Most autoimmune diseases preferentially affect women. The female to male ratio is particularly marked for (PBC) in which ratios of 10 to 1 have been reported. The peak incidence of PBC in women follows childbearing years. As a result of the applications of molecular biological techniques to the study of human pregnancy it is now known that there is bi-directional traffic of cells from fetus to mother and mother to fetus. Moreover, fetal cells have recently been found to persist in maternal peripheral blood for decades after pregnancy completion. Chronic grant-versus-host disease is a condition of known chimerism that occurs after allogeneic stem cell transplantation. This disorder has both clinical and pathological similarities to some autoimmune diseases, mot notably PBC and Ssc. These observations, when considered together, led the investigator to propose the hypothesis that microchimerism is involved in the pathogenesis of PBC and Ssc. Preliminary studies in women with Ssc support the hypothesis that persistent fetal microchimerism plays a role in this diseases. Studies in the current proposal will investigate the hypothesis that microchimerism is involved in the etiology and pathogenesis of PBC. The proposed studies will focus on women who had children prior to the onset of their PBC. However, the hypothesis regarding microchimerism also has applicability to men and women who have never been pregnant because there are alternative sources on microchimerism including engraftment from a blood transfusion, from a twin or from the mother. The first specific aim is to investigate microchimerism in liver specimens from women with PBC. DNA will be extracted from liver specimens and subjected to PCR for a Y-chromosome specific sequence in women who have given birth to sons, and to HLA-specific PCR for women who have had daughters. Tissue samples from women with sons will also be studied using in situ hybridization with double labeling for Y and X specific sequences.
In specific aim 2, peripheral blood of women with sons will be studied using quantitative PCR for male DNA and peripheral blood mononuclear cell subpopulations will be investigated for microchimerism after fluorescence-activated-cell-sorting.
In specific aim 3 the mother/child HLA relationship will be investigated as a potential risk factor for subsequent PBC in the mother. Although PBC and Ssc are both diseases with a striking predominance for middle-aged women there are no previous studies that have examined pregnancy as a risk factor in these diseases. Both disorders are poorly treated with available therapeutic agents. If microchimerism is involved in the pathogenesis of PBC, new therapies might be developed on this basis.
| Gammill, Hilary S; Nelson, J Lee (2010) Naturally acquired microchimerism. Int J Dev Biol 54:531-43 |
| Mullarkey, M E; Stevens, A M; McDonnell, W M et al. (2005) Human leukocyte antigen class II alleles in Caucasian women with primary biliary cirrhosis. Tissue Antigens 65:199-205 |
| Stevens, Anne M; McDonnell, W Michael; Mullarkey, Meghan E et al. (2004) Liver biopsies from human females contain male hepatocytes in the absence of transplantation. Lab Invest 84:1603-9 |
| Nelson, J L (2000) The Dunlop-Dottridge Lecture. Longterm persistence of fetal and maternal cells: implications for systemic sclerosis and other autoimmune diseases. J Rheumatol 27:2922-6 |
