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
"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.
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
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
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
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."
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AIDS, tuberculosis, malaria, asthma and allergies. NIH is an agency
of the U.S. Department of Health and Human Services.
Press releases, fact sheets and other NIAID-related materials are
available via the NIAID home page at http://www.niaid.nih.gov.