The Gender Gap in autoimmune disease

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News & Features Fall 1997The Gender Gap in Autoimmune Diseases:Looking for Answers

Women are much more likely than men to suffer from autoimmune diseases, a group of diseases that result from their disease-fighting immune systems misfiring on healthy tissue. Scientists are looking at both the genetics and immunology of autoimmune diseases in an effort to explain why this occurs. Hormones and the Immune System Determining the underlying cause of these diseases — and of the often skewed sex ratio — is not proving easy. One of the first things that scientists looked at for clues to explain the higher incidence in women than men of autoimmune disorders was whether diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) get better, worse, or stay the same during the menstrual cycle, pregnancy, and menopause. Although anecdotal reports vary, RA is the only one of these diseases in which a well-documented pattern appears during pregnancy. Frequently, RA improves while a woman is pregnant, and worsens again after delivery. Estrogen levels soar during pregnancy, but the studies that have been conducted to determine whether supplemental estrogen could ameliorate RA have yielded only negative results. The effects of the menstrual cycle, pregnancy, and menopause in other autoimmune diseases are inconsistent, casting doubt on the notion that fluctuating hormone levels can, alone, explain the female predominance of these disorders. High levels of female hormones like estrogen have traditionally been thought harmful to women with lupus, based in part on the long-time belief by many that pregnancy is deleterious for women with lupus. Limited data from more recent studies have caused researchers to question that notion, and NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has begun the first clinical trial on the safety of estrogens for women with SLE. Researchers will conduct randomized, double-blind studies on the effects of hormone replacement therapy with estrogens and cyclic low-dose progestins in postmenopausal women with SLE and on the effects of oral contraceptives on disease activity in younger women with SLE. Genetics and the Complex Interaction with Immunity Though hormones play a role in the immune response, researchers are exploring other possibilities to explain the female predominance of autoimmune diseases. From the point of view of geneticists, autoimmune diseases are considered "complex" — the result of inheritance of many genes instead of just one, and an as-yet-unexplained interaction between these genes and the environment. These factors make it much more difficult to track inheritance of specific genes involved in an autoimmune disease than in other diseases that result from one gene acting with little or no environmental influence. One lead came out of the observation that during pregnancy a mother's immune system — normally programmed to reject any foreign tissue — tolerates the presence of a fetus, half of whose genetic make-up is from the father. The mechanisms of this "privileged" immune state of the fetus remain a mystery. NIAMS-supported J. Lee at the Fred Hutchinson Cancer Research Center in Seattle, Washington, has used this natural anomaly as a starting point to investigate why RA often remits during pregnancy. In mothers with RA and their children, Dr. and coworkers investigated the genes that contain the molecular blueprint or code for HLA (human leukocyte antigen) proteins. These are the antigens on cell surfaces that enable the immune system to distinguish between the body's own cells and those that are foreign. The presence of certain HLA genes has been found to be associated with susceptibility to some autoimmune diseases, including RA.

"Scientists study why more women are affected than men."

Dr. found that certain HLA gene markers were more frequently dissimilar between mother and child in pregnancies in which the mother's RA improved. Without proposing a single specific mechanism, hypothesizes that the mother's immune response to the fetus may play a role in the improvement in RA during pregnancy. Other studies are looking at the possible role of HLA compatibility between mother and child in scleroderma (a disease marked by thickening and hardening of the body's connective tissues). Recent research supported by the National Institute of Child Health and Human Development found that fetal cells could persist in the bloodstream of the mother for as long as 27 years after birth. The peak incidence of scleroderma in women is between the ages of 35 to 54, just after the childbearing years. Dr. 's group is looking to see whether scleroderma — which shares some features with graft vs. host disease, an immune reaction of a donor's transplanted cells to the tissues of the recipient of a bone marrow transplant — is more frequent in women whose HLA types are more similar to that of their offspring.

Other Approaches Explored Research continues to turn up clues of other mechanisms that might be at work to make women more vulnerable to autoimmune disorders. NIAMS-supported research on an animal model of lupus suggests that multiple genes convey susceptibility and shape exactly how the disease will manifest itself. NIAMS has also started a lupus registry in an effort to identify people with the disease as a resource for searching for genes involved in the origin of lupus. Results from human studies are beginning to shed light on the role of genes in determining susceptibility to SLE.

Autoimmune Diseases

Autoimmune diseases encompass a broad group of disorders, all marked by the immune system attacking normal tissue. The internal targets of autoimmune disease span the body's systems and functions: rheumatoid arthritis (RA) affects the joints and joint linings, chronic active hepatitis and biliary cirrhosis damage liver function, insulin-dependent diabetes impairs sugar metabolism, and multiple sclerosis damages nerves.

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National Institute of Neurological Disorders and Stroke-supported researchers are exploring differences seen under varying experimental conditions in the immune responses of female vs. male rats with an induced illness resembling multiple sclerosis. Scientists are also learning more about imprinting, in which the effects of genes are altered by which parent — male or female — transmitted them to their offspring. There may be other gender-related effects on gene activation that play a role in autoimmunity.

A more complete understanding of why these diseases happen will eventually explain why women's immune systems are more likely to turn on them — and how to prevent and treat the resulting illness. Charlotte Armstrong, writer/editor, Office of the Director, Office of Communications.

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