The Rise of Autoimmune Diseases
Autoimmune disease arises when the body loses the ability to distinguish between its own components (like proteins and nucleic acids) and foreign substances (like viruses), and ultimately, attacks its own healthy cells and tissues. There are over 100 types of autoimmune diseases, including Sjögren’s, system lupus erythematosus (lupus), rheumatoid arthritis, and type 1 diabetes. Due to the dysregulation of the immune system and its complex, overlapping signaling pathways, approximately 25% of people who develop an autoimmune disease will develop another.1 Heredity also plays a large role in the development of autoimmune diseases. Interestingly, 30-35% of patients who are the first person in their family diagnosed with Sjögren’s have family members with other autoimmune diseases.2
Over 50 million Americans (8% of the U.S. population) are affected by autoimmune diseases and current data suggests that the prevalence of autoimmune diseases is rising.1,3 Epidemiological studies have shown that the incidence (rate of new cases) of global autoimmune diseases has risen yearly by 19.1% with rheumatological diseases such as Sjögren’s and lupus rising 7.1% per year.4
More women are affected by autoimmune diseases and make up approximately 80% of the current cases of autoimmune diseases. There is a well-established link between the X chromosome and the prevalence of autoimmune diseases. The X chromosome contains several genes that regulate the immune response, including CD40 ligand which is a new mechanistic target for current clinical trials for systemic disease (affecting multiple organ systems) in Sjögren’s. A recent study looking at the prevalence of Sjögren’s in genetic disorders containing an extra X chromosome revealed a 6.6-fold increase in the prevalence of Sjögren’s in men with Klinefelter Syndrome (XXY) and a 2.3-fold increase in women with triple X (XXX) syndrome.5 This suggests that genes on the X chromosome may play a crucial role in the development of Sjögren’s.
Autoimmunity in Sjögren’s
Like many other autoimmune diseases, the cause of Sjögren’s is still unknown. Genetic predisposition plays a significant role in developing autoimmune diseases but are often triggered by environmental factors such as infections, sex hormone dysregulation, chemicals, and other exposures.
Although the cause is unknown, Sjögren’s is characterized by overactive innate and adaptive immune responses. The adaptive immune response is controlled by B and T cells, which are types of lymphocytes (white blood cells) that aid in producing antibodies and target infected cells or pathogens. In Sjögren’s, B and T cells are activated and affect the glandular (tissues that excrete mucus, hormones, and other substances such as salivary glands) and systemic tissues. Activated T cells can produce inflammatory signaling that causes dysregulation of B cells and can lead to autoimmune diseases and B-cell lymphoma.6 Lymphocytic infiltration (the presence of T cells in salivary and lacrimal or tear glands) is a key diagnostic measure for Sjögren’s because it indicates the pattern of inflammation and immune cell activity that damages glandular tissue.7
The adaptive immune response can be activated by the innate immune response, which serves to sense pathogens and other foreign substances in the body. However, there are some host-derived molecules (originating from the patient) that can initiate the innate immune response as well. The role of the innate immune response is also poorly understood, but genes associated with the innate immune response are dysregulated prior to lymphocytic infiltration suggesting its role in the activation of the adaptive immune response and the development of Sjögren’s. While the innate immune response plays a role, the adaptive immune response is the key contributor of disease manifestations in Sjögren’s.6
Potential Triggers of Autoimmunity in Sjögren’s
Viruses
There are several studies of the impact of viral triggers, including Epstein-Barr virus (EBV) and COVID-19, increasing the risk of developing autoimmune diseases and autoinflammatory connective tissue disorders like Sjögren’s. In one study consisting of approximately three million people who had COVID-19, there was a 13% increased risk of developing Sjögren’s and the role of autoimmunity in developing long COVID is currently being investigated.8
EBV is highly prevalent and approximately 90% of the population has been exposed to EBV. However, patients with Sjögren’s have higher levels of EBV DNA in their salivary and lacrimal (tear) glands as well as serum antibodies against EBV in their blood.9,10 Furthermore, patients with Sjögren’s-associated dry eye also had higher levels of EBV serum antibodies compared to those with simple dry eye or other autoimmune disease-associated dry eye.9 As with most viruses, EBV lives within the body and can be reactivated. Reactivation of EBV has been associated with joint involvement in patients with Sjögren’s.11 These studies suggest that EBV may be a risk factor for Sjögren’s and potentially increase certain clinical manifestations of Sjögren’s such as dry eye and joint involvement.
