Autoimmune diseases are a group of more than 80 clinically distinct, chronic disorders predominantly affecting women.1 These diseases — which include systemic lupus erythematosus (SLE), multiple sclerosis (MS), scleroderma/systemic sclerosis (SSc), Sjogren’s syndrome (SS), Type 1 diabetes, and rheumatoid arthritis (RA) — are a leading cause of death and disability among young and middle-aged women in most industrialized countries. In the United States, autoimmune diseases are the fifth and seventh leading causes of death by disease for women aged 15 to 44 and 45 to 65, respectively.2 Overall, the prevalence of autoimmune diseases is about 3% of the population,3 and 75% of those with autoimmune diseases are women, most often in their childbearing years.1
Autoimmune diseases are more prevalent among women and are a leading cause of death and disability among young and middle-aged women.
Autoimmune reactions occur when the immune system inappropriately attacks “self,” causing pathological changes in organs, tissues, and cells.4 Diseases that result from the attack are classified either as organ specific (e.g., Type 1 diabetes and thyroiditis), in which only one organ or tissue is affected, or as systemic or non-organ specific (e.g., systemic lupus erythematosus and rheumatoid arthritis), in which most tissues throughout the body are affected.4 Normally, the immune system can distinguish the body’s own cells (self-antigens) from foreign cells (non-self antigens). It does this through distinctive marker protein molecules called the major histocompatibility complex (MHC) that are unique to each individual.4 These marker proteins are an extended cluster of genes displayed on almost all cell surfaces. The function of MHC is to display the internal contents of each cell in the body to the T-cells in the immune system.4 For example, when a cell is infected with a virus, MHC presents fragments of viral proteins (foreign antigens) on the infected cell surface, so the cell can be destroyed by the cytotoxic T-cells (killer cells) of the immune system.4 This interaction of the T-cells and MHC causes the release of special proteins called cytokines that activate other immune system cells and attract them to the site of infection.4
Causes of autoimmune disease
Still not yet fully understood and often poorly recognized, autoimmune diseases are thought to be the result of a variety of factors.1 It is suspected that ones sex, environmental exposures, and genetic makeup, especially MHC genotypes, play an important role.
Genetic factors. Most autoimmune diseases have a genetic component, and studies provide evidence that genes of the major histocompatibility complex make an important contribution to disease susceptibility.4 Linkage to specific MHC genes can be determined by comparing the frequency of the particular gene in patients with an autoimmune disease to that in the general population. People with SLE are six times more likely to have a specific MHC gene.4 Additional evidence for genetic susceptibility comes from family studies. Studies with twins have shown that if one identical twin develops Type 1 diabetes, rheumatoid arthritis, multiple sclerosis, or SLE, the other has roughly a 20% chance of developing the disease, compared with a less than 5% chance in nonidentical twins.4 Autoimmune disease can also cluster in families.3 For example, one female family member may have systemic lupus erythematosus; her mother, daughter, or siblings may have rheumatoid arthritis or Type 1 diabetes.
