Brain Research, 532 (1990) 25-33 25 Elsevier BRES 15985 Brain abnormalities in immune defective mice Gordon F. Sherman 1, Lindsay Morrison 2, Glenn D. Rosen 1, Peter O. Behan 2 and Albert M. Galaburda 1 1Dyslexia Research Laboratory and Charles A. Dana Research Institute, Beth Israel Hospital; Department o f Neurology, Harvard Medical School, and Beth Israel Hospital, Boston, MA 02215 (U.S.A.) and 2Department of Neurology, University of Glasgow, and Institute of Neurological Sciences, Southern General Hospital, Glasgow (U.K.) (Accepted 8 May 1990) Key words: Autoimmunity; Cerebral cortex; Developmental dyslexia; Dysplasia; Ectopia; Neuronal migration Mouse strains with or without immune disorders were examined in order to further assess the incidence of brain anomalies in immune-disordered strains. The brain was examined in Nissl-stained serial sections under a light microscope for the presence of abnormalities, with specific attention to ectopic collections of neurons in layer I of the neocortex, as reported in the autoimmune New Zealand Black (NZB) and BXSB strains. The present study was designed to survey additional strains with immune disorders (Snell dwarf, C57BL/6J-nu/nu, BALB/cByJ-nu/nu, and SJL) and 7 control strains without immune disorders. In addition, we attempted to replicate past findings in the highly affected BXSB strain and the MRL/1 strain, which develops autoimmune disease, but has a low incidence of brain abnormalities. The largest number of brain abnormalities (20-40%) were seen in the C57BL/6J-nu/nu, Snell dwarf and BXSB strains. The anomalies in the C57BL/6J-nu/nu and BXSB mice consisted of ectopic neurons in layer I of the neocortex, whereas the Snell dwarf mice had either neuron-free areas in the cortex, or rippling of cortical layers II-IV, and one case had agenesis of the corpus callosum. Between 4% and 8% of the mice from the SJL, MRL/1, and MRL +/+ strains had either neuron-free areas in the cortex or ectopic neurons in layer I. The BALB/cByJ-nu/nu and control strains did not have any cortical abnormalities. Future studies will be designed to determine whether immune-based alterations to the developing brain are responsible for the brain anomalies present in immune-disordered strains. INTRODUCTION New Zealand Black mice (NZB/BINJ) develop severe autoimmune disease characterized by abnormalities of stem cells, macrophages, and T and B lymphocytes, and by the production of anti-erythrocyte antibodies. Death usually occurs from hemolytic anemia at 16-17 months a9" 51,52. At least 20% of NZB mice have ectopic collections of neurons in layer I of the cerebral cortex with dysplasia of the underlying cortical laminae. Because of similarities in appearance with ectopias reported in the dyslexic brain 15"a6, it was suggested that NZB mice would be a useful model for the study of the anomalies present in the brains of dyslexics41'42. The microdysgenesis in the NZB is usually seen in the somatosensory cortex, and is attributed to an unspecified disturbance of neuronal migration to the cortex as described elsewhere 6"11"12"26. These neocortical ectopic foci display abnormal patterns of local neuronal circuitry as disclosed by neurofilament stains 43, and increased numbers and altered location of VIP-positive neurons, both in the ectopias and in other regions within the hemisphere containing an ectopia (submitted for publi- cation). In addition, hippocampal anomalies also attrib- uted to a disturbance in migration are present in the NZB m o u s e 33,34. In a follow-up study designed to determine whether other autoimmune strains have cortical anomalies 4°, we found neuronal ectopias in cortical layer I of about 30% of BXSB autoimmune mice. Most of the ectopic neurons in the BXSB were present in frontal/motor regions of the cortex, usually on the left side. The BXSB strain, originally raised from the mating of a C57BL/6J female and SB/Le male, develops severe autoimmune disease consisting of the production of auto-antibodies, prolifer- ation of B-cells, and immune complex glomeru- lonephritis 1'5°'52'53. BXSB males die at 5 months of age while females die at 15 months, which is related to the presence on the Y chromosome of the Yaa gene that accelerates immune disease in males 5z. The presence of anomalies in the NZB and BXSB prompted us to suggest that an abnormally-functioning immune system (probably that of the mother, since these ectopias must occur early) may play an etiologic role in the production of developmental brain abnormalities. Not all autoimmune mouse strains, however, show Correspondence: G.F. Sherman, Department of Neurology, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA, 02215, U.S.A. 0006-8993/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)