While the role of viral triggers in autoimmune diseases is still being investigated, a potential mechanism for the link between viruses and autoimmune disease may be a concept called molecular mimicry. Molecular mimicry is when the body attacks a foreign substance that may have similar structure to other proteins in the body and as such, may mistakenly attack the body's own proteins. In the case of EBV, there is evidence that the viral protein EBNA-2 (a common viral protein for EBV and has been found in salivary glands of patients with Sjögren’s) has similar structure to the SSA/Ro60 that naturally occurs within the body, where antibodies against SSA/Ro60 are a common marker for diagnosis of Sjögren’s.12 The role of viral triggers in developing autoimmune diseases is somewhat controversial and more studies are needed to determine their relationship with autoimmunity in Sjögren’s.
Sex Hormone Dysregulation
Another trigger for autoimmune disease is sex hormone dysregulation. Menopause in women causes a decline in estrogen and progesterone. Patients with Sjögren’s who are post-menopausal have an elevated interferon signature, which means that genes regulated by interferon (a family of cytokines or signaling proteins that play a role in the body's immune defense against viral infections and other pathogens) are upregulated. This increase in gene expression can contribute to heightened immune and inflammatory responses.13 Furthermore, patients with a higher interferon signature often have increased biological and hematological involvement related to Sjögren’s. 14,15
Another study looking at exposure of women with Sjögren’s to estrogen and the onset of menopause (decreased estrogen) showed an increased risk of Sjögren’s in women with low estrogen exposure.16 While there is no direct link between estrogen and Sjögren’s disease activity, these studies and others suggest that estrogen has a protective role in the development and progression of Sjögren’s. Since estrogen regulation is controlled by genes on the X chromosome, this provides further evidence that regulation of genes on the X chromosome contributes to Sjögren’s disease development.
Autoimmune Disease and Sjögren's Research
Although some experts say that the increase in the number of new cases of autoimmune diseases is concerning and approaching epidemic levels, autoimmune research is actively progressing with increased funding and the development of better diagnostic tools and treatments. The National Institutes of Health (NIH) investment in autoimmune disease research has drastically increased over the past few years with a significant increase from $800 million to over $1 billion in funding in 2022. There has also been an increase in the number of grants with almost 1500 new research grants awarded from fiscal year 2021 to 2022 (Note: statistics were provided from the Office of Autoimmune Disease Research- https://orwh.od.nih.gov/OADR-ORWH). Furthermore, the implementation of the Women’s Health Research Initiative in 2023 aimed to improve women’s health by addressing health needs and research gaps, including the study of autoimmune diseases.
The Sjögren’s Foundation has continuously supported the advancement of research in Sjögren’s. It is our mission to lead, encourage, and fund innovative research projects to better understand, diagnose, and treat Sjögren’s. Over the past five years, the Sjögren’s Foundation has supported over $1.8 million in research grants and provided research support for projects aimed to improve Sjögren’s research such as the Accelerating Medicines Partnership® Autoimmune and Immune-Mediated Diseases (AMP® AIM) Program.
The Foundation is energized by the momentum in Sjögren’s research and remains committed to supporting work that leads to better treatments and outcomes for patients.
References
- “Autoimmune Awareness Month.” Autoimmune Association, autoimmune.org/autoimmune-awareness-month/. Accessed March 19, 2025.
