Systemic Lupus Erythematosus

Description

Alternative Names

Causes

Systemic lupus erythematosus is a complex disorder that occurs as a consequence of a number of independent processes and factors.

Environmental factors, such as viruses, exposure to chemicals, or sunlight trigger inflammatory or immune activity. This immune activation may begin as an appropriate response to an unwanted "invader." But, because of a combination of genetic factors, an individual with lupus develops an ongoing immune response that does not shut itself off appropriately. This leads to waxing and waning flares of inflammation that can involve various organs of the body, depending on specific features of this self-perpetuating immune response in individual patients.

The exact combination of genes that predispose individuals to SLE may differ somewhat from patient to patient, but probably share certain common features which tend to impair the ability of the body to rid itself of immune-triggering particles and which tend to prolong or increase the degree of immune responsiveness to these triggers.

A major characteristic of lupus is that it is an autoimmune response, in which immune factors, called autoantibodies, seem to attack the person's own cells. However, it should be stressed that some autoantibodies are probably normal in a well-balanced immune system, serving various roles to help the body dispose of wastes, protect from invaders that have similarity to human structures, and to keep blood vessels clear. In healthy people, autoantibodies tend to be well-regulated and well "masked," or covered up, until needed. Therefore, it is probably the high activity and high detectability of autoantibodies that makes lupus unique, not the fact that they exist.

In line with this, many people who have viral syndromes or have reached the age of 50 have a positive test for the anti-nuclear autoantibody (ANA). Thus, this common screening test for lupus is actually an autoantibody which is found in many healthy people, and a positive ANA would never give someone a diagnosis of lupus in the absence of other disease features.

The Inflammatory Process and Autoimmunity

The Normal Immune System Response. The inflammatory process is a byproduct of the activity of body's immune system, which fights infection and heals wounds and injuries:

• When an injury or an infection occurs, white blood cells are mobilized to rid the body of any foreign proteins, such as a virus.
• The masses of blood cells that gather at the injured or infected site produce factors to fight any infective agents.
• In the process the surrounding area becomes inflamed and some healthy tissue is injured. The immune system is then called upon to repair wounds by clotting off any bleeding blood vessels and initiating fiber-like patches to the tissue.
• Under normal conditions, the immune system has special factors that control and limit this inflammatory process.

The Infection Fighters. Two important components of the immune system that play a role in the inflammation associated with lupus are B cells and T cells, both of which belong to a family of immune cells called lymphocytes.

When macrophages recognize foreign particles entering the bloodstream, they are programmed to ingest them, split them into pieces, and bring specific sections of them (antigens) into contact with the surface of the T cell. These antigens are placed within specialized proteins on the surface of the T cell that signal to a T cell and begin a process of immune system inspection. This process involves the interaction of several proteins on B cells and T cells, which seem to signal back and forth. If the T cell recognizes an antigen as "non-self," then it will produce chemicals (cytokines) that cause B cells to multiply and release many immune proteins (antibodies). These antibodies circulate widely in the bloodstream, recognizing the foreign particles and triggering inflammation in order to rid the body of the invasion.

An antigen is a substance that can provoke an immune response. Typically antigens are substances not usually found in the body.

T-cells can be further categorized as killer T-cells or helper T-cells. Killer T-cells directly attack antigens, such as viruses and tumor cells. Helper T-cells recognize antigens that are presented to them by macrophages (or other specialized cells), and can stimulate B cells to mount various kinds of attacks on the antigen. They also produce chemicals (cytokines) that can have a more direct role in the inflammatory process.

For reasons that are still not completely understood (and may be multi-factorial), both the T-cells and the B cells become overactive in certain ways in lupus patients. In an immune response it is normal for the antibody response to change over time, particularly if the first antibodies that are made do not eliminate the invading particles. Little by little, the types of antibodies being made undergo changes in an attempt to find better recognition and stronger inflammatory responses against a recalcitrant invader. In lupus, a complex interaction between activated immune cells and an impaired antigen-elimination process leads to a greater than normal repertoire of what the antibodies recognize. Eventually, antibodies are made that recognize more of the bodys own tissues in a stronger or more persistent manner than is healthy, and inflammatory responses are mounted in these tissues.

