ALLOIMMUNITY IN AUTO IMMUNE DISEASE

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

Advances with molecular biological techniques have led to the appreciation that there is bi-directional traffic of cells during pregnancy. Fetal cells are found in maternal peripheral blood in the majority of first pregnancies and evidence for maternal cells has been found in over 40 percent of cord blood samples. Recently, the surprising observation was reported that fetal cells also can persist in maternal blood for decades after pregnancy completion. This observation raises the important question as to whether maternal cells also persist long-term in some offspring. It is well known that maternal cells engraft and persist in infants with severe combined immunodeficiency, but no previous study has investigated long-term persistence of maternal cells in normal individuals. In support of this probability, a cytogenetic study of male infants who received in utero transfusions from their mothers revealed some lymphocytes were XX at more than five years of age. In initial studies from our laboratory we report evidence for long-term persistence of maternal cells in some individuals up to 47 years after birth. Bi-directional traffic of cells during pregnancy, and long-term persistence of microchimerism in some individuals, when considered together with observations in experimental models and in human diseases characterized by chimerism (nonhost cells), led the investigator to propose the hypothesis that alloimmunity may contribute to some autoimmune disease. Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease for which a well-recognized experimental model involves the introduction of parental cells into F1 progeny. Some manifestations of SLE are also mimicked in human chronic graft-versus-host-disease that occurs after allogenic hematopoietic stem cell transplantation. The studies in this proposal are designed to investigate the hypothesis that maternal cells and/or DNA persist in some progeny and that maternal microchimerism contributes to the pathogenesis of some autoimmune diseases, specifically SLE. The proposed studies will investigate qualitative and quantitative aspects of persistent maternal microchimerism. To further address pathogenicity disease-affected tissues of SLE patients will be examined for maternal DNA and cells. The HLA- relationship of mother and her progeny will be investigated as a potential factor in the persistence and/or pathogenicity of persistent maternal microchimerism. The studies that are proposed may result in a new understanding of immunologic aspects and consequences of pregnancy. If persistent maternal microchimerism is involved in the pathogenesis of SLE new therapeutic modalities could be developed on this basis.