Fetal cells may trigger mother's systemic sclerosis

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Fetal cells may trigger mother's systemic sclerosis

Rheumawire

Aug 11, 2004

Janis

Philadelphia, PA - The presence of male fetal " microchimeric " cells in

the skin of women with systemic sclerosis (SSc) who have borne sons

supports the hypothesis that an influx of such cells may be an early

step in the pathway leading to this autoimmune disease, Dr HHB Sawaya

( Jefferson University, Philadelphia, PA) and colleagues report in

the August 2004 issue of Rheumatology [1].

" The identification of microchimeric cells in the peripheral blood of a

large number of normal women who do not develop SSc suggests that the

immunopathogenesis in many SSc cases may require a second event capable

of inducing differentiation and activation of microchimeric cells from a

pregnancy remote in time, which in turn initiates a graft-vs-host

reaction, " senior author Dr Carol M Artlett tells rheumawire. " The

second event required for breakdown of tolerance would most likely be of

environmental origin such as chemical (eg, organic solvents, aniline

derivatives), physical (eg, radiation, silica dust exposure) or

infections (eg, viruses). This sequence of events would be compatible

with the well-known observations that there is little contribution of a

genetic component in SSc. "

Artlett says that her group's most significant finding was that there

are high numbers of microchimeric fetal cells even in the unaffected

skin of SSc patients before there is any clinical evidence of sclerotic

changes. The researchers discovered this by analyzing skin biopsies from

5 female SSc patients with diffuse cutaneous SSc and 10 healthy women.

All the women were the mothers of sons.

Fluorescence in situ hybridization (FISH) and real-time polymerase chain

reaction (PCR) were done on paired skin punch biopsies from the affected

and unaffected skin areas in the SSc patients and from the healthy

subjects. None of the women were taking immunosuppressive therapy or

penicillamine at the time of biopsy, and all of the SSc patients had

disease onset after the birth of a male child.

" The persistence of fetal microchimeric cells in the maternal

circulation could induce a graft-vs-host-disease (GVHD)-like disease

that manifests as SSc. If fetal cells participate in the pathogenesis of

SSc, it would be expected that they are present in affected organs and

tissues. As the skin is the major and, in most cases, the first

clinically involved organ, it was speculated that male fetal cells

should be present in the skin, " the investigators write.

Specimens were stained with DNA probes specific for the alpha satellite

region of the X and Y chromosomes. The X-chromosome probe was labeled

with SpectrumRed (Vysis, Downers Grove, IL), and the Y-chromosome probe

was labeled with SpectrumGreen, making it possible to detect cells with

X (red) and Y (green) chromosomes. DNA was extracted from skin and

quantified, as were the number of Y chromosomes in skin samples.

Artlett found that in the SSc patients there were similar numbers of

microchimeric cells in the affected and unaffected skin biopsies. FISH

confirmed the presence of male cells in 4 of the 5 SSc patients but in

none of the samples from healthy subjects. Analysis with PCR, which is a

more sensitive technique, identified male DNA in microchimeric cells in

all of the samples from the SSc patients but in none of the samples from

healthy subjects. One of the positive samples was in a woman

approximately 50 years after the birth of her son, suggesting that

microchimeric cells, once established, remain for the life of the

individual.

" The present study . . . shows for the first time that microchimeric

cells were also present in uninvolved skin biopsies of women with SSc, "

the authors write.

Previous work had identified increased numbers of CD4+ T cells in skin

and affected organs during the early stages of SSc. A comparison of

T-cell clones from peripheral blood and skin biopsies from women with

SSc vs healthy controls showed increased number of T-cell clones from

SSc patients, and these T cells proliferated in response to autologous T

cells, but the T-cell clones from healthy women did not. The clones from

SSc women also produced higher levels of interleukin-4 (IL-4), which is

profibrotic.

" This observation suggests that male fetal cells are present in the

circulation and/or skin of women with SSc, are reactive against maternal

major histocompatibility complex antigens, and display a Th2-oriented

profile, " the investigators note.

The microchimeric cells may be necessary for triggering SSc but

obviously are not sufficient, since the presence of such cells is quite

common in women who have been pregnant. Artlett suggests that a second

event is required to activate the cells and inspire them to move to

areas that will become lesions. She also suspects that men or

nulliparous women with SSc might retain microchimeric cells of maternal

origin.

" SSc has many clinical features similar to those of patients who develop

the chronic form of GVHD, which typically presents with severe

sclerodermatous skin changes. The skin is the major target organ in both

GVHD and SSc, and both diseases can present clinically with skin

sclerosis, joint contractures, and lung and esophageal involvement.

Similarities in cytokine abnormalities, fibrosis in the dermis and

subcutis, and increased fibroblast collagen production are also common

features of both diseases. The activation of the immune system appears

to be an early event in SSc and GVHD, and T cells, which appear to be

central to the development of tissue damage, dominate the inflammatory

infiltrates present in affected tissues from patients with both

diseases, " Artlett tells rheumawire.

However, Artlett emphasizes that the presence of fetal cells in the

active lesions and peripheral blood of patients with SSc does not

conclusively prove that they are an immunopathogenic mechanism in the

development of SSc. " Although the microchimeric cells were there early

in the disease course, so were other autologous inflammatory cells. We

really do not know which group was there first or whether they arrived

at the same time due to other disease processes (such as a viral

infection), " she says.

Source

Sawaya HHB, Jimenez SA, Artlett CM. Quantification of

fetal microchimeric cells in clinically affected and unaffected skin of

patients with systemic sclerosis. Rheumatology 2004; 43:965-968.

I'll tell you where to go!

Mayo Clinic in Rochester

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s Hopkins Medicine

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