Autoantibodies to Nervous System Tissue in Human and Murine

Systemic Lupus Erythematosus PATRICIA M. MOORE'

Department of Neurology Wayne State University School of Medicine

4201 St. Antoine Detroit, Michigan 48201

Autoantibodies, the hallmark of SLE, are prominent in the pathogenesis of cutaneous, renal, and hematological manifestations of the disease.'-5 The immunopathogeneses of the neuropsychiatric (NP) features of SLE, however, remain enigmatic. Although a variety of antibodies correlate with clinical features of NP, there is as yet no definitive evidence for a pathogenic antibody. In other areas of neuroscience, autoantibodies are increasingly recognized for their potential importance in diseases, such as paraneoplas- tic syndromes, Rasmussen's encephalitis, Lambert-Eaton syndrome, myotonic dystro- phy, and, possibly, some human peripheral neuropathies."" Several decades of study of autoantibodies to the acetylcholine receptor in myasthenia gravis provide illustra- tion on how autoantibody-mediated responses can be dissected in the nervous system when the autoantibodies, autoantigens, and appropriate tools for evaluating the cellular response are a~ailable. '~- '~ Similarly, in a particular cutaneous disorder, bullous pem- phigoid, identification of a specific autoantibody and autoantigen demonstrates the facility of in vitro and in vivo studies of an autoantibody-mediated pathologic There is some progress in central nervous system diseases. Recent studies describe that immunization of rabbits with a glutamate (an excitatory neurotransmitter) receptor protein elicits seizures. The clinical features and the brain histology suggest that this is an antibody-mediated disease model of Rasmussen's encephalitis, a rare hemispheric seizure di~order. '~ Further, in vitro studies demonstrate that the antibody has agonist properties at the receptor.*O Other neurologic diseases with strong clinical associations, although less easily attributed to mechanisms of autoantibody action, are certain forms of paraneoplastic cerebellitis, limbic encephalitis, and ganglioni- tis.Zl-24 In other circumstances antibodies may have a protective or healing role as in the remyelination associated with autoantibodies in a viral model of central nervous system (CNS) demyelinati0n.2~ Whether these autoantibodies are markers for disease or pathogenic remains unresolved.2"28 In human or murine SLE, there is, as yet, no convincing evidence that an individual antibody alters neuronal function or reliably marks a particular clinical feature as autoimmune. We will review the history of the search for and the potential mechanisms of antineuronal antibodies.

Autoantibodies to CNS tissue in SLE can be broadly categorized into three groups: (1) those antibodies identified in the cerebrospinal fluid (CSF) or bound to CNS

'Tel: (313) 577-1244; fax: (313) 745-4216.

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tissue, (2) serum autoantibodies with a clinical correlation with NP abnormalities, and (3) autoantibodies that bind to nervous system tissue preferentially or exclusively.

ANTIBODIES IN CSFKNS

Immunoglobulins are increased disproportionately in the CSF of patients with NP-SLE compared with patients with SLE without NP features, and control patients with inflammatory diseases. This appears to reflect intrathecal synthesis on the basis of a calculated index of blood-brain barrier integrity, although a hematogenous source of some of the antibodies may be pre~ent."~' Although IgG is the subclass usually identified, IgM and IgA are also detectable. Oligoclonal bands (OCB), indicating a narrow range of immunoglobulin production, such as seen in the CSF in CNS infections, and autoimmune diseases, such as multiple sclerosis, are present in possibly half the patients with NP-SLE.3'-33 Studies to date have failed to define the antibody specificity of most of the CSF immunoglobulins; this has also been true of the OCB in multiple sclerosis. In CNS infections, the antibody specificity of the OCB is usually to the infectious agent. Comparison of the serum:CSF antibodies against clinically defined autoantigens reveals antibodies to some antigens (neuroblastoma antigens, brain cortex antigen) that are at least as prominent in the CSF as serum; one other (ribosomal P) is more prominent in the serum than the CSF.28,34*35

Antibodies are also detected bound to brain tissue in the CNS. They have been identified by indirect immunofluorescence in the blood vessels and choroid plexus as well as by acid elution from homogenized brain p a r e n ~ h y m a . ~ ~ . ~ ~ In the human disease, there is little correlation between clinical neurologic abnormalities and anti- bodies in the choroid plexus. Detection of antibodies within the choroid plexus remains an interesting topic, however, because of the close similarities of surface charge and vasculature between the choroid plexus and renal g l ~ m e r u l i . ~ * ~ ~ ~ More recent studies of the choroid plexus revealing their potential role in endocrine functions suggest indirect mechanisms of antibody-mediated NP changes.40 In murine SLE, elution of antibodies from brain tissue exhibits different spectra of binding than antibodies isolated from the serum!'