Autoantibodies. In the majority of patients with SLE, antinuclear antibodies (ANA) are detectable. Important research published in 2003 has found, in fact, that such autoantibodies may be present in individuals up to seven years prior to their developing symptoms of lupus. Some subtypes of ANA are found in lupus patients and only rarely in people without lupus. These include:

• Anti-ds DNA. An autoantibody called anti-double stranded DNA (anti-ds DNA) may play an important role in some lupus patients. A 2001 study suggested that some of these antibodies specifically recognize a protein in the kidney called alpha-actinin, which researchers suspect may also occur in other tissues that are affected by SLE, such as in the skin, joints, and brain. A subset of anti-DNA has also been found to target nerve-cell receptors in the brains of SLE patients.
• Anti-Sm antibodies. This antibody is found most often in lupus patients of African descent and is almost never detected in people without lupus. Although it is not usually seen in lupus patients, it is almost diagnostic of SLE when it is detected.

Other autoantibodies found in lupus patients include:

• Anti-Ro (SSA) and Anti-La (SSB). These autoantibodies may be involved in the sun-sensitive rashes sensitivity experienced by SLE patients and are also found in association with neonatal lupus syndrome, in which a pregnant mothers antibodies can cross the placenta and cause inflammation in the developing child's skin or heart.
• Antiphospholipid antibodies. A quarter to a half of SLE patients may have these antibodies. They attack blood clotting regulator proteins which stick to phospholipids, fatty compounds found in cell membranes throughout the body. Antiphospholipid antibodies increase the risks for blood clots and may be responsible for narrowing of and irregularities in blood vessels. Antiphospholipid antibodies are linked with miscarriages and other pregnancy complications, strokes, heart attacks and blood clots in almost any part of the body, including kidneys, legs, lungs, and eyes.

Cytokines. Most immune cells secrete or stimulate the production of powerful immune factors called cytokines. In small amounts, cytokines are indispensable for maintaining the balance of the body during immune responses, infections, injuries, tissue repair, blood clotting, clearing of debris from inflamed blood vessels, and other aspects of healing. If overproduced, however, they can cause serious damage, including dangerous levels of inflammation and cellular injury. Specific Cytokines called interferons and interleukins play a critical role in SLE by regulating the secretion of autoantibodies by B-cells. Researchers are currently interested in interferon alpha; some evidence suggests high levels of this cytokine may underlie the autoimmune response in SLE.

Complement. Another immune factor of high interest in SLE is the complement system. This is comprised of more than 30 proteins and is important for defending and regulating the immune response. Inherited deficiencies in certain complement components (C1q, C1r, C1s, C4, and C2) have long been associated with SLE. Deficiencies may contribute to SLE in the following manner:

• Complement may protect against autoimmune disease by normalizing apoptosis, the natural process by which cells self-destruct. This natural self-destruction process is an important part of the normal way in which the body keeps house in its tissues, eliminating damaged or no longer useful cells. Natural autoantibodies (the autoantibodies of healthy people) may also play a role in regulating apoptosis by triggering complement activation and rapid destruction of these self-destructive cells so that dangerous autoantigens are not left in the bloodstream long enough to trigger a more global (dysregulated) immune response. In the absence of an effective complement system, then, apoptosis goes awry and leads to persistent exposure of autoantigens to the immune system. These autoantigens sometimes take the form of nucleosomes (collections of DNA and protein) that trigger the destructive forms of SLE autoantibodies.
• Complement components are also necessary for clearing molecular rubble called immune complexes. These are the end product of the previous intense immune activity consisting of autoantibodies and antigens, leftover debris when the battle is over. In the absence of complement, this debris accumulates and is deposited in the kidneys, blood vessels, joints, and other sites where it might further incite the immune system to produce inflammation and tissue damage.

