Chimeric maternal cells as T lymphocyte targets in pediatric SLE

Abstract

Background: Maternal cells passing into the fetus can persist for decades after birth, creating a state of maternal microchimerism. Loss of tolerance to non-shared antigens from maternal cells could lead to chronic activation of host T lymphocytes, with subsequent nullautoimmunitynull similar to the graft-versus-host disease seen after parental to F1 stem cell transplantation. Hypothesis: Normal T lymphocytes are tolerant to chimeric maternal cells; in SLE T cells specific for maternal cells are expanded. Methods: PBMC from 22 pediatric SLE patients and 27 age-matched controls were stimulated with maternal or HLA incompatible unrelated donor PBMC for 5 days. Cytokine expression and proliferation in T cell subsets was assayed by flow cytometry. Maternal microchimerism was assayed by Real-Time QPCR amplification of non-shared maternal alleles using >100,000 genome equivalents of genomic DNA isolated from the child's PBMC. SLE disease activity was assessed by the SELENA-SLEDAI. Results: Levels of maternal microchimerism were not increased in SLE patients with active disease, but rather tended to be lower (126 per million maternal cells in controls versus 5.2 in SLE, P>0.05). T lymphocytes in patients with SLE were hyperactive in response to maternal cells. Proliferation of CD4+ T lymphocytes in response to maternal cells was increased 2-fold in SLE patients compared to controls, and IFN-(gamma) production by CD4+ lymphocytes was increased in patients with active SLE (SLEDAI> 4), but not in those in remission or controls. TNF-(alpha) production by CD4+ T lymphocytes specific for maternal cells correlated with SLE disease activity. Conclusions: Elevated CD4+ T lymphocyte responses to maternal cells are consistent with a model of persistent T lymphocyte activation by chimeric maternal cells within target organs with subsequent T cell-mediated elimination of chimeric maternal cells in the periphery.