Female sex and the immune system. MHC genes are not the only determinants of autoimmunity. Men and women respond differently to infections. Men have a less vigorous immune response with less antibody production and are more susceptible to a variety of infections. Women have a more intense immune response to infections and are more successful in fighting off infections.5 When challenged with a foreign antigen, women develop higher antibody levels and an increased number of CD4+ helper T-cells in peripheral blood. (CD4+ helper T-cells are essential for turning on antibody production and activating cytotoxic T-cells). Thus, women are at greater risk of illnesses caused by an overactive immune response. For example, in SLE, autoimmune thyroid disease (Hashimoto’s thyroiditis and Graves’ disease), scleroderma, and Sjogren’s syndrome, more than 80% of the patient population are women; in rheumatoid arthritis, MS, and myasthenia gravis, 60% to 75% are women.6
Furthermore, in both sexes, adrenal hormones and androgens are low in autoimmune disease patients when compared to healthy controls.7 This suggests a relationship between these altered steroid profiles in the blood and the autoimmune diseases: androgens are anti-inflammatory and protect from autoimmune diseases, whereas estrogens are pro-inflammatory and favor autoimmunity.7,8 Applied to autoimmune diseases, data suggest that there is a lack of active androgens within synovial tissue in inflammation.7 This local androgen deficiency causes local estrogen excess generating a pro-inflammatory environment.7 Androgen supplementation improves clinical outcomes in male and female patients with RA.7
Female hormones. The female predominance in autoimmune diseases suggests that sex hormones may influence susceptibility. Although the role of sex hormones is not clear, many autoimmune diseases show a high incidence in the childbearing years, when female hormones are at their highest levels.4 During pregnancy, when estrogen and progesterone levels increase, symptoms of RA and MS usually improve, while those of SLE worsen or remain the same. Note that all three diseases may flare postpartum. Oral contraceptives seem to be protective with rheumatoid arthritis and MS, but not with SLE. SLE appears to be worsened by estrogen.5,6
*The children of mothers with autoimmune diseases may be affected if the mother has anti-Ro/SS-A and/or anti-La/SS-B antibodies as in SS, SLE, or RA. These antibodies cross the placenta, bind with the cardiac conduction tissue, and can be responsible for a syndrome that includes complete congenital heart block.9 Preterm births are common (40%) in children born to mothers with systemic sclerosis (scleroderma).10 Other effects can be found in children of women with hypothyroidism.9 Preterm births are common (40%) in children born to mothers with systemic sclerosis (scleroderma).10
Other effects can be found in children of women with hypothyroidism. Such effects include impaired neuropsychological development and other adverse outcomes such as premature birth, preeclampsia, breech delivery, and increased fetal mortality.11 Both fetal hypo- and hyperthyroidism may occur, and maternal hypothyroidism is associated with delayed mental and motor development.12 Autoimmune thyroid disease is the most common cause of hypothyroidism in the reproductive years of a woman.13
However, because the incidence of autoimmune disease, with the exception of SLE, peaks during menopause, the male-female differences in sex hormones cannot be the explanation for female predominance in autoimmune disease.14
Microchimerism (the presence of cells from two individuals coexisting in the same body).15 Some people with autoimmune diseases may have a component of non-self that triggers autoimmunity. For example, fetal cells can circulate for decades in the blood of women who have had children.16 (During pregnancy, fetal cells can travel from mother to child and vice versa.) When the maternal MHC (self-marker proteins) is very different from the fetal MHC, the woman ’ s immune system will recognize the fetal cells as foreign and destroy them. However, when the maternal and fetal MHC are similar, fetal cells may escape destruction. Subsequent events such as a viral infection may activate these fetal cells and initiate an autoimmune reaction. This may be a cause of scleroderma, an autoimmune disease similar to the graft-vs.-host disease that occurs in transplant recipients.14,16 The correlation is that women with scleroderma have been found to have significantly higher levels of circulating fetal cells. Although less common, scleroderma does occur in males and in women who have not been pregnant. One possible reason for this may be that maternal cells also cross over to fetuses, where they can survive for decades.16 Maternal cells are detected in up to 40% of umbilical-cord blood samples.14
Environment. It seems evident, even with genetically predisposed individuals, that additional factors — such as infectious agents, environmental toxins, sunlight, diet, and allergens — are needed for autoimmunity to develop.5 For example, the number of cases of MS in a population increases the farther members live from the equator. Furthermore, if a person moves from an equatorial region to a high-risk region before age 15, he or she acquires a high-risk susceptibility to MS; conversely, if a person moves to a low-risk region before 15, the person acquires the risk of the area to which he or she moves. Childhood infections, more common in northern areas, may be an explanation.17
Molecular mimicry. Molecular mimicry is a possible cause for the immune system to attack the myelin proteins of the central nervous system in MS. A number of viruses associated with MS (e.g., Epstein-Barr virus, human herpes virus7 [roseola], human papillomavirus, and influenza virus type A) have microbial proteins that closely resemble parts of the myelin proteins in the central nervous system of the host they infect.18 Consequently, in genetically susceptible people, when the activated immune system mounts a defense against the infecting microbes, it is possible that it could inadvertently attack the myelin sheath within the central nervous system, causing demyelination.17 Another example of molecular mimicry is the cross-reactions of the cell wall protein of the Streptococcus Group A bacteria with the kidney, joint, and heart antigens to produce rheumatic fever.18