When it comes to autoimmunity, the sexes respond in their own ways
The Scientist 16:26, Feb. 18, 2002
By Karen Young Kreeger
In the 1970s, medical textbooks noted that lupus patients should not get pregnant because it could kill them, recalls physician Michael Lockshin. "I was challenged by a medical student, who had lupus, to show the data to prove that. But it didn't exist and it was all, forgive the implied pun, an old wives' tale that was just being passed on," says Lockshin, now director of the Barbara Volcker Center for Women and Rheumatic Disease, Hospital for Special Surgery, New York City. The third-year medical student, who was two months' pregnant, ignored the textbooks, and Lockshin for that matter, and went on to have a large family. (Lupus is still considered high-risk for pregnancy, but it is possible, with medical help, if the lupus is under control and the woman's kidneys are healthy.)
The encounter led him to a new research path. "What it amounted to was a career that I hadn't considered," says Lockshin, who is also a professor of medicine at the Weill College of Medicine of Cornell University, New York, and a member of the Institute of Medicine's study panel on sex differences.1
Today, though scientists understand autoimmune diseases such as systemic lupus erythematosus (LSE) better than they did 30 years ago, this group of ailments is still mystery-laden, especially regarding mechanism and cause. In autoimmunity, immune-response cells direct themselves against self-antigens instead of foreign microbes. Most common autoimmune diseases (e.g., rheumatoid arthritis) occur more frequently in women than men. But a few are not predominant in either sex, and others are more prevalent in men. Some, like LSE, are more severe in men than women, although not more widespread. What's more, there is a mix of genetic, environmental, and hormonal causes for the different autoimmune diseases. "The only circumstance where there appears to be a suggestion of a difference between men and women is in vaccines," notes Lockshin. "Women make higher antibody titers than men for the most part. And those vaccinations that [cause] arthritis, tend to [do so] more in women than men."
The Same, but Different
Noel Rose, director of the Johns Hopkins Center for Autoimmune Disease Research, studies how genetics and the environment interact to find a mechanism for thyroiditis and myocarditis, two autoimmune diseases that affect men and women in different ways. Thyroiditis occurs 7 to 8 times more in women, whereas myocarditis occurs evenly but might be more severe in men.
Rose's two animal models are related to genetic predisposition and the environmental factors that initiate the ailments. Myocarditis, or heart muscle inflammation, is triggered by a coxsackie viral infection in the heart. In humans, about half of myocarditis cases in North America are related to the common coxsackie virus, which causes a flu-like disease. People who are genetically predisposed will develop an autoimmune myocarditis after contracting the virus. In Rose's myocarditis mouse model, different cytokine amounts are produced in males and females.2 "This may explain why more men go on to develop autoimmune myocarditis," he says. Some cytokines, such as interleukin (IL)-12, promote autoimmune myocarditis development, whereas others, such as interferon (IFN)-g, retard it.
Estrogen and Disease
When Lockshin was a National Institutes of Health researcher in the late 1980s, reporters often asked him why lupus is a woman's disease. His pat answer, "it's hormones," was based on estrogen-level work conducted in the prior decade. "But that turned out to be a less and less satisfying answer," he says. "The biggest component was that whenever we talked about how hormones modulate immunity, it had to do with quantitative aspects of immunity; the more hormones, the worse the symptoms would be."
But the way in which SLE expresses itself in humans, as opposed to animal models, is that the disorder shows a higher prevalence in women over men, but not a greater severity. One theory is that there is an estrogen-threshold mechanism. "It's an off-on switch, not X amount of estrogen, [and therefore] X amount of disease," says Lockshin.
Betty Diamond, a professor of medicine, microbiology, and immunology at Albert Einstein College of Medicine, New York, is not sure her work speaks directly to lupus prevalence in women, but, she says, it offers a mechanism regarding its relationship to estrogen. Diamond gave a non-autoimmune lupus mouse model low estrogen levels, but higher than the normal amounts circulating in normal mice. In mouse models, she says, SLE worsens when estrogen levels are increased, and improves when ovaries are removed. Her team showed that this mouse made anti-DNA antibodies, or antibodies against itself. They concluded that a small amount of estrogen could essentially change a non-autoimmune mouse into an autoimmune mouse. "Essentially the mouse got lupus," says Diamond. The mechanism they proposed is that the bone-marrow-derived B-cells that normally get deleted in the non-autoimmune mouse, when given estrogen, were activated and not deleted.3
Ward Wakeland, University of Texas Southwestern Medical Center, surmises that in mice, advancing to lupus development requires a mechanism involving up to three genes. Diamond found that this happened in one strain of mice but not another, showing that lupus susceptibility is genetically determined. In some women, SLE may be hormonally turned on, and in others it may not. Estrogen also stimulates the gene for corticotropin-releasing hormone (CRH), the brain protein that promotes secretion of the stress hormone cortisol. George Chrousos, chief of the Pediatric and Reproductive Endocrinology Branch at the National Institute of Child Health and Human Development, studies sex-based differences in the brain's stress system and how they may relate to the higher prevalence of autoimmune diseases in women.