- Bolstad AI, Jonsson R. Genetic aspects of Sjögren's syndrome. Arthritis Res. 2002;4(6):353-9. doi: 10.1186/ar599. Epub 2002 Sep 24. PMID: 12453311; PMCID: PMC153844.
- Fairweather, D., Frisancho-Kiss, S., & Rose, N. R. (2008). Sex differences in autoimmune disease from a pathological perspective. The American Journal of Pathology, 173(3), 600–609. https://doi.org/10.2353/ajpath.2008.071008
- Lerner A, Jeremias P, Matthias T: The World Incidence and Prevalence of Autoimmune Diseases is Increasing. International Journal of Celiac Disease 2016, 3:151–155.
- Palmer AK, Tan IJ. Synergistic Effects of Extra X Chromosome on Development of Systemic Lupus Erythematosus and Sjögren Disease in Klinefelter and Triple X Syndrome: A Retrospective Cohort Study. ACR Open Rheumatol. 2025;7(1):e11778. doi:10.1002/acr2.11778
- Kiripolsky J, McCabe LG, Kramer JM. Innate immunity in Sjögren's syndrome. Clin Immunol. 2017 Sep;182:4-13. doi: 10.1016/j.clim.2017.04.003. Epub 2017 Apr 8. PMID: 28396235; PMCID: PMC6025757.
- Douglas, L. Facilitating timely diagnosis of Sjögren's syndrome. BDJ Team 5, 18026 (2018). https://doi.org/10.1038/bdjteam.2018.26
- Heo Y, Jeon JJ, Ha MC, Kim YH, Lee S. Long-Term Risk of Autoimmune and Autoinflammatory Connective Tissue Disorders Following COVID-19. JAMA Dermatol. 2024;160(12):1278–1287. doi:10.1001/jamadermatol.2024.4233
- Saito I, Servenius B, Compton T, Fox RI. Detection of Epstein-Barr virus DNA by polymerase chain reaction in blood and tissue biopsies from patients with Sjogren's syndrome. J Exp Med. 1989;169(6):2191-2198. doi:10.1084/jem.169.6.2191
- Toda I, Ono M, Fujishima H, Tsubota K. Sjögren's syndrome (SS) and Epstein-Barr virus (EBV) reactivation. Ocul Immunol Inflamm. 1994;2(2):101-109. doi:10.3109/09273949409057066
- Pasoto SG, Natalino RR, Chakkour HP, et al. EBV reactivation serological profile in primary Sjögren's syndrome: an underlying trigger of active articular involvement?. Rheumatol Int. 2013;33(5):1149-1157. doi:10.1007/s00296-012-2504-3
- Maślińska M. The role of Epstein-Barr virus infection in primary Sjögren's syndrome. Curr Opin Rheumatol. 2019;31(5):475-483. doi:10.1097/BOR.0000000000000622
- Brandt, J.E., Priori, R., Valesini, G. et al. Sex differences in Sjögren’s syndrome: a comprehensive review of immune mechanisms. Biol Sex Differ 6, 19 (2015). https://doi.org/10.1186/s13293-015-0037-7
- Gottenberg JE, Bost PE, Schwikowski B, et al. Type I High-IFN Gene Signature in Associated with Higher Essdai at Enrollmment and Follow-up in the Prospective Multicenter Assess Cohort of 395 Patients [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/type-i-high-ifn-gene-signature-in-ass…. Accessed March 19, 2025.
- Maria NI, Brkic Z, Waris M, et al MxA as a clinically applicable biomarker for identifying systemic interferon type I in primary Sjögren's syndrome. Annals of the Rheumatic Diseases 2014;73:1052-1059.
- McCoy SS, Sampene E, Baer AN. Association of Sjögren's Syndrome With Reduced Lifetime Sex Hormone Exposure: A Case-Control Study. Arthritis Care Res (Hoboken). 2020 Sep;72(9):1315-1322. doi: 10.1002/acr.24014. PMID: 31233285; PMCID: PMC6928446.
