What Causes Lupus: Genetic, Environmental, and Hormonal Causes

Lupus, often known as systemic lupus erythematosus (SLE), is a chronic autoimmune disease that can affect nearly every organ in the body. The immune system, which normally protects against harmful invaders, mistakenly attacks healthy cells and tissues. 

Understanding the root causes of lupus helps to individualize a patient’s care, and provides more opportunities to improve treatments and improve the patient’s quality of life. 

Here we’ll explore the primary causes of lupus including genetic predispositions, environmental triggers, and hormonal factors, using current research to shed light on how these elements intersect to provoke lupus symptoms. 

The goal is to provide new insights that can improve patient care and bring hope and healing to people living with lupus. 

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What is Lupus?

Lupus is a complex, chronic autoimmune condition that can manifest in symptoms throughout the body. Recognizing the widespread symptoms as a constellation of lupus and not as separate and unrelated signs is essential for early diagnosis.

What is Lupus? Definition and Overview

Typically, when people discuss lupus they’re referring to Systemic Lupus Erythematosus, or SLE, which affects many systems. SLE is the most common form of lupus; however, there are actually four types of lupus: 

• Systemic lupus erythematosus

• Lupus of the skin, which encompasses acute, subacute, or chronic (discoid) lupus erythematosus

• Drug-induced lupus erythematosus

• Neonatal lupus erythematosus, a rare condition usually caused when autoantibodies are passed from mother to child

Broadly speaking, lupus is an autoimmune disorder where the immune system malfunctions, mistakenly attacking the body’s healthy tissues instead of foreign invaders like bacteria and viruses. 

This immune response leads to widespread inflammation and tissue damage in organs such as the kidneys, heart, skin, lungs, and brain.

Symptoms and Complications

Lupus manifests in diverse ways due to the immune system’s attack on various parts of the body.  

The common symptoms of SLE include fatigue, joint pain, skin rashes, and photosensitivity which may result in a "butterfly" rash on the face (sun-exposed areas), sensitivity to sunlight, and fever. 

Other symptoms can include hair loss, muscle weakness, headaches, decreased appetite, weight loss, dry eyes and eye problems, reproductive issues, swollen lymph nodes, and more.

Symptoms of lupus can vary widely, and untreated lupus can cause serious complications.

Common and serious complications of SLE include:

• Lupus nephritis, a kidney inflammation that can lead to kidney failure if not adequately treated. 

• Heart and lung problems like inflammation of the heart lining (pericarditis), inflammation of the lung lining (pleuritis), and blood clots and high blood pressure in the lungs (pulmonary embolism and pulmonary hypertension).

• It can also lead to brain and nerve issues like seizures, mental confusion, or strokes that affect the brain.

• Additionally, lupus can affect the blood, causing conditions like anemia (low red blood cells), leukopenia (low white blood cells), and thrombocytopenia (low platelet count).

Prevalence and Demographics

Lupus disproportionately affects certain demographics. 

Systemic lupus erythematosus (SLE) overwhelmingly affects women, especially during their reproductive years, with a female-to-male ratio as high as 15:1. 

Lupus also occurs more frequently among individuals of African, Asian, Hispanic, and Native American descent. 

These disparities suggest that hormonal and genetic factors may play significant roles in lupus development.

Genetic Factors in Lupus

There are well-known links between certain genetic factors and the development of lupus. 

Inheritance Patterns

Family history is a well-established risk factor for lupus. A Danish study involving over 5 million people found that having a family member with systemic lupus erythematosus (SLE) greatly increases the risk of developing SLE or other autoimmune diseases. 

First-degree relatives, like siblings or children, are about 10 times more likely to get SLE and are also at a higher risk for other autoimmune diseases like rheumatoid arthritis (RA) and type 1 diabetes. 

Relatives who are second- or third-degree, like cousins or grandparents, also face an increased risk, though it’s lower than that of close family members. 

Even though the relative risk is much higher in families with a history of SLE, the actual chance of developing it is still low, with only about 2% of first-degree relatives being diagnosed over a 22-year period.

Epigenetics

The concept of epigenetics is vital to understanding the environmental impact on who develops lupus. Epigenetics refers to changes in gene expression that do not alter the DNA sequence itself. 

Essentially, how can environmental factors such as diet, stress, and exposure to toxins "turn on" or "turn off" genes that influence lupus development? 

For example, two people might carry the same genes associated with lupus, but environmental exposures could activate those genes and trigger lupus in one person, while the other person, who does not have the same environmental exposures, does not develop lupus. This is an epigenetic effect. 

