J. Lee Nelson
INTERDISCIPLINARY RESEARCH IN CHIMERISM
Autoimmunity, Reproduction, Cancer, Infectious Disease and Transplantation
Some cells are known to traffic from a mother into the fetus and from the fetus into the mother during pregnancy. Surprisingly, a small number of these cells persist in their respective hosts decades later. This phenomenon is referred to as microchimerism. The shared goal of our interdisciplinary research team is to identify the good and bad consequences of microchimerism for human health and to utilize this knowledge to develop novel strategies for treatment and prevention of human diseases.
In addition to the long-term effects of microchimerism, we are studying immune system effects of maternal-fetal exchange during the course of pregnancy. We are doing this work for a number of reasons. First, the autoimmune diseases rheumatoid arthritis and multiple sclerosis improve during pregnancy. Second, some complications of pregnancy are thought to have an immune basis. Third, studying pregnancy could lead to insights that are helpful for improving transplantation success because, although a fetus is genetically half foreign (genes inherited from the father), the mother does not reject and instead nourishes the growing fetus.
* Autoimmune Disease
In 1996 we proposed that fetal microchimerism might in part explain the female predilection to autoimmune disease. In work that was reported in 1998 we discovered elevated levels of fetal microchimerism in the blood of women with scleroderma compared to healthy women. This was the first study to look at microchimerism in an autoimmune disease. Subsequent studies found fetal microchimerism in internal organs and in skin affected by scleroderma. Ongoing studies in our research group investigate microchimerism in the autoimmune diseases rheumatoid arthritis, scleroderma, type 1 diabetes and primary biliary cirrhosis.
In 1999 we found that maternal microchimerism persists into adult life in individuals who have normal immune systems. Presumably this is due to engraftment with maternal stem cells. Stem cells can become multiple different types of cells. We therefore asked whether maternal cells can become part of the cells that make up tissues. We found maternal cells in the hearts of infants who died from heart block due to neonatal lupus and most of the maternal cells were cardiac myocytes (heart muscle cells). Our theory is that the maternal cells are the target of an immune attack. In other studies we found elevated levels of maternal microchimerism in patients with insulin-dependent (type 1) diabetes. In the pancreas we identified maternal cells that produce insulin (islet beta cells). In type 1 diabetes, for a number of reasons, we believe these cells are helping to repair damaged tissues.
Microchimerism has been studied by our group and by others in a number of different autoimmune diseases including systemic and neonatal lupus, myositis, multiple sclerosis, scleroderma, thyroiditis, primary biliary cirrhosis, Sjogren's syndrome and rheumatoid arthritis.
Women with rheumatoid arthritis often have their disease improve or even disappear during pregnancy. A beneficial role of fetal microchimerism is suggested by our finding that elevated levels of fetal microchimerism significantly correlated with pregnancy-induced amelioration of rheumatoid arthritis.
We are investigating microchimerism in complications of pregnancy, especially preeclampsia, a disorder characterized by high blood pressure in women in their third trimester of pregnancy, and in recurrent pregnancy loss. As noted above, we are studying the role of fetal microchimerism in women with rheumatoid arthritis who become pregnant because pregnancy often induces remission or improvement of rheumatoid arthritis.
In hematopoietic cell (bone marrow or stem cell) transplantation donor cells provide an advantage against recurrent leukemia and other malignancies. By analogy, we asked whether fetal microchimerism might contribute to the protection from breast cancer observed in women who have had children. Supporting this possibility we found a significant decrease of fetal microchimerism among women with breast cancer compared to healthy women. Conversely the question of whether microchimeric cells sometimes "go bad" and result in malignancy is of interest as suggested in some anecdotal reports.
* Infectious Disease
The T lymphocyte is a key determinant of immune reactions between a person's own cells and foreign cells. Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) are characterized by critical deficiencies in CD4+ T lymphocytes. We are studying maternal microchimerism in patients with HIV and are looking at whether maternal microchimerism levels correlate with whether there is progression or non-progression to AIDS.
Transplantation results in chimerism (called "iatrogenic chimerism"). In hematopoietic cell transplantation, graft-vs.-host disease occurs more often if the donor is a woman with prior pregnancies. We tested female apheresis products and found they contained male microchimerism, consistent with the interpretation that fetal microchimerism contributes to graft-vs.-host disease. In kidney, pancreas and islet transplantation we have tested serial serum samples and found that donor-specific microchimerism detection may become a useful non-invasive test for early rejection. Several other groups are now therapeutically exploiting the principles of naturally-acquired microchimerism in their selection of donors for transplantation.