The Rise of Autoimmune Diseases
Autoimmune disease arises when the body loses the ability to distinguish between its own components (like proteins and nucleic acids) and foreign substances (like viruses), and ultimately, attacks its own healthy cells and tissues. There are over 100 types of autoimmune diseases, including Sjögren’s, system lupus erythematosus (lupus), rheumatoid arthritis, and type 1 diabetes. Due to the dysregulation of the immune system and its complex, overlapping signaling pathways, approximately 25% of people who develop an autoimmune disease will develop another.1 Heredity also plays a large role in the development of autoimmune diseases. Interestingly, 30-35% of patients who are the first person in their family diagnosed with Sjögren’s have family members with other autoimmune diseases.2
Over 50 million Americans (8% of the U.S. population) are affected by autoimmune diseases and current data suggests that the prevalence of autoimmune diseases is rising.1,3 Epidemiological studies have shown that the incidence (rate of new cases) of global autoimmune diseases has risen yearly by 19.1% with rheumatological diseases such as Sjögren’s and lupus rising 7.1% per year.4
More women are affected by autoimmune diseases and make up approximately 80% of the current cases of autoimmune diseases. There is a well-established link between the X chromosome and the prevalence of autoimmune diseases. The X chromosome contains several genes that regulate the immune response, including CD40 ligand which is a new mechanistic target for current clinical trials for systemic disease (affecting multiple organ systems) in Sjögren’s. A recent study looking at the prevalence of Sjögren’s in genetic disorders containing an extra X chromosome revealed a 6.6-fold increase in the prevalence of Sjögren’s in men with Klinefelter Syndrome (XXY) and a 2.3-fold increase in women with triple X (XXX) syndrome.5 This suggests that genes on the X chromosome may play a crucial role in the development of Sjögren’s.
Autoimmunity in Sjögren’s
Like many other autoimmune diseases, the cause of Sjögren’s is still unknown. Genetic predisposition plays a significant role in developing autoimmune diseases but are often triggered by environmental factors such as infections, sex hormone dysregulation, chemicals, and other exposures.
Although the cause is unknown, Sjögren’s is characterized by overactive innate and adaptive immune responses. The adaptive immune response is controlled by B and T cells, which are types of lymphocytes (white blood cells) that aid in producing antibodies and target infected cells or pathogens. In Sjögren’s, B and T cells are activated and affect the glandular (tissues that excrete mucus, hormones, and other substances such as salivary glands) and systemic tissues. Activated T cells can produce inflammatory signaling that causes dysregulation of B cells and can lead to autoimmune diseases and B-cell lymphoma.6 Lymphocytic infiltration (the presence of T cells in salivary and lacrimal or tear glands) is a key diagnostic measure for Sjögren’s because it indicates the pattern of inflammation and immune cell activity that damages glandular tissue.7
The adaptive immune response can be activated by the innate immune response, which serves to sense pathogens and other foreign substances in the body. However, there are some host-derived molecules (originating from the patient) that can initiate the innate immune response as well. The role of the innate immune response is also poorly understood, but genes associated with the innate immune response are dysregulated prior to lymphocytic infiltration suggesting its role in the activation of the adaptive immune response and the development of Sjögren’s. While the innate immune response plays a role, the adaptive immune response is the key contributor of disease manifestations in Sjögren’s.6
Potential Triggers of Autoimmunity in Sjögren’s
Viruses
There are several studies of the impact of viral triggers, including Epstein-Barr virus (EBV) and COVID-19, increasing the risk of developing autoimmune diseases and autoinflammatory connective tissue disorders like Sjögren’s. In one study consisting of approximately three million people who had COVID-19, there was a 13% increased risk of developing Sjögren’s and the role of autoimmunity in developing long COVID is currently being investigated.8
EBV is highly prevalent and approximately 90% of the population has been exposed to EBV. However, patients with Sjögren’s have higher levels of EBV DNA in their salivary and lacrimal (tear) glands as well as serum antibodies against EBV in their blood.9,10 Furthermore, patients with Sjögren’s-associated dry eye also had higher levels of EBV serum antibodies compared to those with simple dry eye or other autoimmune disease-associated dry eye.9 As with most viruses, EBV lives within the body and can be reactivated. Reactivation of EBV has been associated with joint involvement in patients with Sjögren’s.11 These studies suggest that EBV may be a risk factor for Sjögren’s and potentially increase certain clinical manifestations of Sjögren’s such as dry eye and joint involvement.