Genetic Defects

Researchers estimated that between 20 and 100 different genetic factors may be involved in the alterations of the immune system set point that could make a person susceptible to SLE.

• Research published in 2003 has identified a particular set of genes, now commonly called the interferon signature, that is activated by interferon in patients with severe lupus. This discovery may help physicians be able to identify patients at particular risk for severe disease before they develop symptoms.
• A genetic risk factor for lupus in African American women was identified in 2003. This defect causes increased production of nitric oxide, an anomaly that appears to predispose individuals to lupus, and to severe disease in particular.
• Other research has identified defects in genes that regulate apoptosis, the natural process by which cells self-destruct.
• Another study has identified an abnormal gene in some SLE patients that promotes the build-up of immune complexes that can cause kidney damage. HLA (human leukocyte antigen) is a protein that presents antigens to T cells by holding them up from the surface of macrophages or other antigen-presenting cells. There are varieties of HLA molecules that are determined by the genes that are inherited. Small differences in HLA from person to person can determine which antigens are presented in triggering an immune response and how strongly the immune system will respond to these antigens. Among the types of HLA associated with lupus are some structures known as HLA-DR2, -DR3, -A1, -B8, and DMA*0104.
• Many other small differences in important immune-regulating proteins are genetically determined and are currently.

Triggers of the Immune Response

One or more external factors appear to initiate this autoimmune response in genetically susceptible people. Possible SLE triggers include colds, fatigue, stress, oral contraceptives, chemicals, sunlight, and certain drugs.

Viruses. Blood tests reveal that SLE patients are more likely to have been exposed to certain viruses than the general population. Among the viruses that provoke the most interest are the Epstein-Barr virus (the cause of mononucleosis), cytomegalovirus, and parvovirus-B1. These viruses are very common, however, and in any case, it is unlikely that viruses are the sole cause of SLE, but would rather serve as triggering agents in people with genetically susceptible immune systems.

Click the icon to see an image of mononucleosis.

Some research suggests that different viruses may imprint specific types of SLE. For instance cytomegalovirus may affect blood vessels and cause problems such as Raynaud's phenomenon or blood abnormalities, but may not affect the kidney as much. These are speculations, however, and not a proven association.

Sunlight. Ultraviolet (UV) rays found in sunlight are important SLE triggers. When they bombard the skin, they can alter the structure of DNA in cells below the surface. The immune system may perceive these altered skin cells as foreign and trigger an autoimmune response against them. UV light is categorized as UVB or UVA depending on the length of the wave.

• UVB are short waves (280 to 320 nm). The shorter the wavelengths, the more damage they do.
• UVA are longer waves (320 to 400 nm). Of interest is research suggesting that UVA wavelengths in the longest range, known as UVA1 (340 to 400 nm), may actually repair DNA and normalize immune responses.

Chemicals. Clusters of SLE cases have occurred in certain populations with high exposure to certain chemicals. For example, in a 2001 study, citizens in a small town in Arizona had two to seven times the prevalence of SLE, which was associated with a high exposure to chlorinated pesticides. Crystalline silica is another suspect. A number of other chemicals are under investigation. However, it is very difficult to determine a causal role for any specific agents. (Silicone breast implants have been under intense scrutiny as a possible trigger of autoimmune diseases, including SLE. The weight of evidence to date, however, finds no support for this concern.) It is very interesting that some drugs have been associated with a temporary lupus syndrome (drug-induced lupus), which resolves when these drugs are withdrawn. This has led to some insights about some of the ways in which the regulation of changes in DNA structure inside cells might influence autoimmunity. This regulation of DNA structure might be important when immune cells unravel and rewrap the DNA while making important immune-regulating proteins, or while dividing in order to multiply.

Hormones. Cytokines, major immune factors that are active in SLE, are directly affected by sex hormones. In general, estrogen enhances antibody production and testosterone reduces antibody production, although their exact role in SLE may be more complicated than that, since there are various ways in which each hormone might influence various immune cells. Women with SLE may have lower levels of several active male hormones (androgens), and some men who are affected by SLE may also have abnormal androgen levels.