Lupus: Systemic Lupus Erythematosus (SLE)
Lupus Pathophysiology and Manifestations
Inflammation and Tissue Injury
The principle cause of lupus-mediated tissue injury is inflammation triggered by autoantibody complexes.
B cells, so-called because these immune cells originate in the Bone marrow, produce and secrete the antibodies, which are specialized proteins that bind to other molecules. The immune system generates millions of different antibodies that target an extremely large variety of molecules on the surface of microbes, such as bacteria and viruses. The antibody binds its specific molecule on a microbe in similar fashion to a key in a certain lock. When the "key" (antibody) and "lock" (microbe) fit together, the antibody sticks tightly to the microbe and marks it to be removed from the body. In people with lupus, many of the B cells secrete autoantibodies, which means that these antibodies bind to molecules on otherwise healthy tissues instead of molecules on microbes.
T cells, which are generated in the Thymus, produce various proteins called cytokines that help B cells grow, become activated, and stimulate B cells to produce antibodies. Other immune cells, including macrophages and neutrophils, migrate to the site of inflammation and produce tissue damaging reactive oxygen species (ROS), as well as engulf microbes and cells through a process called phagocytosis. One of the ways macrophages know when to engulf a microbe is by sensing that antibodies are stuck to their surface. All of these cells collectively are called leukocytes or white blood cells because of their lack of color. B and T cells are a subset of leukocytes called lymphocytes.
The types of self-molecules ("the lock") that stick to autoantibodies ("the key") vary in each case of lupus. Self-molecules common in lupus often are associated with the cell nucleus, which is the compartment within a cell that contains DNA and other proteins that make up genes.
Lupus-mediated tissue damage can be summarized as follows:
- B cells become activated and produce autoantibodies that bind various self-molecules.
- Activated T cells produce proteins called cytokines that help activate more B cells.
- Large complexes of antibodies stuck to self-molecules are formed.
- These complexes become lodged in various tissues throughout the body, such as the kidney and joints.
- The complexes cause an influx of neutrophils, macrophages, and other B cells and T cells into the tissue
- Proinflammatory cells secrete damaging reactive oxygen species and more proteins that cause tissue damage.
- If the inflammation is not treated and persists over time, the tissue may become permanently damaged.
Vitamin D Balances Immune Reactivity in Autoimmune Diseases
Vitamin D intervenes in the process of autoimmunity by tilting the properties of T and B cells towards "tolerance" of self-tissues. Tolerance is a phenomenon orchestrated by a variety of highly specialized cytokines and other cell-signaling molecules.
Early in the developmental process of immune cells, they are directed to become either "effector" or "regulatory" immune cells. In other words, to become immune cells that promote tissue destruction, or those that suppress tissue destruction.
Patients with lupus have elevated numbers of effector cells and lower numbers of regulatory cells. Moreover, the regulatory cells of lupus patients are malfunctional.17 Vitamin D exerts multiple actions at the cellular level to balance the population of effector cells and regulatory cells.18 In a 2012 study, 20 lupus patients with initially low vitamin D blood levels received 100,000 IU of vitamin D weekly for four weeks, followed by 100,000 IU monthly for six months. The treatment resulted in significantly increased vitamin D blood levels (from 18 ng/mL at baseline to 51 ng/mL at 2- and 6-month follow-ups), decreased effector T-cell counts and anti-DNA antibodies, and increased regulatory T cells. Over the 6-month follow-up period, no disease flares were noted.19 These lines of evidence establish a very strong case for the importance of maintaining sufficient vitamin D blood levels to combat lupus disease activity. Life Extension suggests an optimal vitamin D blood level of 50–80 ng/mL (measured as 25-hydroxyvitamin D).
The Hormone Connection
The link between sex hormones as lupus disease activity has been the subject of debate for decades. The fact that women are considerably more likely to develop autoimmune diseases than men suggests that steroid hormones, especially estrogen and progesterone, influence the immune system.
Estrogen actions tend to be proinflammatory, while the actions of progesterone, androgens, and glucocorticoids are anti-inflammatory.20 Studies have documented low progesterone levels in women with lupus, suggesting that a relative imbalance in favor of estrogen may contribute to immune reactivity in some female patients.21
Accordingly, studies in women with lupus revealed an increased rate of mild to moderate intensity disease flares associated with estrogen-containing hormone replacement therapy.22 Experimental studies have suggested that testosterone may suppress immune reactivity in lupus animal models and in cells from patients with lupus.23,24
Based on the available data, Life Extension suggests that women with lupus evaluate their sex hormone levels and ensure that progesterone and testosterone levels are sufficient. If progesterone or testosterone levels are found to be low, women should consider using bioidentical progesterone or and/or testosterone creams to restore levels to a normal range.25
Kidney disease is a common complication in people with lupus; in fact, almost 50% of those with lupus have some degree of kidney disease.6 Like other affected tissues in lupus, damaging inflammation from autoimmune attack causes a kidney disease called lupus nephritis.
