Alloimmunity in autoimmune disease

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DESCRIPTION (provided by applicant): During pregnancy it is now recognized that some cells traffic between the mother and fetus. Microchimerism refers to a small number of cells (or DNA) from one individual harbored by another. The current proposal is the first renewal of studies investigating the hypothesis that maternal microchimerism (MMc) persists long-term in immune competent individuals. As a result of initial studies we know that MMc persists in her progeny into adult life. In the prior grant period we found MMc in almost one-fourth of healthy adults in a single blood draw. That MMc is not uncommon in healthy adults suggests harboring semiallogeneic cells is not intrinsically detrimental to the host, but begs the question of how damage to self is avoided. An overall hypothesis of this proposal is that MMc and allo-immunity are integral aspects of normal health, but that MMc can also contribute to autoimmune disease, with specific HLA genes of mother and progeny key determinants of the result. It is unlikely that MMc has a single continuous effect on her progeny given persistence from infancy through adult life. However no information is available regarding MMc as the individual ages. Moreover, it is unknown how MMc is affected and what effects it might have when the proband acquires new sources of (fetal) microchimerism through her own pregnancies. Studies in this proposal begin by determining quantitative and qualitative aspects of MMc in the stages of aging, childhood, reproductive and older years in Specific Aim 1. Specific Aim 2 will investigate MMc according to consequences of accumulating new sources of (fetal) microchimerism through pregnancy in women. Specific Aims 3 and 4 will investigate MMc in polyarticular rheumatoid arthritis (RA), because "noninherited" maternal HLA genes have been implicated in disease risk and because in preliminary studies for this proposal we identified MMc and also fetal microchimerism with RA-associated HLA alleles in patients who themselves lack an RA-associated HLA allele. Thus Specific Aims 3 and 4 test the hypothesis that an individual can acquire disease risk (or protection) through microchimerism; Specific Aim 5 will investigate phenotype and functionality of MMc in proband-mother pairs and in the context of multi-generational microchimerism in parous women. Studies of apheresis products will permit investigation of additive sources of microchimerism across generations where exposures differ according to age, immune system development, and the effects of residing in another host for decades ("immigrant status"). The overall approach of this proposal is intended to generate a window of insight into the interface of allo-immunity in health and auto-immune disease where little information is currently available.