Patricia M. Moore

Immune mechanisms in the primary and secondary vasculitides

Vasculitis, or angiitis, affects both the central and peripheral nervous systems and is increasingly recognized as a cause of neurologic dysfunction. The vascular inflammation may be systemic or organ restricted. Recent work has expanded our knowledge on the pathogeneses of vasculitis. Historically, immune complex mediated vasculitis is best defined but studies now delineate cell mediated immune mechanisms including T cell and endothelial cell interactions. Additional factors in the genesis of vascular inflammatory diseases are also being explored. There are numerous underlying etiologies ranging from primary immunologic disturbances to infections, malignancies, and toxins. In order to plan rational therapies, clinicians need to be aware of current work on the pathogeneses of vascular inflammation as well as exploring specific etiologies in their individual patients.

Evidence for bound antineuronal antibodies in brains of NZB/W mice

Antibodies reactive with neuronal tissue are present in the sera of the murine models of systemic lupus erythematosus (SLE). Access of these antibodies to the central nervous system is an important prerequisite to the hypothesis that these antibodies affect neuronal function. In this study, we isolated antibodies from neutral and acid washes of brain parenchyma of NZB/W F1 mice. Antibody could be eluted from the brains of NZB/W F1 but not control mice. The immunoglobulin was predominantly IgG1; the binding characteristics of the brain eluted antibody were narrower than those of antibody from sera and eluted from visceral organ.

Systemic lupus erythematosus: immunopathogenesis of neurologic dysfunction

SummaryNeurologic complications of systemic lupus erythematous (neuro-SLE) are common. The most frequent manifestations of neuro-SLE are seizures, encephalopathy, and behavioral changes, but a wide variety of other neurologic abnormalities affecting the central and peripheral nervous system and muscle also occur. Although the prevalence of neuro-SLE is high, the diversity of clinical presentations, the multiple potential etiologies, and the absence of sensitive and specific diagnostic tests render diagnosis difficult. Recent advances in understanding mechanisms of neuronal dysfunction combined with advances in imaging techniques, including functional imaging, should help in diagnosis and management. The mechanisms of neurologic injury can be divided into three broad categories. First, neuronal dysfunction may result from direct effects of the immune system on brain cells such as autoantibody binding to cell surface, immune complex deposition with secondary inflammation, and effects of cytokines. Second, immune-mediated injury to supportive structures such as the vasculature may also affect the nervous system by producing ischemia. Finally, the neuraxis may be affected by any one of several immune and non-immune effects of infection, toxins, and metabolic disturbances.

Immunoglobulin binding to neuronal cell surface epitopes in murine systemic lupus erythematosus

Screening serum by enzyme-linked immunosorbent assay (ELISA) to paraformaldehyde-fixed neuroblastoma cells revealed spontaneous neuron-reactive antibodies in three strains of autoimmune mice not present in comparable studies of BALB/c mice. Immunoglobulin isolation from pooled sera by either ammonium sulfate precipitation or passage over a protein G column enabled quantitative binding by (1) ELISA to neuroblastoma cells and (2) Western blots of plasma membrane preparations of brain cortex and neuroblastoma cells. The antibodies recognized proteins of apparent molecular weights 101,000, 68,000, 63,000, 57,000, 53,000, 43,000, 39,000, and 31,000 Da on the brain cortex and 63,000, 57,000, and 43,000 Da on the neuroblastoma cell membranes. The class of antibody binding was predominantly IgG in the MRL/lpr and IgM in the NZB/W. Differences between MRL/lpr, NZB/W and BXSB mice were observed although it is not yet apparent if this represents a difference in autoantibody production between the strains.

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

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. Addition 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 an 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.

