The National Institutes of Health has launched its first agencywide Strategic Plan for Autoimmune Disease Research, a five-year initiative aimed at accelerating research into diseases that affect an estimated 50 million Americans and cost more than $100 billion annually.

Autoimmune disorders occur when the immune system, designed to protect the body from viruses, bacteria and other threats, mistakenly attacks healthy tissues. Nearly every part of the body can be affected, including the skin, joints, heart, lungs and nervous system.

The result is often chronic and debilitating illness as most autoimmune diseases have no permanent cure and require lifelong management. While treatments continue to improve, many patients still rely on the long-term use of immunosuppressive therapies to manage their disease.

One of the key features of autoimmune diseases is that they disproportionately affect women, who account for more than 70% of patients worldwide, a distinction the NIH initiative will explore.

At Cedars-Sinai, scientists and clinicians with the Kao Autoimmunity Institute are working to understand how biological sex influences immune responses and disease risk. In lupus, for example, 90% of the patients are women and investigators are trying to understand what factors drive that enormous disparity and what could improve treatment.

Autoimmune disease and lupus investigator Caroline Jefferies, PhD, scientific director of the Center for Research in Women’s Health Science at Cedars-Sinai, and rheumatologist Mariko Ishimori, MD, associate director of the Clinical and Translational Research Center, sat down with the Cedars-Sinai Newsroom to discuss how sex differences can shape lupus risk, symptoms and patient care.

Why do autoimmune diseases affect women more often than men?

Jefferies: Differences in sex chromosomes, hormones and environmental exposures all influence the immune system. Some genes involved in regulating immune responses are located on the X chromosome. Although females typically have two X chromosomes, one is usually switched off in each cell. Certain immune-related genes, however, can escape that inactivation process and remain active, which may contribute to a heightened immune response and help explain why autoimmune diseases are more common in women.

How does the immune system function differently in women compared to men?

Jefferies: Women generally mount stronger immune responses than men, resulting in faster responses to viruses and better responses to vaccines. This was especially evident during the COVID-19 pandemic, when men experienced higher mortality and more severe disease. But that significant antiviral advantage also may contribute to the higher rates of inflammatory and autoimmune diseases seen in women, including lupus.

Why is lupus a key example of sex differences in autoimmune disease?

Jefferies: About 9 out of 10 lupus patients are women, and lupus was one of the first autoimmune diseases linked to overactivation of antiviral immunity. Decades ago, researchers discovered that interferons—proteins released when the body detects viruses—were elevated in lupus patients. Interferons drive immune cell activation, antibody production and cell death, all of which can contribute to the development of autoimmunity and illness.

Does lupus present differently in women and men, and can those differences affect diagnosis or treatment?

Ishimori: Women are far more likely to develop lupus, especially during their reproductive years, when the ratio of women to men with the disease is about 9 to 1.

Lupus symptoms can vary widely, but women commonly experience fatigue, joint pain, swelling, rashes and oral ulcers. Men may be more likely to develop inflammation around the heart or lungs, or organ-threatening disease affecting the kidneys or heart. Because there is no definitive blood test, or single symptom, that confirm lupus, delays in diagnosis can occur. Men may face additional delays because lupus is generally considered more common in women and may be less likely to be considered in the differential diagnosis in men.

Are there stages in a woman’s life when autoimmune symptoms may change or become more noticeable?

Ishimori: During pregnancy, the immune system adapts to tolerate a growing fetus while continuing to protect the mother. Some women with autoimmune disease experience flares during pregnancy, while others do not. Patients with known autoimmune disease are generally encouraged to achieve good disease control before conception because well-controlled disease is associated with fewer pregnancy complications. Several weeks after delivery, there may be an increased risk of disease flare or even a first presentation of autoimmune disease as the immune system readjusts.

Around menopause, some autoimmune symptoms can overlap with changes naturally associated with that stage of life, which can sometimes complicate diagnosis of a specific disorder.

What should women do if they think they may have an autoimmune disease?

Ishimori: Autoimmune symptoms often persist over time, although they may come and go. Because infections and other illnesses can sometimes cause similar symptoms, it’s important to look at the bigger picture. Keeping track of symptoms—such as fevers, rashes or patterns of joint pain—can help patients have more informed conversations with their doctors. Patients should feel comfortable asking what conditions are being considered, what tests are being ordered and whether autoimmune disease could be a possible explanation for their symptoms.

How could a better understanding of sex differences change autoimmune disease treatment?

Jefferies: One of the biggest gaps in our knowledge is understanding how sex chromosomes and sex hormones influence the immune system across different tissues and organs. A better understanding of those mechanisms could eventually help researchers develop more targeted treatments for organ-specific complications of lupus, including heart and lung disease. Ultimately, that is why we do this work—to help patients, many of them women, live healthier lives.

Read more from Cedars-Sinai Stories and Insights: Cultivated Care for Autoimmune Diseases

According to a recent study published in The Journal of Clinical Investigation, 67% of autoimmune diagnoses are in women, and 18 out of the 20 most common autoimmune diseases—such as rheumatoid arthritis, psoriasis, multiple sclerosis and lupus—are more prevalent in women than in men.

Ishimori, who was not involved in the study, said chromosomal and hormonal differences likely explain why women are diagnosed with autoimmune disease more often than men. She said variations in immune system responses may play a role as well.

“Generally, women at every age group have more powerful immune systems than men,” Ishimori told HealthCentral. While a stronger immune system can help fend off illness, it also may increase women’s likelihood of developing autoimmune disease.

Among patients with autoimmune conditions, women also are more likely than men to develop a mood disorder such as depression or anxiety, according to research recently published in BMJ Mental Health. Ishimori said inflammation associated with autoimmune disease may contribute to these mental health conditions, as well as hormonal and chromosomal dynamics.

Sex differences aside, the strain of living with a chronic disease can take a toll on mental health, Ishimori told HealthCentral.

“It’s difficult to wrap your mind around, and it can be anxiety provoking and lead to depression in some patients when there’s sadness or hopelessness that things won’t get better,” Ishimori said.

Read the complete article from HealthCentral.