Note: For further description of our work and this field for the general reader please see "Your cells are my cells." JL Nelson. Scientific American 298:72-79, 2008.
Microchimerism in autoimmune disease, reproduction, cancer, degenerative diseases and transplantation
All of our work is human-based with direct implications for the development of new therapeutic interventions.
Reading, Writing, Speaking
French: Functional, Functional, Functional
Italian: Functional, Functional, Functional
American Association of Immunologists
American College of Rheumatology
American Society for Histocompatibility and Immunogenetics
Association of American Physicians
Honors and Awards
2006, Distinguished Annual Lecturer, College of Veterinary Medicine Biomedical Sciences, Colorado State University
2006, Featured speaker, Society of Reproductive Biology, Australian Health and Medical Congress
2005, The Davidson Lecture, Royal College of Physicians, Edinburgh
2005, The President's Lecture, Society for the Study of Reproduction
2003, Kurt Benirschke Lecture, University of California, San Diego
2002, JFL Woodbury Lecture, University of Halifax, Nova Scotia
2002, 50th Anniversary Research Hero Awardee, National Arthritis Foundation
2001, Association of American Physicians,
2000, Dunlop-Dotteridge speaker, National Canadian Rheumatology Association
1998, Keynote speaker, Rune Grubb Symposium University of Lund, Sweden
1995, J. Christian Herr Award, American Society for Reproductive Immunology
1988-1991, Arthritis Investigator Award, Arthritis Foundation
1982-1983, NIH Fellowship Award, National Institutes of Health
1971, Phi Beta Kappa, Stanford University
1971, Magna Cum Laude Stanford University
Treatment of Scleroderma and Related Diseases, Patent Number: 5759766, 1998, Institution-owned, United States.
Characterization Of HLA-DRB1 Distribution By 3rd Hypervariable Region Sequence In Systemic Sclerosis and Control Populations. Arthritis and Rheumatism. 65:S810-S811.. 2013.
Meeting report of the First Symposium on Chimerism.. Chimerism. 4(4). 2013.
Microchimerism in the human brain: More questions than answers.. Chimerism. 4(1). 2013.
Adverse pregnancy outcomes and risk of subsequent rheumatoid arthritis.. Arthritis and rheumatism.. 2013.
Cellular fetal microchimerism in preeclampsia.. Hypertension. 62(6):1062-7.. 2013.
Intrauterine environment and multiple sclerosis: a population- based case-control study.. Multiple sclerosis (Houndmills, Basingstoke, England).. 2012.
The otherness of self: microchimerism in health and disease.. Trends in immunology.. 2012.
Microchimerism in cord blood: Mother as anticancer drug.. Proceedings of the National Academy of Sciences of the United States of America. 109(7):2190-1.. 2012.
Microchimerism in the rheumatoid nodules of rheumatoid arthritis patients.. Arthritis and rheumatism. 64(2):380-388.. 2012.
Male microchimerism in the human female brain.. PloS one. 7(9):e45592.. 2012.
Soluble donor DNA and islet injury after transplantation.. Transplantation. 92(5):607-11.. 2011.
Acquisition of the rheumatoid arthritis HLA shared epitope through microchimerism.. Arthritis and rheumatism. 63(3):640-4.. 2011.
Pregnancy and reproduction in autoimmune rheumatic diseases.. Rheumatology (Oxford, England). 50(4):657-64.. 2011.
Parity and HLA alleles in risk of rheumatoid arthritis.. Chimerism (Print). 2(1):11-15.. 2011.
Pregnancy, microchimerism, and the maternal grandmother.. PloS one. 6(8):e24101.. 2011.
Effect of parity on fetal and maternal microchimerism: interaction of grafts within a host? Blood. 116(15):2706-12.. 2010.
Does pregnancy provide vaccine-like protection against rheumatoid arthritis? Arthritis and rheumatism. 62(7):1842-8.. 2010.
Naturally acquired microchimerism.. The International journal of developmental biology. 54(2-3):531-43.. 2010.
Chimeric maternal cells with tissue-specific antigen expression and morphology are common in infant tissues.. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 12(5):337-46.. 2009.
Non-inherited maternal human leukocyte antigen alleles in susceptibility to familial rheumatoid arthritis.. Annals of the rheumatic diseases. 68(1):107-9.. 2009.
Skewed X-chromosome inactivation in scleroderma.. Clinical reviews in allergy & immunology. 34(3):352-5.. 2008.
Case-control study of fetal microchimerism and breast cancer.. PloS one. 3(3):e1706.. 2008.