Inflammatory diseases in women are influenced by a combination of estrogen-dependent factors that regulate the type of an immune response; these include CRH, cortisol and the catecholamines. "During pregnancy, when cortisol is high, women are prone to develop humoral-immunity types of autoimmune diseases like systemic lupus erythematosus, while in the postpartum and menopause phases, when cortisol is low, they develop innate- and cellular-immunity types of diseases, such as rheumatoid arthritis and multiple sclerosis," explains Chrousos. "Although overall, women have a slightly higher cortisol secretion than men. The estrogen-caused fluctuations of this hormone and the increased secretion of peripheral CRH explain the higher prevalence of certain autoimmune disorders in women than in men."4
The influence of sex on disease penetrance may help explain some aspects of autoimmune diseases, according to Denise Faustman, associate professor of medicine, Harvard Medical School. Penetrance is the proportion of those with a specific genotype who express it in the phenotype. The odds of an identical twin contracting rheumatoid arthritis, for example, whose sibling already has it, ranges from 5% to 30%. In some autoimmune diseases, Faustman argues, environmental influences can modify disease onset, but that "it's more likely how the genes are expressed and in what order and sequence and in what cells" that determines disease penetrance.
Faustman says she thinks that imprinting, in which gene expression depends on the sex of the transmitting parent, will help to explain differential penetrances among identical twins.5 "If you have a gene that causes disease on one chromosome and you inactivate it, you're OK," she speculates. "The other twin randomly inactivates the other chromosome, but it makes the disease-causing protein, so that twin gets the disease. Whether you get the disease depends on if you get the imprinted gene from mom or dad." Faustman has also found that men and women may make proteins differently.6 The current thinking is that the proteasome, located in the cytoplasm, cuts and cleaves the proteins, and thereby activates them. Faustman says the proteasome is the "garbage disposal-Cuisinart of the cell."
Faustman's group is now looking at some of those processes as they relate to autoimmunity. "We know that how proteins are processed by male proteasomes are different than how proteins are processed by female proteasomes, a gender specific proteasome, as it were," she explains.
Rheumatologist J. Lee Nelson, Fred Hutchison Cancer Research Center, Seattle, and a professor of medicine, University of Washington, became interested in autoimmunity and pregnancy because rheumatoid arthritis goes into remission during pregnancy, and then recurs after delivery. She has since expanded to scleroderma, an autoimmune disease of the skin and internal organs that affects mostly women, and peaks in postreproductive years. Several lines of evidence helped Nelson and colleagues hypothesize that microchimerism (a small number of non-host cells in a sea of host cells) in part may cause scleroderma and perhaps other autoimmune diseases: Fetal cells can persist in minute amounts (as small as one fetal cell per one million maternal cells) in the mother's blood for decades after birth. Scleroderma and graft-versus-host disease also share many of the same symptoms, thickening of the skin and some internal organs, for example. And, HLA (human leukocyte antigen) genes, central to distinguishing self from what is foreign, are important in both graft-versus-host disease and scleroderma.
Nelson's team found that the amount of fetal cells is higher in women with scleroderma than those without it; moreover, a child's HLA compatibility to his or her mother increased the woman's risk of subsequent scleroderma.7 She surmises that the mechanism for microchimeric autoimmunity may be a biochemical miscommunication between a mother's and child's cells when the two are genetically similar, but not identical.
The scientific jury is still out about the hypothesis, but Nelson says that the persistence of fetal cells in the mother's body over decades, although at first surprising, has proven to be rather common. She's now working on the role of HLA genes in modulating the beneficial, neutral, or detrimental effect of microchimeric cells.
Karen Young Kreeger is a contributing editor.
1. Institute of Medicine, Exploring the Biological Contributions to Human Health: Does Sex Matter? T.M. Wizemann, M. Pardue, eds., Washington DC: National academy Press, 2001.
2. S.A. Huber and B. Pfaeffle, "Differential Th1 and Th2 cell responses in male and female BALB/c mice infected with Coxsackievirus Group B Type 3," Journal of Virology, 68:5126-32, 1994.
3. M.S. Bynoe et al., "Estrogen up-regulates Bcl-2 and blocks tolerance induction of naïve B cells," Proceedings of the National Academy of Sciences, 97:2703-8, 2000.
4. I. Elenkov et al., "Interleukin 12, Tumor Necrosis Factor-* and Hormonal Changes during Late Pregnancy and Early Postpartum: Implications for Autoimmune Disease Activity during These Times," Journal of Clinical Endocrinology and Metabolism, 86:4933-8, 2001.
5. K.Y. Kreeger, "X and Y chromosomes concern more than reproduction," The Scientist, 16:25-6, February 4, 2002.
6. T. Hayashi and D.L. Faustman, "NOD mice are defective in proteasome production and activation of NFkB," Molecular and Cellular Biology, 19: 8646-59, 1999.
7. J.L. Nelson et al., "Microchimerism and HLA-compatible relationships
of pregnancy in scleroderma," Lancet, 351:559-62, 1998.
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