another example is the polymorphism of thyroid-associated genes like the TSHR gene, which is related to the risk of autoimmune thyroid disease (AITD), including Hashimoto's thyroiditis (HT), Graves' disease (GD),  postpartum thyroiditis, and atrophic autoimmune thyroiditis (6). Genetic polymorphisms in PTPN22 are recognized as a significant risk factor for type 1 diabetes, systemic lupus erythematosus, and rheumatoid arthritis. Polymorphisms in IL23R have been linked to ankylosing spondylitis, Crohn’s disease, psoriasis, and ulcerative colitis (7). Other individual immune-modulating genes, like PTPN22 and IL2RA, contribute less dramatically to the susceptibility to autoimmunity.

In rare cases, autoimmune disorders may be influenced by monogenetic mutations like mutations in AIRE, IFIH1, FOXP3, Fas, TREX1, DNASE1, C1Q, and C4A. In particular, mutations in AIRE and FOXP may result in a predisposition to autoimmune polyendocrine syndrome (APS) and immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome (8). Mutations in Fas is associated with autoimmune lymphoproliferative syndrome (ALPS) (9). 

Although how environmental triggers like infections, diet, drugs, ultraviolet irradiation, stress, air pollution, and exposure to xenobiotics are precisely involved in the development of many autoimmune diseases is still a mystery, they are likely significant contributors too in their interaction with susceptibility genes.

Because autoimmune diseases are rare and diverse and many patients show symptoms long after the initiation of the dysfunctional immune system response, their exact causes remain unclear and require further research. 

References

1. Ershadinia N, Mortazavinia N, Babaniamansour S, Najafi-Nesheli M, Babaniamansour P, Aliniagerdroudbari E. The prevalence of autoimmune diseases in patients with multiple sclerosis: A cross-sectional study in Qom, Iran, in 2018. Curr J Neurol. 2020;19(3):98-102. doi:10.18502/cjn.v19i3.5421

2. Miller FW. The increasing prevalence of autoimmunity and autoimmune diseases: an urgent call to action for improved understanding, diagnosis, treatment, and prevention. Curr Opin Immunol. 2023;80:102266. doi:10.1016/j.coi.2022.102266

3. Overview of autoimmunity. UpToDate. March 31, 2022.

4. Rosenblum MD, Remedios KA, Abbas AK. Mechanisms of human autoimmunity. J Clin Invest. 2015;125(6):2228-2233. doi:10.1172/JCI78088

5. Firth, John D. and others (eds), 'Autoimmunity', in John Firth, Christopher Conlon, and Timothy Cox (eds), Oxford Textbook of Medicine, 6 edn (Oxford, 2020; online edn, Oxford Academic, 1 Jan. 2020), https://doi.org/10.1093/med/9780198746690.003.0043

6. Zaaber I, Mestiri S, Marmouch H, Bel Hadj Jrad Tensaout B. Polymorphisms in TSHR gene and the risk and prognosis of autoimmune thyroid disease in Tunisian population. Acta Endocrinol (Buchar). 2020;16(1):1-8. doi:10.4183/aeb.2020.

7. Theofilopoulos AN, Kono DH, Baccala R. The multiple pathways to autoimmunity. Nat Immunol. 2017;18(7):716-724. doi:10.1038/ni.3731

8. Pisetsky DS. Pathogenesis of autoimmune disease [published online ahead of print, 2023 May 10]. Nat Rev Nephrol. 2023;1-16. doi:10.1038/s41581-023-00720-1

9. Price S, Shaw PA, Seitz A, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood. 2014;123(13):1989-1999. doi:10.1182/blood-2013-10-535393