While genetic predisposition is important, it may not be enough to cause lupus on its own. For people at increased risk of developing lupus, understanding environmental influence is essential.

In the next section, we’ll explore some well-known environmental triggers for lupus. 

Environmental Triggers for Lupus

Environmental triggers for lupus stimulate epigenetic changes that turn on or turn off the genes related to lupus.

Sunlight Exposure

Sunlight, particularly ultraviolet (UV) radiation, is one of the most well-known environmental triggers for lupus flares. 

Sunlight can trigger lupus flares by causing changes in how genes are regulated. UV light reduces the activity of an enzyme called DNMT1, which normally helps control DNA methylation—a process that keeps certain genes turned off. 

When these genes become more active than they should, it ultimately leads to increased disease activity. UV exposure can also increase the production of a protein called GADD45α, which further makes the immune system overreact and may cause lupus symptoms to worsen.

Sunlight can also trigger lupus flares by causing oxidative stress, which leads to changes in how the immune system functions. 

When people with lupus are exposed to UV light it generates inflammatory reactive oxygen species (ROS), which ultimately also reduces DNMT1 activity. This epigenetic shift in gene expression causes immune cells to start attacking the body's own tissues, leading to lupus flares.

Infections

Some infections can trigger lupus by affecting the immune system and causing epigenetic changes. 

These infections trick and over-activate immune cells, triggering lupus in susceptible people. 

Epigenetic changes that cause lupus flares often involve DNA methylation. DNA methylation normally helps control which genes are active or inactive. In lupus patients, infections can decrease DNA methylation, ultimately promoting immune overreaction which results in autoimmune attacks. 

Infections can also cause inflammation and produce excessive oxidative stress. Oxidative stress decreases DNMT1 activity in T cells, causing DNA demethylation and triggering autoimmune reactions.

Specific infections linked to lupus include:

• Epstein-Barr Virus (EBV): EBV is strongly associated with lupus due to its ability to disrupt the immune system and trigger abnormal antibody production.

• Parvovirus B19: this virus can cause lupus flares by confusing the immune system, leading it to attack its own tissues.

• HTLV-1 and HIV-1: these viruses directly affect immune cells, potentially causing lupus-like symptoms in genetically predisposed individuals.

• Endogenous retroviruses (ERVs): these are viral remnants in human DNA that can be reactivated by infections, contributing to lupus.

Toxins and Medications

Some environmental toxins are known to increase the risk of lupus. 

Additionally, certain medications can induce a form of lupus known as drug-induced lupus, especially hydralazine and procainamide, which are both DNA methylation inhibitors that provoke drug-induced lupus. Unlike SLE, drug-induced lupus tends to resolve once the triggering medication is discontinued.

Some commonly-associated drugs and toxins associated with lupus include: 

Hydralazine: a hypertension medication that reduces DNA methylation by blocking protein kinase Cδ, leading to lupus-like symptoms in genetically predisposed individuals.

Procainamide: induces lupus-like symptoms by inhibiting DNA methyltransferase 1 (DNMT1), leading to T cell DNA demethylation and autoimmune responses.

Methotrexate: used for autoimmune diseases and cancer, it depletes SAM which is required for DNA methylation, potentially triggering lupus flares.

Cyclophosphamide: a treatment for lupus and systemic vasculitis that increases DNA methylation, affecting immune regulation and lupus development.

Valproic Acid: an epilepsy drug that inhibits histone deacetylases (HDACs), sometimes causing lupus-like symptoms.

Cigarette smoke: contains toxins that induce oxidative stress, reducing DNA methylation in immune cells, which may trigger lupus.

Alcohol: moderate use may lower lupus risk, but heavy drinking is associated with increased onset in some cases.

Chemicals: exposure to substances like silica, mercury, and pesticides increases lupus risk through oxidative stress and immune disruption.

Hormonal Influences in Lupus

Because of the overwhelming gender disparity in lupus, the effect of hormones on lupus onset and flares have been studied. 

Gender Disparity in Lupus

Lupus overwhelmingly affects women, with approximately 90% of patients being female. 

This gender disparity suggests that hormones, particularly estrogen, play a significant role in lupus onset and progression. Estrogen modulates immune function and may contribute to immune system dysregulation, increasing the risk of lupus, especially during childbearing years.

Estrogen promotes B cell activity (a type of white blood cell that makes antibodies) and autoantibody production, potentially leading to autoimmunity, while testosterone has protective, immunosuppressive effects. 

