Autoimmune diseases are a mystery. Scientists around the world, including those working at Genentech, are continuously working to find an answer to the question: what causes the body to suddenly turn on itself? Though we haven’t found an answer, below we’ve laid out some of what the field has learned over the years, as well as links to more specific work we’ve done (for a primer on autoimmune diseases, check out Autoimmune Disease 101).

Mapping Autoimmune Disease

A key component of understanding autoimmune diseases is identifying the cellular pathways and molecular processes that are interrupted as part of the disease. In other words, where do the signals get crossed at the cellular level that causes a healthy immune system to attack the body? B-cells, T-cells, cytokines and kinases have been identified as playing a crucial role in autoimmune disease, and knowledge of their errant signaling pathways has been used to develop treatments that inhibit, or suppress, the disease.^1,2

B-cells, a type of white blood cell, are one of the main components of the body’s immune defense system, which fights off infections and foreign bodies. In people with normal immune systems, B-cells help detect foreign antigens and produce antibodies to block them and render them harmless. T-cells are another type of white blood cell that attack invaders in the body.² But sometimes this defense system goes haywire, and instead of fighting foreign antigens, the body sends out a cascade of immune reactions against its own tissues. This overactive immune response can lead to autoimmune diseases such as vasculitis and lupus.²

Gender

In the U.S., 75 percent of those affected by autoimmune diseases are women, many within their childbearing years.¹ Some autoimmune diseases primarily affect women, such as rheumatoid arthritis (RA), which affects three times as many women as men, and systemic lupus erythematosus (SLE), commonly known as lupus, in which 90% of those affected are female.^1,3 Though there are some autoimmune diseases that affect men and women equally, there are none that primarily affect men. In addition, menopause and pregnancy have been shown to have impact on autoimmune disease – both positively and negatively.^3,4 Unsurprisingly, a significant amount of research has been dedicated to this question, and has supported the hypothesis that hormones play a factor.

Genetics

The relationship between the incidence of autoimmune disease within the same family, and that some autoimmune diseases are more prevalent in certain populations, has led scientists to explore the genetic link of autoimmune disease.⁴ For example, giant cell arteritis (GCA), which usually develops after the age of 50, is more common in people of Northern European descent; SLE occurs almost exclusively in women, and is more common in women of African American, Hispanic and Native American descent; pemphigus vulgaris (PV) is more likely to affect those of Mediterranean descent.^4,5

Familial predisposition has also been identified within autoimmune diseases, particularly in RA and SLE, though interestingly, it is not always the same disease.^4,6 A woman whose mother has RA may develop SLE.¹ Understanding the role of population genetics and familial autoimmunity may help predict and prevent disease development, and tailor or personalize medicine in autoimmune diseases.⁴

Environmental/Lifestyle Factors

Research has also indicated that environmental and lifestyle factors may play an important role in the development and progression of autoimmune diseases.⁷ For example, a study between twins examined the difference between an affected twin with an autoimmune disease and their unaffected counterpart showed that smoking is strongly correlated with the development of RA and other autoimmune diseases.⁸ Additional studies suggest those living in an urban environment are more susceptible to developing an autoimmune disease after exposure to various pollutants. Similar to smoking, polluted air and chemicals that are commonly present in cities may induce lung inflammation and irritation to the immune system. And research by a U.S. government agency has tied exposure to certain chemicals and solvents to the development of some autoimmune diseases.⁷ For unknown reasons, autoimmune diseases are increasing in prevalence, which has led to some conjecture that there is an environmental link.⁷

Although scientists have found many factors that may play a role in the development of autoimmune diseases, and the consensus is that a combination of genetic and environmental factors play a role in triggering autoimmune diseases, we still don’t know exactly why they develop.¹ With more than 80 autoimmune diseases, it is unlikely that there will ever be a single answer. More research is needed to gain a larger understanding of the factors leading to these diseases, which could in turn lead to prevention guidelines or treatment options for autoimmune diseases.

Read more about what we’ve been working on to gain a better understanding of autoimmune diseases:

• Insight to Inhibitor
• A Decade in the Making
• Are Biomarkers the Future of RA Treatment?
• Putting the “B” in Rheumatology

<sup>References:
1. American Autoimmune Related Diseases Association, Inc. https://www.aarda.org/ [Last accessed: October 2, 2018]
2. PK Gregersen, et al. Genetics of autoimmune diseases — disorders of immune homeostasis. Nature Reviews Genetics volume 7, pages 917–928 (2006) https://www.nature.com/articles/nrg1944
3. Medscape, Effects of Menopause on Autoimmune Diseases. https://www.medscape.com/viewarticle/775536_6 [Last accessed: October 2, 2018]
4. PS Ramos et al. Genetics of autoimmune diseases: insights from population genetics. Journal of Human Genetics volume 60, pages 657–664 (2015). https://www.nature.com/articles/jhg201594
5. Healthline: Pemphigus. https://www.healthline.com/health/pemphigus-vulgaris [Last accessed: October 2, 2018]
6. J Cárdenas-Roldán et al. How do autoimmune diseases cluster in families? A systematic review and meta-analysis. BMC Medicine. 2013;11:73. doi:10.1186/1741-7015-11-73.
7. National Institute of Environmental Health Sciences: Autoimmune Diseases. https://www.niehs.nih.gov/health/topics/conditions/autoimmune/index.cfm [Last accessed: October 2, 2018]
8. AJ Silman et al. Cigarette smoking increases the risk of rheumatoid arthritis: Results from a nationwide study of disease‐discordant twins. Arthritis & Rheumatism. May 1996. https://doi.org/10.1002/art.1780390504</sup>