Identification and cloning of a brain autoantigen in neuro-behavioral SLE

Abstract

In murine models of SLE, particular patterns of abnormalities of social interaction and memory collectively known as neurobehavioral dysfunction (NBD) correlate with the occurrence of brain reactive autoantibodies. Study of the immunopathogenic effects of these antibodies has been limited by the absence of isolated autoantibodies and antigens. In order to identify the molecular targets, we isolated autoantibodies highly specific for brain plasma membranes from MRL/lpr mice. After immunoscreening a brain expression library with these brain specific autoantibodies, we identified a single cDNA clone of unique sequence and relevant anatomic distribution. Transcript for this cDNA is wide spread among mammalian species but appears to be present only in the brain. Additional features suggesting this cDNA is pertinent for further study include (1) the expressed protein, called lupus brain antigen 1, reacts with the screening immunoglobulins as well as immunoglobulins from other strains of murine neuro-SLE not used to screen the library, but not with immunoglobulins from normal mice, (2) the transcript distribution within the brain is similar to immunochemical localization of binding of the spontaneous autoantibodies and (3) the localization of transcript within the brain, in the hippocampus, hypothalamus and cingulate gyrus, corresponds to anticipated anatomical regions of clinical dysfunction. Further, the transcript is a large, potentially structural molecule of unique sequence. Antibodies to this molecule may mediate changes in behavior either by direct interactions with the cognate antigen or by indirect influences through neuro-endocrine axes.