SERUM ANTIBODIES WITH CLINICAL CORRELATION WITH NP SYMPTOMS

Most descriptions of autoantibodies in NP-SLE depend upon identification of serum immunoglobulins with certain patterns of binding in the context of a clinical neuropsychiatric event. These antibodies may be cross-reactive with blood cells (lymphocytes, platelets) or bind to widely dispersed antigens (ribosomal P, cardiolipin, or phospholipids) as well as demonstrate binding to peripheral nervous system (PNS) or CNS targets.

Links between these antibodies and neurologic abnormalities proceed from studies of clinical correlations.4248 Associating autoantibodies with specific disease features is a routine method of surveying for antibodies of interest. There are, however, numerous limitations in the design and interpretation of these studies, which account for the often conflicting reports in the literature. In most of these studies, the immuno-

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TABLE 1. Autoantibodies Described as Potentially Pathogenic in the CNS

Antibodies to lymphocyte membrane antigens. Antibodies to platelets. Antibodies binding to frozen brain sections. Antibodies to brain plasma membranes. Antibodies to cerebellar cells. Antibodies to caudate nuclei. Antibodies to neuroblastoma cells.

globulins are part of a polyclonal population; it is difficult to identify the immune effects mediated by a specific antibody. Also, as assays may vary in both target tissue and methods, it is often difficult to compare results from one lab to another. Even when the technical variables are established, confounding features will include selection of patients, presence of disease activity, and postulated mechanisms whereby the antibodies may exert their effects. Studies investigating associations of neurologic or psychiatric disorders with autoantibodies to structures not restricted to the CNS, including the ribosomal P and antiphospholipid antibodies, are discussed in other papers in this volume.

ANTIBODIES WITH SPECIFICITY FOR NERVOUS SYSTEM TISSUE

Collectively, these are called antineuronal or neuron-reactive antibodies (although it is not clear that the neurons are the only affected cells). Another term, antibrain or brain-reactive antibodies is equally misleading, as most of these studies are done with neuroblastoma tissue, a peripheral nervous system cell. Antibodies reactive with neuroblastoma antigens occur in both human and murine SLE. Investigations of these antibodies is either by study of binding activity in polyspecific serum or immunoglobulins, isolation of individual antibodies, or isolated monoclonal antibod- ies. TABLE 1 lists some of the binding specificities described.

Antibodies reactive with neuronal tissue have been identified by several maneu- vers: identification of neuron-reactive antibodies using absorptions with brain tissue, indirect immunofluorescence of cells within the CNS, cytotoxicity to neuroblastoma cells, and Western analysis of membrane proteins from brain or neuroblastoma Ce]ls.35A7.4946

ANTIBODY ACCESS TO AUTOANTIGENS

Access of antibodies to the CNS is limited for most circulating antibodies, but there is considerable evidence that (1) antibodies can enter the CNS in regions where the blood-brain barrier (BBB) is not intact, such as occurs in the area postrema,” (2) antibodies cross the BBB during those physiologic (hypertension) or pathologic (infection) circumstances when the BBB is d i s r ~ p t e d , ~ ~ . ~ ~ (3) some antibodies do cross

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TABLE 2. Potential Reasons Why a Pathogenic Antineuronal Antibody Is Not Yet Identified

1. Specific pathogenic autoantibodies may exist, but the individual antibodies or their effects have not yet been delineated.

2. The antibodies are already described, but they are pathogenic in only a small subset of patients that have yet to be defined.

3. Antibodies are part of the multiple-hit model of neuronal damage (EAA, changes in energy balance) that is cumulative and difficult to establish out of the context of the other injuries in human and murine disease.

4. Antibodies act upon regulatory mechanisms in the control of cerebral blood flow; glucoconi- coid or mineralocorticoid sensitivity; autonomic nervous system effects on immunosuppres- sion; and modulation of adrenal, thyroid, or gonadal function.

the BBB, and (4) lymphocytes do traffic across the BBB into the CNS parenchyma. Although the data is not quite as clear as for the immune surveillance of the brain by T cells, B cells or the immunoglobulin-producing plasma cells appear to traffic into and remain in the CNS paren~hyma.6~-~~ Determining whether the antibodies are initially stimulated by antigen in the CNS or the periphery would help explain features of numerous diseases observed to date.

Similar concerns that antibodies do not have access to intracellular antigens are ameliorated by recent evidence showing expression of peptides corresponding to intracellular antigens on the surface of cells as well as the potential for antibody uptake by neuron^.^^.^^

