Women are significantly more likely than men to develop autoimmune diseases like lupus, with biological sex playing a major role in immune system function. A new National Institutes of Health (NIH) Strategic Plan for Autoimmune Disease Research is investigating why women account for more than 70% of the estimated 50 million Americans living with autoimmune disorders, which cost the healthcare system more than $100 billion annually.

Why Do Women Develop Autoimmune Diseases More Often Than Men?

The answer lies in fundamental differences in how male and female immune systems work. Women naturally mount stronger immune responses than men, which provides advantages in fighting off infections and responding to vaccines. However, this same strength can backfire, leading to higher rates of inflammatory and autoimmune diseases where the immune system mistakenly attacks the body's own healthy tissues.

Several biological factors contribute to this sex difference:

• X Chromosome Genes: Some immune-related genes are located on the X chromosome. While females typically have two X chromosomes, one is usually inactivated in each cell. However, certain immune genes can escape this inactivation and remain active, potentially heightening immune responses.
• Hormonal Influences: Sex hormones play a significant role in regulating immune function, with estrogen and other female hormones affecting how immune cells behave and respond to threats.
• Environmental Exposures: Differences in how men and women are exposed to environmental factors, infections, and other triggers can shape immune system development and reactivity over time.

"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," explained Caroline Jefferies, PhD, scientific director of the Center for Research in Women's Health Science at Cedars-Sinai.

Caroline Jefferies, PhD, Scientific Director of the Center for Research in Women's Health Science at Cedars-Sinai

What Makes Lupus a Key Example of Sex Differences in Autoimmunity?

Lupus stands out as one of the most striking examples of sex-based autoimmune disease disparity. Approximately 90% of lupus patients are women, particularly during their reproductive years when the ratio of women to men with the disease reaches about 9 to 1. Lupus was one of the first autoimmune diseases linked to overactivation of antiviral immunity, with researchers discovering decades ago that interferons, proteins released when the body detects viruses, were elevated in lupus patients. These interferons drive immune cell activation, antibody production, and cell death, all of which can contribute to autoimmunity and illness.

The disease also presents differently in women and men, which can affect diagnosis and treatment. Women commonly experience fatigue, joint pain, swelling, rashes, and oral ulcers. Men, by contrast, 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 confirms lupus, delays in diagnosis can occur, and men may face additional delays because lupus is generally considered more common in women.

How Life Stages Affect Autoimmune Symptoms in Women

Autoimmune disease symptoms can shift dramatically across different stages of a woman's life. 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.

Steps to Take If You Suspect an Autoimmune Disease

• Track Your Symptoms: Keep detailed records of symptoms such as fevers, rashes, or patterns of joint pain over time. Autoimmune symptoms often persist, although they may come and go, and patterns can help doctors identify the underlying condition.
• Look at the Bigger Picture: Because infections and other illnesses can sometimes cause similar symptoms, it is important to consider how symptoms cluster together and whether they follow a pattern consistent with autoimmune disease rather than acute illness.
• Ask Your Doctor Questions: Feel comfortable asking what conditions are being considered, what tests are being ordered, and whether autoimmune disease could be a possible explanation for your symptoms. Early diagnosis can lead to better outcomes.

"Autoimmune symptoms often persist over time, although they may come and go. Because infections and other illnesses can sometimes cause similar symptoms, it is important to look at the bigger picture. Keeping track of symptoms can help patients have more informed conversations with their doctors," noted Mariko Ishimori, MD, rheumatologist and associate director of the Clinical and Translational Research Center at Cedars-Sinai.

Mariko Ishimori, MD, Rheumatologist and Associate Director of the Clinical and Translational Research Center at Cedars-Sinai

What Could Better Understanding of Sex Differences Mean for Treatment?

One of the biggest gaps in current 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. The NIH's new five-year Strategic Plan for Autoimmune Disease Research, launched in 2026, aims to accelerate research into these questions and ultimately help the millions of patients, many of them women, live healthier lives.

At Cedars-Sinai's Kao Autoimmunity Institute, scientists and clinicians are actively working to understand how biological sex influences immune responses and disease risk. This research represents a critical shift toward personalized medicine that accounts for the fundamental biological differences between men and women, rather than treating autoimmune disease as a one-size-fits-all condition.