While the role of viral triggers in autoimmune diseases is still being investigated, a potential mechanism for the link between viruses and autoimmune disease may be a concept called molecular mimicry. Molecular mimicry is when the body attacks a foreign substance that may have similar structure to other proteins in the body and as such, may mistakenly attack the body's own proteins. In the case of EBV, there is evidence that the viral protein EBNA-2 (a common viral protein for EBV and has been found in salivary glands of patients with Sjögren’s) has similar structure to the SSA/Ro60 that naturally occurs within the body, where antibodies against SSA/Ro60 are a common marker for diagnosis of Sjögren’s.12 The role of viral triggers in developing autoimmune diseases is somewhat controversial and more studies are needed to determine their relationship with autoimmunity in Sjögren’s.
Sex Hormone Dysregulation
Another trigger for autoimmune disease is sex hormone dysregulation. Menopause in women causes a decline in estrogen and progesterone. Patients with Sjögren’s who are post-menopausal have an elevated interferon signature, which means that genes regulated by interferon (a family of cytokines or signaling proteins that play a role in the body's immune defense against viral infections and other pathogens) are upregulated. This increase in gene expression can contribute to heightened immune and inflammatory responses.13 Furthermore, patients with a higher interferon signature often have increased biological and hematological involvement related to Sjögren’s. 14,15
Another study looking at exposure of women with Sjögren’s to estrogen and the onset of menopause (decreased estrogen) showed an increased risk of Sjögren’s in women with low estrogen exposure.16 While there is no direct link between estrogen and Sjögren’s disease activity, these studies and others suggest that estrogen has a protective role in the development and progression of Sjögren’s. Since estrogen regulation is controlled by genes on the X chromosome, this provides further evidence that regulation of genes on the X chromosome contributes to Sjögren’s disease development.
Autoimmune Disease and Sjögren's Research
Although some experts say that the increase in the number of new cases of autoimmune diseases is concerning and approaching epidemic levels, autoimmune research is actively progressing with increased funding and the development of better diagnostic tools and treatments. The National Institutes of Health (NIH) investment in autoimmune disease research has drastically increased over the past few years with a significant increase from $800 million to over $1 billion in funding in 2022. There has also been an increase in the number of grants with almost 1500 new research grants awarded from fiscal year 2021 to 2022 (Note: statistics were provided from the Office of Autoimmune Disease Research- https://orwh.od.nih.gov/OADR-ORWH). Furthermore, the implementation of the Women’s Health Research Initiative in 2023 aimed to improve women’s health by addressing health needs and research gaps, including the study of autoimmune diseases.
The Sjögren’s Foundation has continuously supported the advancement of research in Sjögren’s. It is our mission to lead, encourage, and fund innovative research projects to better understand, diagnose, and treat Sjögren’s. Over the past five years, the Sjögren’s Foundation has supported over $1.8 million in research grants and provided research support for projects aimed to improve Sjögren’s research such as the Accelerating Medicines Partnership® Autoimmune and Immune-Mediated Diseases (AMP® AIM) Program.
The Foundation is energized by the momentum in Sjögren’s research and remains committed to supporting work that leads to better treatments and outcomes for patients.
References