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Fetal microchimerism in Sjögren's syndrome
  1. Vall D'Hebron General Hospital
  2. Internal Medicine Department
  3. Barcelona, Spain
  4. Autoimmune Research Unit
  5. Universitat Autonoma de Barcelona
  6. P1 Vall D'Hebron 119-139
  7. Barcelona 08035, Spain
  1. aselva{at}
  1. M KUWANA,
  2. Y OGAWA
  1. I TODA
  1. Institute for Advanced Medical Research
  2. Keio University School of Medicine
  3. Japan
  4. Department of Ophthalmology
  5. Tokyo Dental College, Japan
  1. kuwanam{at}

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Toda and colleagues report that microchimerism of fetal cells is uncommon in women with Sjögren's syndrome (SS).1 They performed a nested polymerase chain reaction (PCR) that amplified a Y chromosome-specific sequence to detect male cells in peripheral blood of women who had male offspring to prove the hypothesis that microchimerism can induce Sjögren's syndrome as a manifestation of a chronic graft-versus-host like reaction.

We have also analysed for the presence of the Y chromosome in DNA extracted from peripheral blood nucleated cells of 20 Spanish women with SS (mean age 54.6 years (range 31–77)). These women had male children and were selected from our series of 92 female patients2 who fulfilled four or more of the diagnostic criteria for SS proposed in 1993 by the European Community Study Group. All 20 female patients analysed for the presence of fetal microchimerism were also classified as having definite SS according to the San Diego criteria. A PCR was performed that could detect one male cell in a background of 5×105 female cells. The amount of genomic DNA used in the PCR reaction was 3 μg, and more than five samples were tested for each woman. Eighteen healthy Spanish women (mean age 48.7 years (range 32–65)) who had male children comprised the control group. Using this method, we found no Y chromosome-specific DNA in either patients or controls.

Clinical manifestations of Sjögren's syndrome, as those of other autoimmune diseases such as systemic sclerosis, polymyositis, or primary biliary cirrhosis, are similar to those of chronic graft versus host disease. Microchimerism of fetal cells has been investigated in patients with systemic sclerosis by both quantitative and non-quantitative methods, the results being controversial.3-5 It has also been investigated in primary biliary cirrhosis and inflammatory myopathies by non-quantitative methods, yielding negative or non-conclusive results.6 ,7 Our results are similar to those reported by Toda and colleagues1; nevertheless, this does not exclude the possibility that microchimerism may play a part in the pathogenesis of Sjögren's syndrome. To support this hypothesis, quantitative methods should be used and other sources of microchimerism should be searched for, as has been done already in systemic sclerosis and juvenile dermatomyositis.8-10


Authors' reply

We read with interest this letter by Mijares-Boeckh-Behrenset al commenting on our previous paper.1-1 They failed to detect fetal DNA in peripheral blood nucleated cells from women with Sjögren's syndrome (SS) who had male children. This finding is principally concordant with our study.1-1 Nelson raised the fascinating possibility that some autoimmune diseases, including scleroderma, SS, and primary biliary cirrhosis, are fetal anti-maternal chronic graft versus host disease (GVHD),1-2 though this theory is still controversial.1-3

Based on the study by Mijares-Boeckh-Behrens et al and our study, the ratio of non-host to host cells in circulation is less than one to 105 cells in women with SS who were previously pregnant. In contrast, blood cells in patients with chronic GVHD who received haemopoietic stem cell transplantation are totally replaced by donor derived cells. Because of the exceedingly low ratio of non-host to host cells in women with SS, in contrast with chronic GVHD, it is believed that the pathogenic process in SS is not similar to that in chronic GVHD. In this regard, donor cell microchimerism is often seen in patients who received solid organ transplantation, but these patients rarely develop chronic GVHD.1-4 The ratio of non-host to host cells in patients receiving liver transplants is shown to be more than one to 104 peripheral blood nucleated cells1-5—that is, at least 10 times more frequent than the ratio in women with SS who have sons.

Our recent electron microscopic analysis of lachrymal gland biopsy specimens from patients with SS and those with chronic GVHD after haemopoietic stem cell transplantation clearly indicated a substantial difference in pathogenic processes between these two disease conditions.1-6 T cells were mainly detected in the periductal area, and some T cells had infiltrated into the ductal epithelia through disrupted basal laminae in patients with chronic GVHD. In patients with SS, the T cells were diffusely found in both acinar and periductal areas, but scarcely detected in the ductal epithelia. T cells which had infiltrated into the ductal epithelia in chronic GVHD were activated CD8+ cytotoxic T cells, indicating that T cell invasion leads to the destruction of the ductal epithelium (Ogawa Y, Kuwana M, manuscript in preparation). Based on this finding, chronic GVHD in the lachrymal gland can be simply explained by an allo-immune response to the ductal epithelium by donor-derived T cells. On the other hand, a recently proposed pathogenic process in SS described an inappropriate apoptosis in lachrymal epithelial cells as the initial phase, followed by lymphocyte infiltration and autoimmune aggregation, resulting in further glandular destruction.1-7

However, the results of Mijares-Boeckh-Behrens and those of our study1-1 do not exclude the possibility that microchimerism has a role in the pathogenesis of SS. The presence of a small population of non-host cells would not evoke a putative GVHD mechanism itself, but would result in induction and/or promotion of autoimmunity. For example, non-host cells could differentiate into immune regulatory cells, thereby disregulating the immune system under certain exogenous conditions, such as concurrent infection. Because persistent fetal microchimerism is common in normal women, further work should aim at functional studies of immune cells originating from fetal cells in patients with SS and from healthy women who were previously pregnant.


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