Hormonal changes during menstruation, pregnancy, or hormone replacement therapy (HRT) can cause lupus flares. Many women experience these disease flares during pregnancy, menstruation, or when using estrogen-based therapies. Conversely, the risk of flares decreases after menopause as estrogen levels decline.

Hormone therapies like oral contraceptives and HRT (hormone replacement therapy) may increase flare risks and cardiovascular complications, especially in women with antiphospholipid antibodies or a history of thrombosis.

Pregnancy and Hormonal Fluctuations

Increasing estrogen and changes in the immune system play a key role in how lupus affects pregnancy. Higher estrogen levels, especially in the third trimester, can increase immune activity and make autoimmune diseases like lupus worse. 

Additionally, Treg cells—regulatory T cells that help maintain immune balance—are often reduced and don’t function properly in lupus patients. 

During pregnancy, these cells are supposed to increase at the maternal-fetal interface to prevent immune system overreactions. In lupus patients, this response may be inadequate, leading to a higher risk of flare-ups and pregnancy complications.

Pregnancy complications in women with lupus are complex. Patients with systemic lupus erythematosus (SLE) are more likely to experience issues like miscarriage, preeclampsia, preterm birth, and fetal loss, especially if their lupus is active or they have certain antibodies, such as Anti-Ro and Anti-La. 

These antibodies can cross the placenta and cause neonatal lupus, which might appear as a skin rash, liver problems, or even a serious heart condition in the baby. 

Active lupus nephritis during the six months leading up to conception also significantly increases the risk of adverse pregnancy outcomes, including preterm birth, fetal loss, and maternal complications.

Planning and managing pregnancy carefully is essential for lupus patients, particularly if their disease hasn’t been controlled for at least six months before conception. 

Flares during pregnancy can increase the chances of complications like fetal loss, low birth weight, and preterm birth. Keeping lupus under control is essential to reduce these risks.

Interplay Between Genetics, Environment, and Hormones

The relationship between a person’s genetic inheritance, her or his exposure to environmental triggers, and hormone levels all influence whether lupus develops, or not.

Complex Interactions

Lupus does not have a single cause but is rather the result of complex interactions between genetic predispositions, environmental exposures, and hormonal influences. 

For example, a person may carry genes that make them susceptible to lupus, but activating epigenetic changes in those gene’s expression could require a combination of UV exposure, viral infection, and hormonal changes that ultimately trigger the disease. 

Understanding this interplay is necessary for both clinicians and patients in developing personalized treatment plans and helping patients reduce their risk of lupus flares.

Personalized Medicine Approach

As research into the causes of lupus advances, the future of lupus treatment may lie in personalized medicine. 

By understanding a patient’s unique genetic makeup, environmental exposures, and hormonal profile, clinicians may be able to tailor treatments that are more effective and reduce the risk of flares, leading to better patient outcomes.

Diagnosis and Risk Identification

Identifying early signs of lupus is necessary for proper diagnosis and ultimately reducing a patient’s risk of developing serious complications.

Early Warning Signs

Identifying lupus early is critical to preventing long-term organ damage. 

Early symptoms often include fatigue, joint pain, unexplained fevers, and skin rashes, which are easily mistaken for other conditions. Family history, as well as exposure to environmental factors like sunlight and infections, should alert clinicians to the possibility of lupus. 

Diagnostic Testing

Diagnosing lupus requires a combination of clinical examination and laboratory tests. The most common test is the antinuclear antibody (ANA) test, which detects autoantibodies that attack the body's tissues. 

Genetic screenings and tests for specific biomarkers can help confirm lupus in patients with ambiguous symptoms. 

Early detection is key to managing lupus effectively, and a multidisciplinary approach involving rheumatologists, dermatologists, and nephrologists is often necessary for comprehensive care. 

Functional medicine practitioners can also complement a patient’s treatment plan by helping them maintain an anti-inflammatory lifestyle that reduces the risk of autoimmune flares.

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Key Takeaways

• Lupus is a complex autoimmune disease that results from a combination of genetic predispositions, environmental triggers, and hormonal factors, affecting multiple organs and leading to symptoms like fatigue, joint pain, and inflammation.

• Environmental factors like UV exposure and infections, along with dietary and toxin exposure, can trigger lupus flares, while hormonal changes, especially estrogen, can exacerbate the condition, particularly in women.

• Personalized care and early detection are essential for lupus management, as understanding a patient’s genetic background, environmental exposures, and hormonal influences can help tailor treatments and improve outcomes.