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Microchimerism: An Investigative Frontier in Autoimmunity and Transplantation
Abstract & Commentary
Synopsis: Maternal-to-fetal and fetal-to-maternal microchimerism likely play a role in the development of several autoimmune conditions and may modulate the severity of host-vs-graft disease after transplantation.
Source: Adams KM, Nelson JL. JAMA. 2004;291(9): 1127-1131.
In this article, Adams and Nelson integrate results from several disparate fields to advance the concept that autoimmune conditions resemble host vs graft disease and that the "graft" in many cases may be fetal or maternal cells that lodge in the "host," namely the mother or fetus, respectively. Technically, microchimerism refers to a small population of cells or DNA in one individual that derives from another genetically distinct individual. Cell traffic between mother and fetus during pregnancy is common and has been demonstrated to lead to long-term persistence of fetal cells in the mother (fetal microchimerism) and maternal cells in the progeny (maternal microchimerism). In this context, long-term means decades or forever. Apparently, microchimerism may follow ectopic pregnancy, miscarriage, and abortion as well as term pregnancy. Potentially, during multiple gestation, there may be fetus-to-fetus transmission.
Microchimerism may also result from blood or other transfusions. Autoimmune conditions that have been linked to microchimerism include scleroderma, thyroiditis, primary biliary cirrhosis, Sjögren syndrome, adult and neonatal lupus, and dermatomyositis. To enhance detection of microchimerism, studies initially used women who had delivered sons to demonstrate the persistence of cells with XY chromosomal status lodged in maternal tissues. Using these techniques, fetal cells were found in the skin of women with scleroderma. Not unexpectedly, HLA genes appear to be involved. For instance, prior birth of a child that is identical to the mother at the HLA-DR locus increases the risk of scleroderma by 7-fold. The extent (dose) of microchimerism may also gate the likelihood of developing an autoimmune condition or modulate its severity. Immune responses could be amplified by indirect antigen presentation from "graft cells" or by T-cells released from the "graft" into the host circulation. Microchimerism of maternal cells in the fetus may have different effects than vice versa, because the maternal cells are present while the fetal immune system is still developing. This is a new field, so long-term prospective data are not available. Adams and Nelson conclude that fetal and maternal microchimerism can have adverse, neutral, or beneficial effects on the host, depending on many factors, including HLA subtypes and fetal-maternal HLA concordance.
Comment by Sarah L. Berga
This article is particularly germane to physicians who care for women as it may help to explain sex-based differences in disease presentation or incidence. It has long been recognized that there is a female preponderance in autoimmune conditions. Microchimerism provides a putative reason for why women, especially those who have had several pregnancies, might have a higher incidence of immune dysregulation than men. It is not yet clear whether reproductive events lead to a greater risk of maternal or fetal microchimerism, but advances in molecular detection will likely permit the conduct of more detailed and longitudinal studies. Being able to rapidly and accurately detect microchimerism raises the hope that we can then implement therapies to control its negative consequences. For instance, knowledge about the effect of hormone perturbations, such as those that accompany puberty or perimenopause, upon microchimeric rests may explain the timing of the presentation of conditions such as lupus or fibromyalgia. This study raises many questions. Would postmenopausal hormone use exacerbate or ameliorate latent graft vs host reactions? What is the effect of hormonal contraceptives?
Since microchimerism appears to be a common consequence of pregnancy, one wonders if there are ways to minimize the likelihood of this bidirectional transfer. For instance, does fetal surgery, umbilical vein sampling, version, or even amniocentesis increase the likelihood of microchimerism? Is the likelihood greater after cesarean section as opposed to vaginal delivery? As we improve our ability to perform pre-implantation genetic diagnosis, might we want to select against replacing embryos that are identical to the mother at the HLA-D locus for both maternal and fetal reasons? There is clearly much to learn, but until a few years ago, we never knew that we could or should address these questions.
As our techniques improve, we might be able to define the fetal and maternal consequences of pregnancy in women with established maternal microchimerism (ie, when the mother harbors cells from her mother dating to her fetal life) or in women who becomes engrafted during a preceding pregnancy. If immune activation or tolerance plays a role in recurrent miscarriage, would this risk increase or decrease with increasing microchimeric burden or activity? Further, one would expect that we might be able to determine if endometriosis is more or less common in women with microchimerism or if the HLA-D locus of the engrafted cells plays a role in who does and does not get endometriosis.
The main focus of this article was on the consequences of microchimerism for elucidating why rejection does or does not occur in individuals with relatively appropriately matched transplants. Given the likelihood that there will be increasing use of transplantation, it will clearly be important to know what gates rejection. In the article, the notion is advanced that immune tolerance may be enhanced by promoting microchimerism via repeated blood transfusions. This is reminiscent of the use of paternal cells to induce immune tolerance in women with recurrent miscarriage. Perhaps more rational approaches can be devised if we can accurately determine who is a candidate for immune modulation. In short, this is a noteworthy article because it brings to our attention an area of immunology likely to play an increasing role in understanding and treating women’s health conditions.
Sarah L. Berga, MD, James Robert McCord Professor and Chair Department of Gynecology and Obstetrics, Emory University School of Medicine, is an Associate Editor for OB/GYN Clinical Alert.