Preface

Abstract

Recent data heralds new frontiers in the understanding of cerebrovascular disease as well as the interactions between the immune, neuroendocrine, and vascular systems. The potential utility of these studies to the research of the neuropsychiatric manifestations of systemic lupus erythematosus (NP-SLE) is substantial. There are three aspects of NP-SLE where recent work is appropriate for integrated discussion: cerebrovascular disease, autoantibodies and their regulation, and neuroendocrine pathways in response to stress. In the neuroscience community, interest in the biology of stress is high; broadening this information by sharing information on cellular mechanisms and clinical effects will affect approaches to prevention and treatment of human disease. Clinical stroke is a variable feature in SLE; some series report a high incidence, others a low incidence. Most investigators agree that small vessel disease is more prevalent than middle- or large-sized vessel abnormalities. In contrast to the systemic vasculature, inflammation of the cerebral blood vessels rarely occurs. Nonetheless, because the cerebrovasculature is subject to recurrent circulating immunoglobulins and, in some patients, antibodies reactive with phospholipids in endothelial cells and platelet membranes, other chronic abnormalities of neurovascular function may develop. Much recent information on the role of cytokines, adhesion molecules, and vasomotor reactivity in normal vascular function may apply to the pathophysiology of SLE. Central questions for us are, How important is ischemia in the pathogenesis of NP-SLE? Can we distinguish between tissue changes of ischemia and inflammation? What is the specificity and utility of neurodiagnostic imaging? What neurodiagnostic can help us understand the tissue changes in patients? If multiple immunopathogenic events in the CNS share similar mechanisms of damage, is it necessary or possible to distinguish ischemia from other initiators of cell injury? Will therapies to limit damage and repair cells be aimed at the mechanism of damage rather than the cause? Bidirectional communications between the neuroendocrine system and the immune system mediate critical features of normal immunity and homeostasis. Conditions that stress the body initiate a series of events, which, in health, protect the organism and attempt to restore basal conditions. The hypothalamic-pituitary-adrenal (HPA) axis is the principal neuroendocrine pathway for hormonal responses, as is the brain stem/autonomic nervous system a principle noradrenergic pathway for stress-mediated cardiovascular responses. Recent investigations explore the regulatory role of the hippocampus and amygdala on the hypothalamus and effects of the predominant hypothalamic secretatogues on cortical motor and limbic systems. Similarly, the production of intracranial soluble mediators, such as cytokines and nitric oxide, mediate local changes in neuronal, glial, and vascular function. The prominent effects of glucocorticoids and gonadal steroids on brain development and plasticity of neuronal structures throughout adult life raise important questions for the pharmacotherapy of chronic inflammatory diseases. What are the effects of chronic inflammation, recurrent CNS ischemia, and circulating antibrain antibodies on the HPA axis activity? Are the effects of chronic elevation of steroids on cognition and hippocampal architecture in humans similar to the experimental models? Does the prominent sex bias in distribution of disease influence the incidence of side effects of therapy? Finally, autoantibody formation is a sine qua non in SLE. Several different populations of biologically interesting autoantibodies correlate with the presence of NP abnormalities in patients and neurobehavioral changes in murine SLE. Are any of these antibodies pathogenic? If so, are their effects mediated (1) by binding directly on cortical or hippocampal cells, reducing their normal function; (2) through the cerebrovasculature, inducing NP abnormalities by ischemia; or (3) by binding to brain structures, altering regulatory controls over hypothalamic-adrenal or hypothalamicgonadal axes? This symposium unites speakers and participants from diverse specialties: neurology, rheumatology, neuroendocrinology, hematology, and immunology. The volume is divided into five sections: (1) stress, stroke, and seizures; (2) cerebrovascular disease in SLE; (3) neuroendocrine aspects of SLE; (4) autoantibodies and SLE; and (5) planning studies.