Date: Fri, 16 Jun 2000 13:53:59 +1200

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From: USSW

Date: Monday, 8 June 1998 23:21 

Subject: Fetal Cells Found In Skin Lesions Of Women With Scleroderma 

WASHINGTON, MD -- April 23, 1998 -- Researchers have found evidence of lingering fetal cells within the skin lesions of women with scleroderma who had been pregnant years before developing the disease. These results bolster support for the theory that scleroderma may be similar to graft-versus-host disease (GVHD) and may be stimulated, in part, by the presence of fetal cells in some women. 

The fact that we found fetal cells at the site of tissue injury supports the hypothesis that, at least in some patients, fetal cells play a role in the pathogenesis of scleroderma, said the study's senior author Sergio Jimenez, M.D., professor of medicine and professor of biochemistry and molecular pharmacology at Jefferson. 

While the significance of the prolonged survival of fetal cells in women with scleroderma is unclear, it opens up opportunities to look for new mechanisms of interaction between fetal cells and maternal cells and their role in tissue injury and immune activation in scleroderma, added National Institute of Arthritis and Musculoskeletal and Skin Diseases director Stephen I. Katz, M.D., Ph.D. 

Scleroderma is an autoimmune disorder that occurs more frequently in women than in men, usually between the ages of 45 and 55. The hallmark of scleroderma is widespread hardening of the skin. The form of scleroderma in this study, called systemic sclerosis, also involves hardening of tissues in the lungs, heart, kidneys, intestinal tract, muscles and joints. Although the cause of the disease is unknown, researchers believe that both environmental and genetic factors may play a role in scleroderma. 

Graft-versus-host disease most often occurs after organ or bone marrow transplant when the immune system of the recipient or host attempts to defend itself against the foreign cells of the transplant. GVHD and scleroderma share certain clinical features, including a similar immune system response and hardening of the skin and internal organs. 

During pregnancy, cells can migrate in both directions between maternal and fetal circulations. As the pregnancy progresses, cell transfer from fetus to mother increases. By the third trimester, between 40 percent and 70 percent of women carry fetal cells in their blood. In some cases, the fetal cells have antigens or markers on their surface that make them compatible with the mother's immune system. As a result, they escape rejection by the mother's body and can travel freely throughout the mother's circulation. Fetal cells have been found within a mother's circulation decades after she has given birth. This intermixing of very low levels of fetal or non-self cells with the mother's own cells is called microchimerism. 

A recent study published in The Lancet showed the presence of fetal cells in the blood of some women with scleroderma. This new study confirms those findings and for the first time shows the fetal cells within the women's active skin lesions as well. The researchers used Y chromosome-containing cells from male offspring as a marker of fetal cell existence. Detection of X chromosome-containing cells from female offspring in maternal circulation is not possible with current technology. 

In the Jefferson case control study, biopsies from skin lesions in 19 women with early stages of scleroderma, in which the sclerodermatous process within the skin was just beginning, were compared with skin biopsies from a previous study of seven women with osteoarthritis and 61 of their healthy relatives. Also, blood samples were drawn from 69 women with scleroderma and compared with samples from 25 controls or women without the disorder. 

Polymerase chain reaction (PCR) analysis detected DNA from Y chromosome in the skin lesions of 11 of 19 (58 percent) women with scleroderma. Nine of the 11 women were known to have carried male foetuses (one had terminated a pregnancy without determination of the gender of the fetus and another's pregnancy history was unknown). None of the skin biopsies of 68 control women (30 percent of whom had male offspring) contained indications of DNA from a Y chromosome. 

To confirm the PCR findings, fluorescence in-situ hybridisation (FISH) was used to test the skin biopsies of a subset of the women -- seven women with scleroderma whose PCR results had shown evidence of Y chromosome within the lesions and 10 women without scleroderma. FISH provides a visual picture of cells containing Y chromosomes within their nuclei. The Y chromosomes appeared red whereas the mother's X chromosomes appeared green. Cells containing Y chromosome were detected by FISH in the lesions of all seven women with scleroderma. No evidence of Y chromosome was seen in the skin biopsies from the 10 control women. 

The blood analysis using PCR showed evidence of Y chromosome in blood samples of 32 of the 69 (46 percent) women with scleroderma, but only one of the 25 (four percent) women without the disease. Subsequently, FISH was used on purified T cells from blood samples of a small number of women (three with scleroderma who had been pregnant with male foetuses, one with scleroderma who had never been pregnant and two normal women). The FISH technique showed evidence of Y chromosome in lymphocytes from blood samples of all three women with scleroderma who had carried male foetuses. No Y chromosomes were found in the two control women or the woman with scleroderma who had never been pregnant. 

This study does not explain the occurrence of scleroderma in women who have not had children or in men. It is possible that in these situations, cells from the mother that were transferred to the fetus during pregnancy could persist into adulthood and trigger scleroderma in the offspring. This hypothesis is untested. 

Although the fate of the cells that travel from the fetal to the Maternal circulation is not known, the researchers speculate that they would mature to immune cells -- either short-lived B cells or longer-lived T cells. Due to the long time these cells remain in the mother's circulation, the cells found in the skin lesions of women with scleroderma are more likely T cells. When located in close proximity to fibroblasts, T cells can stimulate fibroblasts to produce collagen. Overproduction of collagen results in the leathery thickening of the skin and internal organs that can occur in people with scleroderma. 

Fetal cells that are transferred into the mother can become localised into affected tissue by an unknown mechanism and somehow become activated and attack the patient's cells," Jimenez said. The fetal cells alone don't cause the scleroderma. There needs to be a second hit -- most likely a virus or environmental exposure that activates the foreign T cells to expand and aggressively attack the host's tissue. 

Understanding the mechanism involved may help scientists develop new treatments for scleroderma, such as vaccines or other therapies to block the compatibility of the fetal cells with the mother's cells, so the mother's body will recognise the fetal cells as foreign and remove them.