The placenta was previously thought to barricade the mother and fetus thus preventing maternal rejection of the fetus. It is now known that during pregnancy some cells traffic from mother to fetus and from fetus to mother. Surprisingly, some mother’s cells can be found in her adult offspring and some cells from the fetus can be found in the mother decades later. Microchimerism (Mc) refers to harboring a small number of cells or DNA from a genetically different individual. Our research efforts are directed to elucidating the range of consequences of Mc for human health and disease.
We believe that naturally acquired Mc from pregnancy is likely to provide benefits but also probably sometimes has adverse effects. In 1996 our group proposed that these retained cells from pregnancy be investigated in autoimmune diseases. We are currently studying both beneficial and detrimental effects of Mc for a number of different diseases including autoimmune diseases, degenerative diseases and cancer. The autoimmune diseases we study are rheumatoid arthritis, scleroderma, type 1 diabetes and primary biliary cirrhosis. Anne Stevens, MD, PhD, who previously worked with us and now has her own research team, is investigating Mc in systemic lupus erythematosus. Autoimmune diseases are thought of as disorders in which a body's cells inexplicably attack its own normal tissues.
The new Mc model was conceived by combining observations from different medical subspecialties. One observation came from transplantation, which also results in chimerism. In hematopoietic cell (or bone marrow) transplantation the recipient can develop an illness that looks like autoimmune disease. A second observation was the long-term persistence of maternal and fetal Mc. A third observation was the greater predilection of autoimmune diseases for women (only women with pregnancies acquire fetal Mc). A fourth observation also derives from transplantation and has to do with a group of molecules called human leukocyte antigens (HLA) that are key determinants of transplantation success.
HLA molecules are encoded by genes on the human sixth chromosome. They are critical determinants of the distinction between what is self and what is foreign and are centrally important to a wide variety of immune responses. Donor-recipient matching is the key determinant of graft acceptance in transplantation. Interestingly, particular HLA genes (HLA class II) are associated with autoimmune diseases. Therefore the first question we asked when we began to investigate Mc is whether certain mother-child HLA-relationships predispose a woman to autoimmune disease. Although it might initially seem counter intuitive, our theory was that excessive HLA similarity of fetal Mc might lead to risk of subsequent disease in the mother. The reasoning was that widely HLA disparate cells could easily be identified by the mother, but markedly similar Mc (that was not entirely identical) would be more difficult to distinguish and could disrupt the balance that is characteristic of a normal healthy immune system.
Our initial work investigated Mc in scleroderma, a disease with a peak incidence in women in post reproductive years. Consistent with our hypothesis, children born to women who later developed scleroderma had excessive HLA-sharing with their mothers compared to healthy controls and the increased sharing was found for the same HLA gene region that is associated with susceptibility to scleroderma. We next tested for levels of fetal Mc in women and found significantly higher levels in women with scleroderma compared to healthy controls. Other studies showed persistent fetal cells in the skin and tissues of scleroderma patients. We are now investigating the mechanism by which these cells might contribute to scleroderma. If Mc is involved in the causation of autoimmune diseases such as scleroderma, the cells could be selectively targeted for treatment. It is our hope that research in this field will lead to better therapy for diseases such as scleroderma.
We are currently investigating retained cells from pregnancy in other diseases including cancer, degenerative diseases (e.g. Alzheimer’s disease) and also in transplantation. On the beneficial side we recently tested the hypothesis that persisting fetal Mc might in part explain the protective effect of prior pregnancy on breast cancer risk. Consistent with this hypothesis, we found fetal Mc significantly less often in women with breast cancer compared to healthy women.
In other work we asked if Mc could contribute to specific cell types in tissues. Stem cells are known to have this capacity and, because Mc persists for years, the assumption is made that some maternal and fetal stem cells engraft during pregnancy. We studied the heart tissue of children with neonatal lupus who died from heart block. Maternal cells were found in the heart muscle but they were not blood cells from the circulation. Instead they were mostly heart muscle cells. This finding raised the question of whether autoimmune disease might sometimes occur due to loss of tolerance to maternal Mc in tissues. In other studies we examined maternal Mc in children with type 1 diabetes and found higher levels of maternal Mc in blood. Maternal insulin-producing cells were found in the pancreas and while they could have been targets of an immune attack for a number of reasons we favor the explanation that they were contributing to attempts to repair disease-affected tissues.
In transplantation we have investigated whether these naturally acquired cells from pregnancy influence the results of hematopoietic cell (or bone marrow) transplantation. We found that when the donor is a woman the donor product can contain retained fetal cells. Whereas the donor is selected based on genetic matching the retained fetal cells usually have genetic differences. Therefore, it is possible that removing the cells could lessen some complications of transplantation. Thus in addition to better treatment for autoimmune diseases as noted above, advancing this new research frontier could also contribute to improving transplantation success.
See where we and others have found microchimerism.