Leftover Fetal Cells May Affect Development Of Scleroderma

February 19, 1998

A National Institute of Allergy and Infectious Diseases (NIAID) grantee in Seattle has found experimental data to support a new hypothesis about the genesis of scleroderma, an autoimmune disorder that primarily affects middle-aged women.

J. Lee Nelson, M.D., and her colleagues report in the Feb. 21 issue of The Lancet, that women with scleroderma have significantly higher levels of non-self fetal cells circulating in their blood decades after pregnancy than healthy women who have previously given birth.

Dr. Nelson says the persistence of these cells may indirectly dysregulate the mother's immune system interactions, somewhat like a computer virus disrupting the workings of a computer.

"Traditionally, the autoimmune diseases are described as your cells attacking your own normal, healthy tissue," Dr. Nelson, associate member of the Fred Hutchinson Cancer Research Center and associate professor of rheumatology at the University of Washington, explains. "Our findings," she continues, "raise the question as to whether some autoimmune diseases are not entirely autoimmune, whether they actually have a component that is non-self. It's really an entirely new paradigm." Dr. Nelson says the mix of self and non-self cells, a phenomenon known as chimerism, is somewhat analagous to what happens in a person who receives a non-identical bone marrow transplant and develops graft-versus-host disease (GVHD).

"These findings are intriguing," says Elaine Collier, M.D., chief of NIAID's autoimmunity section, "because they offer another potential explanation, in addition to sex hormones, for the higher incidence of autoimmune diseases in women. While these data are not definitive, they are provocative because of their implications."

Scleroderma, or systemic sclerosis, affects people of all races, with an estimated incidence of 14.1 cases per million population worldwide. Its cause remains unknown. The disease is at least three times more common in women than in men. The peak incidence occurs between ages 35 and 54. The course of the disease varies greatly, with localized or systemic symptoms. The localized form of the disease primarily affects the skin of the face and hands, causing it to become shiny, tight and thick like leather. In contrast, the systemic form, which can lead to premature death, attacks the skin as well as internal organs, including the kidneys, lungs and heart, gastrointestinal tract and joints. Currently there is no way to prevent or cure scleroderma, but treatment can relieve some symptoms.

***Study Details***

The study was conducted in two parts. Part one enrolled 40 women, average age mid-40s, who had previously given birth to at least one son. This group included 17 scleroderma patients with onset of disease around age 40, seven healthy sisters of these patients and 16 healthy unrelated women who served as controls.

In collaboration with co-author Diana W. Bianchi, M.D., Dr. Nelson's team used a sensitive assay known as polymerase chain reaction (PCR) to look for a specific snippet of the male chromosome in blood samples taken from these women. Women who had had sons rather than daughters were chosen for study simply for technical reasons, because within the milieu of the mother's cells, it is easier to detect evidence of the Y chromosome than to distinguish a daughter's DNA. The researchers tested the samples blinded, meaning they had no information by which they could identify the volunteers with the samples.

PCR revealed that women with scleroderma had an average of 11.1 male cells (range from 1 to 61) per 1 tablespoon of blood compared with an average of 1.3 male cells (range 0 to 5) among their sisters and 0.38 (range 0 to 2) in the control group. Use of immunosupressant drugs by some of the patients did not affect the number of cells measured.

The average length of time since birth of the youngest son was 18.5 years in the scleroderma patients compared with 15.4 years in the control group. Notably, some scleroderma patients had levels of male DNA greater than the average level found in most women when pregnant with a son. Even so, fetal cells constituted less than 1 percent of the mother's total white blood cells in all cases.

The fact that the cells came from a son is irrelevant, says Dr. Nelson. "The important point is that non-self fetal cells occur more often and in greater numbers in scleroderma patients than in healthy women."

However, the development of scleroderma in men and in women without children may also be explained by the new hypothesis. Cells can traffic in both directions during pregnancy, so non-self maternal cells could also engraft and persist in a child.

To explore further whether microchimerism, this intermixing of very low levels of non-self cells with one's own, might be involved in scleroderma, they did a second substudy. Here they investigated whether a women who has given birth to a child with "compatible" immune cell markers known as human leukocyte antigens (HLA) class II has a greater risk of developing scleroderma.

Every individual has a specific pair of these markers on each of his or her immune cells, one marker inherited from the mother and one from the father. These markers act like ID tags to identify these cells as self. If the markers on a child's cells are compatible with the mother's, that is, they differ only slightly, the child's cells may not be recognized by the mother's immune system as foreign and would not be destroyed. For example, if the mother's immune cells carry markers A and B, and the child inherits an A gene from the mother and an A gene from the father, that child's cells can escape detection by the mother's immune system, even though they are mismatched.

This substudy enrolled 21 women with scleroderma and all 47 of their children, and 32 healthy women and all 58 of their children. The researchers were particularly interested in genes that encode the class II markers DR and DQ, since they are associated with susceptibility to scleroderma and other autoimmune diseases. The analysis showed that women with scleroderma had previously given birth to at least one child who was HLA class II-compatible significantly more often than healthy women. The strongest association was found for the gene that encodes for DR, where 62 percent of patients had at least one child compatible in this gene compared with 16 percent of healthy controls. Presumably, HLA compatibility is a risk factor for autoimmune disease because the mother's immune system has difficulty recognizing the fetal cells as foreign and killing them. Yet, because the cells are different, their presence may increase the mother's susceptibility to autoimmune disease.

Although Dr. Nelson has been studying pregnancy and autoimmune diseases for 10 years, colleagues at Fred Hutchinson helped the new theory gel in her mind. They frequently perform bone marrow transplants, and much discussion revolves around GVHD, which, by definition, she says, is chimerism. Moreover, clinically GVHD looks like scleroderma. Then two years ago, Dr. Bianchi reported that fetal cells can persist in the mother's circulation up to 27 years after pregnancy. "When the finding came out about fetal cells persisting, it all fell in place for me," Dr. Nelson says.

"It will take time before we know how much this approach helps us understand what causes scleroderma," Dr. Nelson adds. "But this paradigm certainly is potentially applicable to some other autoimmune diseases as well."

NIAID, part of the National Institutes of Health (NIH), supports biomedical research to prevent, diagnose and treat illnesses such as AIDS, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
1. Nelson JL, Furst DE, Maloney S, Gooley T, Evans P, Smith A, Bean MA, Ober C, Bianchi DW. Microchimerism and HLA-compatible relationships of pregnancy in scleroderma. The Lancet 1998;351:559-62.

2. Welsh K. Scleroderma: chimerism, the blind man and the scientist. The Lancet 1998;351:540-1.

3. Nelson JL. Maternal-fetal immunology and autoimmune disease. Arthritis & Rheumatism 1996;39:191-4.

4. Bianchi DW, Zickwolf GK, Weil GJ, Sylvester S, and DeMaria MA. Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proceedings of the National Academy of Sciences 1996;93:705-8.

Press releases, fact sheets and other NIAID-related materials are available via the NIAID home page at http://www.niaid.nih.gov.

NIH/National Institute of Allergy and Infectious Diseases

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.