PHYSIOLOGIC AND PATHOLOGIC EFFECTS OF ANTINEURONAL ANTIBODIES

There is a resurgence of interest in both antibody-mediated neurologic dysfunction and re~air. '~.~~-*l Although autoantibodies act as agonists or antagonists in endocrine diseases, this potential role in CNS neurologic diseases is not yet confirmed (TABLE 2). Autoantibodies are associated with in vivo neurologic abnormalities, although the cellular mechanism may not be defined. Further, even in neuromuscular diseases in which the antibody and antigen are well defined, the tempo and effects of antibody on the cell may vary. In myasthenia gravis, autoantibodies to the acetylcholine receptor (AchR) could cause neuromuscular blockade through action on the pharmacologically active binding site (as happens in acute murine or passively transferred myasthenia); however, the effect of AchR antibodies in human disease appears to result from antibody binding to alternate sites and inducing a turnover or remodeling of the end plate. The resulting simplification of the myoneural junction results in a reduced safety factor of neuromuscular transmission and abnormal fatigability.8244 In Lambert- Eaton syndrome, antibody activity against a voltage-gated membrane channel ap- p e a r ~ . ~ ~ In several paraneoplastic syndromes, a more complex situation exists. Despite strong identification of certain rare clinical features with specific antibodies and demonstrable cell loss in the appropriate target, a mechanism of cellular action is not yet delineated.21~22~24

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STUDIES OF Lbal, A NEWLY DESCRIBED AUTOANTIGEN

Murine models of SLE (including the NZB/W F1, MRLApr, and BXSB strains) exhibit abnormal patterns of behavior, including learning abnormalities, abnormal social interactions, timidity, and perseveration on the exploration of novel ob- j e c t ~ . ~ ~ - ~ ’ Some of these features correspond to cortical ectopias in some strains; other features are associated with the onset of certain patterns of autoantibodies. In our laboratory, we have been investigating the characteristics of spontaneously occurring autoantibody binding to nervous system tissue in the MRL/lpr strain. We isolated a population of spontaneously occurring antibodies using a highly purified preparation of mouse brain cortex plasma membranes conjugated to sepharose beads.” The antibodies, called affinity-purified antineuronal antibodies (AfAnAb), are polyclonal and are first detectable at about 7-8 weeks of age. We investigated the pattern of binding of the antibodies to various neuronal and peripheral tissues by semiquantitative indirect immunofluorescence to viable tissue from (1) cultured cells lines and (2) explanted brain cells and well as by histochemistry on frozen tissue sections. AfAnAb were selectively reactive with murine and human CNS and PNS tissue. Within the brain, antibodies bound to certain cells (cortical and hippocampal) but not to other (striatal) cells (FIG. 1). Confocal imaging determined that antibody bound to cell- surface molecules, particularly in the region of the cell soma, whether or not prominent neurite formation was demonstrable.

In order to further study the target autoantigens, we immunoscreened a brain expression library with the affinity-purified antibodies. After screening more than 500,000 independent plaques, an interesting cDNA clone was chosen for further study, because features of both the expressed protein and transcript suggested this was a pertinent autoantigen. The cDNA was 1.2 kb in size and hybridized to a 13 kb mRNA within the brain, but not liver, kidney, muscle, skin, heart, lung, spleen, and gastrointestinal tract. Thus, the transcript had a similar tissue distribution to the binding of the screening autoantibodies.

After plaque purification, the cDNA was restriction mapped and sequenced. The determined nucleotide sequence (a single long open reading frame without a transla- tion initiation codon) is a previously unidentified sequence highly conserved among mammalian species. Although no obvious functional motifs are identified, several patterns related to antigenicity did appear.”

In situ hybridization demonstrated that the transcript localizes to the limbic system, primarily the cingulate cortex, primary olfactory cortex, and hippocampus, particularly the presubiculum and dentate gyms, as well as the ventromedial hypothalamus. Smaller regions of transcript were detected in the centromedian parafascicular thala- mus and some in the frontoparietal motor cortex. Many areas, including the striatum and the amygdala, were notably without detectable transcript.

After IPTG induction, the translation products were directly analyzed by SDS- PAGE, Western analysis, and ELISA. Autoantibodies from MRLApr and NZB/W F1 mice, but not BXSB or two normal strains, Balbk and C57, bound to the expressed 68 kd peptide. Among patients, 8/12 with NP-SLE and 1/6 with SLE without NP features, 0/4 with multiple sclerosis, and 0/3 with benign increased intracranial hypertension had autoantibodies binding to the peptide.

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X

A x X

x , . ,"'. , ~ ,-, , . 0 20 4 0 60 00 100 120 140

Area (pm * )

FIGURE 1. Indirect immunofluorescence of affinity-purified antineuronal antibodies binding to (A) explanted cells from the cortex (O), hippocampus (A), and striatum (X) of fetal mice, and (B) cultured, viable neuroblastoma cells. In A, the maximal binding of antibody as measured by fluorescence intensity is to cortical as well as to many of the hippocampal neurons. Binding was not dependent on cell size or degree of neurite formation. Little binding was present on striatal cells. There was no detectable binding on cells outside of the nervous system, such as kidney, liver, or spleen cells.

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Thus, we have isolated an autoantigen in SLE that is expressed in a region of the brain that has prominent connections with both cognitive and emotive behaviors, as well as a regulatory role in stress and chronic inflammation. Antibodies to the autoantigen are present in murine and human SLE and correlate either temporally or spatially to the clinical features. Whether the autoantigen (Lbal) is relevant to the pathogenesis of NP-SLE awaits delineation of the cellular effects of the antibody.

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