Maternal lupus and congenital cortical impairment

Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by autoantibodies (AAbs) and preferentially affecting women of childbearing age. Since the offspring of mothers with SLE exhibit a high frequency of learning disorders1-5, we hypothesized that maternally transferred AAbs that bind DNA and the N-methyl-D-aspartate receptor (NMDAR)6-12 could play a pathogenic role during fetal brain development. Here we describe a maternal SLE murine model wherein pregnant dams harbored DNA-specific, NMDAR-specific AAbs throughout gestation. High titers of these AAbs in maternal circulation led to histological abnormalities in fetal brain and subsequent cognitive impairments in adult offspring. These data support a paradigm in which in utero exposure to neurotoxic AAbs causes abnormal brain development with long-term consequences. This paradigm may apply to multiple congenital neuropsychiatric disorders.