Detection of Cerebral Ischemia in Systemic Lupus Erythematosus by Magnetic Resonance Techniques

Systemic lupus erythematosus (SLE) is associated with disorder of the cerebrovasculature that may cause ischemic brain damage during the course of the disease. Ischemia may result from occlusion of large intracranial vessels or from direct pathologic involvement of the microvascular bed. It remains far from clear, however, whether the multifocal or diffuse involvement of brain structures in SLE is primarily due to ischemia or secondary to other pathologic processes of an inflammatory or immunologic basis. This chapter will focus on established and new magnetic resonance imaging (MRI) methods that can be applied to the investigation, diagnosis, and management of brain ischemia, concentrating on how these anatomic and functional methods can be applied to study the cerebrovascular and ischemic complications of SLE as they affect the brain. Whereas there are a number of different techniques that can measure brain blood flow and metabolism, magnetic resonance (MR) methods are chosen because MRI is the investigation of choice to identify structural brain damage in SLE. Overlay of functional MR images can be accomplished more readily to selectively identify the flow and metabolic correlates of any such brain lesions. Comprehensive information on the pathogenesis of ischemic cell damage can be obtained from reference one. In brief, the neurologic symptoms and signs of ischemia in humans occur below a cerebral blood flow (CBF) threshold of around 18-20 cc/ 100 grams of brain per minute. This threshold value holds true across most animal

Neurologic Complications of Collagen Vascular Diseases

Despite the importance of neurologic manifestations of the collagen vascular diseases, it is clear that there are more questions than answers. The use of in vitro culture systems, in vivo models, and clinical and laboratory study of patients that attempt to correlate these findings with immunologic abnormalities, including parallels with animal models, should increase our understanding of these syndromes.

Neuronal cell surface proteins reactive with spontaneously occuring antibodies in NZB/W mouse sera

NZB/W F 1 hybrid mice, an autoimmune model of systemic lupus erythematosus, develop circulat ing autoantibodies to mult iple antigens. Neuron reactive antibodies occur but their access to the CNS has not been established. In the present study, antibodies in PBS washes and acid eluates of 10 NZB/W F 1 hybrid and 10 ~alb/c control mouse brains were compared. The in i t ia l PBS wash and the acid eluates were precipi tated wi th ammonium sulfate and evaluated for protein content and presence of antibody. Both IgG and IgM were detected in the in i t ia l PBS washes of NZB/W and Balb/c brains, IgG alone was present in the acid eluates of NZB/W brains, and no antibody was present in acid eluates of ~lalb/c brains. Samples of the in i t ia l PBS wash and the acid eluate were passed over anti-mouse IgG sepharose columns and the quantity, subclass~ and binding af f in i ty of the IgG compared. A tota l of 9.5 ug of igG was present in the PBS wash end 3.7 ug in the acid eluate of the NZB/W mice. Subclasses G 1, G2a, and G2b were present in PBS wash but only G 1 in the acid eluate. When adjusted for equivalent immunoglobulin concentration, the antibody in the PBS wash bound to DNA, neuroblastoma cells, and l iver cells in an Elisa assays the acid eluted antibody bound prominently to neuroblastoma ceils, only slightly to l iver cells, but not to DNA. This study shows antibody bound to CNS tissue reacts with fewer targets than that found in serum and demonstrate

Immune Mediated Neurovascular Disease

these antibodies do cross the blood/brain barr ier and potent ial ly may affect neuronal function.

Inflammatory Disease as Chronic Stress

This chapter discusses the spectrum of autoimmune, inflammatory, and infectious causes of cerebral and peripheral nerve ischemia. Immune-mediated vascular disease may result from cell mediated interactions, immune complexes, and autoantibodies and the relative contributions vary. The most frequently encountered of all vasculitides is a heterogeneous group of clincial syndromes characterized by inflammation of small vessels, most prominently the venules. The skin is the predominantly affected organ. Rheumatoid arthritis is sometimes associated with a dramatic vasculitis which occasionally affects the central nervous system. In the peripheral nervous system, vasculitis and obliterative vasculopathy causes neuropathies with more acute onset than compressive neuropathies. In the later stages of vasculitic disease, ischemia may result from chronic scarring rather than acute inflammation. This is not responsive to immunosuppressive therapy and the patient should be spared the side-effects of ineffective medication. It is suggested that experience in the use of immunosuppressant medications is also important because of the wide range of potential and actual side-effects.