Identification of Fetal DNA and Cells in Skin Lesions from Women with Systemic Sclerosis
ABSTRACT & COMMENTARY
Synopsis: Fetal antimaternal graft vs. host reactions may be involved in the pathogenesis of systemic sclerosis in some women.
Source: Artlett CM, et al. N Engl J Med 1998;338: 1186-1191.
Systemic sclerosis is a connective tissue disorder of unknown origin in which auto-antibodies cause endothelial cell damage and proliferation of subendothelial connective tissue. It is eight times as frequent in women as men. Because of the similarity between graft-vs.-host disease and systemic sclerosis plus the female preponderance of systemic sclerosis, also known as scleroderma, Artlett and associates hypothesized that persistence of fetal leukocytes may play a role. This hypothesis was further suggested by the finding that fetal stem cells engrafted in the maternal lymphoid organs and bone marrow during pregnancy help to maintain tolerance to the semiallogenic fetoplacental graft. By the third trimester, fetal cells have been detected in the maternal circulation in up to 70% of women. In this study, Y-chromosome sequence was detected in the circulation of 32 of 69 women with systemic sclerosis and 1 of 25 normal women. Y-chromosome DNA was found in skin biopsies of 11 of 19 women with scleroderma and none of those from 68 women with osteoarthritis or their relatives or from women with eosinophilic myalgia syndrome or eosinophilic fasciitis. Nucleated cells containing Y chromosomes were detected in the skin biopsy specimens of all seven women with systemic scleroderma available for this type of testing. Most of the Y-chromosomes containing nucleated cells were present in inflammatory cell infiltrates in the extracellular matrix of the deep dermis or in the walls of small vessels. These findings were not present in skin biopsy specimens from 10 normal women.
COMMENT BY SARAH L. BERGA, MD
The finding that persistent fetal leukocytes may play a role in the pathogenesis of scleroderma heralds a paradigm shift in how we view autoimmune disorders. As the accompanying editorial "Microchimerism and Autoimmune Disease" points out, this mechanism also may be involved in some other autoimmune or "alloimmune" disorders such as biliary cirrhosis, Sjögren's syndrome, polymyositis, and even systemic lupus erythematosis (SLE) (Nelson JL. N Engl J Med 1998;338:1224-1225). Initial evidence from skin biopsies indicate that this mechanism was not involved in eosinophilic myalgia, fasciitis, or osteoarthritis.
Artlett et al looked for evidence of Y-chromosome DNA in women with scleroderma because of methodologic considerations. A piece of Y-chromosome in a woman must have some extraneous source. This does not mean that having a male rather than female child amplifies the risk of getting an autoimmune disorder. Sources of persistent leukocytes include mother-to-fetus, fetus-to-mother, fetus-to-fetus in multiple gestations, and blood product transfusions. Presumably, one could have multiple sources lodged within one's immune system, although one would suspect that pregnancy confers some selective likelihood of taking up these allograft cells. Oddly enough, fetal hematopoietic stem cells have been detected in the circulation of women up to 27 years post-partum (Bianchi DW, et al. Proc Natl Acad Sci USA 1996;93:705-708). Also, up to 4% of lymphocytes were maternal in origin in male infant studies 1-5 years after birth (Nelson JL, et al. Lancet 1998;351:559-562). Since not all women who get pregnant or give birth develop scleroderma, there must be other determinants or triggers. These might include underlying host immunocompetence and other host vulnerabilities, maternal-fetal histocompatibility, viral vectors, stress, and environmental exposures to certain chemicals. What I found so amazing about this article is that it validates a concept that may help us understand and treat a variety of illnesses and syndromes that, heretofore, seemed inexplicable.
When contemplating the never-ending job of motherhood, I like to joke about the "Teflon umbilical cord" that cannot be severed. Little did I know that the fetus may truly always be there in both a literal as well as an emotional sense. This notion gives new meaning to the biological sacrifice inherent in reproduction.
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