The circulatory system delivers blood to the glomeruli, which are the small filtering units of the kidneys, through small capillaries. Glomeruli help to regulate blood pressure and electrolytes by removing or reabsorbing fluids and salt according to the body’s needs. In people with lupus, the large autoantibodies/antigen complexes that circulate in the blood can become lodged in the glomeruli and cause damaging inflammation. The onset of kidney complications generally occurs at least five years after the onset of lupus symptoms.
A healthy kidney only allows small molecules like salts to be removed from the body, and allows large protein molecules to remain in the blood. However, kidney disease—including that caused by lupus nephritis—causes proteins to leak out of the kidney into urine. High levels of protein in the urine, clinically called proteinuria, are indicative of kidney damage. A normal level of protein in a 24-hour urine sample is below 300 mg.26
Heart and Cardiovascular
People with lupus are at a significantly increased risk of developing coronary artery disease (CAD). One study found that women between the ages of 35 and 44 who had lupus were 50 times more likely to have a heart attack than similar aged women without lupus.27 Additionally, heart disease is actually one of the most common causes of death for people with lupus.28 This increased heart disease risk in people with lupus is caused by a several different factors,29 including:
- Lupus-mediated inflammation can directly damage the endothelium, the lining of blood vessels, ultimately leading to atherosclerosis.
- Type 2 diabetes, high blood pressure, and high cholesterol are more likely to be present in people with lupus, all of which make the risk of heart disease greater.
- People with lupus are often less active because of various symptoms such as fatigue, joint pain and muscle pain. A low degree of activity is associated with unhealthy weight gain and high blood pressure, both of which are risk factors of heart disease.
People with lupus should be sure to do everything they can to take care of their heart and vascular system. The Life Extension Magazine article entitled "How to Circumvent 17 Independent Heart Attack Risk Factors" is an excellent resource to help ensure that every risk factor for cardiovascular disease is addressed.
Lupus may also damage the nervous system. The possible signs and symptoms include confusion, excessive tiredness, seizures, difficulty concentrating, and/or headaches.30 The exact mechanisms causing nervous system damage in lupus are still being investigated, but are likely due to two principle factors10,31:
- Specific autoantibodies may inappropriately target molecules on nerve cells, causing inflammation and subsequent nerve damage.
- Inflammation in and around blood vessels prevents the delivery of the nutrients and oxygen nerves need to stay healthy.
Additional signs and symptoms of nervous system involvement in lupus include a very stiff neck reminiscent of meningitis, a high fever, psychosis, and/or seizures.32 Severe neurological disease in lupus can lead to coma and even death and therefore immediate emergency medical attention should be sought at the first sign of these symptoms.
Lupus also causes muscle pain, but fortunately, the strength of the muscle is not affected. Up to 16% of people with lupus experience this painful symptom, which commonly affects the arms and upper thighs.33
Loss of bone density is more common in people with lupus, which can lead to osteoporosis and a greater risk of fracture. The disease itself, and/or disease-related inactivity, can contribute to osteoporosis risk. However, exercise is often difficult or painful for individuals with lupus because of joint and muscle pain and stiffness. Additionally, certain conventional medications used to treat lupus, such as corticosteroids, can also accelerate bone loss.6
These disorders are, unfortunately, very common in people with lupus. Four potentially severe lupus-associated complications are blood count abnormalities. Blood cell counts are typically measured as number of cells in cubic millimeter of blood.
Anemia. Too few red blood cells. A complete blood count (CBC) is a common blood test in which all of the blood cell types are counted in a fixed volume. Normal results for men are 4.7 to 6.1 million red blood cells/µL of blood and normal results for women are 4.2 to 5.4 million red blood cells/µL.34
Thrombyocytopenia. Too few platelets in the blood. Platelets are small cell fragments that, when activated, stick together to form blood clots. Too few platelets may cause a delay in clot formation and excessive bleeding. Normal levels are between 150,000 to 450,000 platelets per cubic millimeter35; thrombocytopenia in context of lupus is defined as platelet levels below 100,000 per cubic millimeter.36
Leukopenia. A reduced level of leukocytes, also called white blood cells due to their lack of color. Defined as a count below 4,000 per cubic millimeter.36 Leukopenia increases the risk of potentially severe infections.
Lymphopenia. A reduced level of a subset of white blood cells called lymphocytes, defined as a count below 1,500 per cubic millimeter.36 B and T cells fall broadly into the leukocyte group and can be more specifically defined lymphocytes. Lymphopenia also increases the risk of severe infections.