Pregnancy, Microchimerism, and Autoimmune Disease

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): During pregnancy some cells traffic between the mother and fetus. Microchimerism (Me) refers to a small number of cells (or DNA) from a genetically distinct individual. In prior studies from this grant we found that maternal Me persists in her immune competent adult progeny and, as reported by others and in our studies, fetal Me persists in the mother decades after pregnancy. HLA molecules are key determinants of the distinction between self and other and HLA class II molecules are implicated in autoimmune diseases. This grant began with investigative studies of the autoimmune disease systemic sclerosis (SSc). Excess fetal- maternal HLA-sharing was found in women with SSc compared to healthy women. Women with SSc also had significantly higher levels of fetal Me than healthy women. The usual measure of fetal Me has been testing for male DNA in women who had sons. In the prior grant cycle, however, we found that women who had never given birth to a son sometimes had male DNA in their peripheral blood. In these women male DNA could originate from a spontaneous or induced abortion, from an older sibling passed via the maternal circulation to a subsequent pregnancy or from a twin. Other methods were needed to more specifically identify the origin of Me and that were more versatile for testing for any source of Me. We therefore developed a panel of HLA-specific and other genetic polymorphism specific quantitative PCR assays. The first two Aims of the current proposal will investigate childhood onset SSc to define HLA alleles associated with SSc, to test the hypotheses that HLA-associated risk is affected by the parent-of-transmission and to quantify Me from the mother and from older siblings. Aims 3 and 4 will investigate adult women in complete three-generation studies including the proband's children and her mother. The overall model considered incorporates the HLA genotype, two and three generation HLA-relationships and all sources of Me. Having established a foundation for mechanistic studies, Aim 5 will conduct functional studies to investigate the role of specific HLA DRp and DQp sequences and of different sources of Me in SSc and healthy individuals. The hypothesis will be tested that SSc pathogenesis involves indirect presentation of peptides from microchimeric sources derived from the 3rd hypervariable region of the HLA-DR(31 molecule and an SSc- associated amino acid motif "FLED" that is shared by some alleles of HLA-DRp1 and DRp5.