Chapter 28 Pathogenesis of the Nervous System

Cynthia Aranow, Betty Diamond, Meggan Mackay

With greater understanding of the immune abnormalities associated with active lupus, new targets have been identified and new therapies are being developed for the treatment of active disease. However, no new potential agents are on the horizon for the treatment of neuropsychiatric lupus (NPSLE). Understanding the pathophysiologic mechanisms that contribute to NPSLE lupus is critical to the design and evaluation of effective interventions. This chapter discusses what is currently known about the causes of NPSLE and tissue injury.

Lupus affects the nervous system, causing numerous manifestations (see Chapter 29) encompassing both the central nervous system (CNS) and peripheral nervous system (PNS) with symptoms that range from focal thrombotic events to diffuse disorders affecting cognition, mood, and level of consciousness. It is clear that there can be no single pathophysiologic mechanism for all NPSLE, and mechanisms are likely to vary according to the pathoanatomic localization of disease—vascular, CNS, and PNS (Box 28-1). Vascular compromise results in local tissue ischemia and symptoms reflective of the damaged area. CNS symptoms develop from injury to the brain parenchyma, vasculature, and blood-brain barrier (BBB); data now suggest that autoantibodies and cytokines may mediate the insults, causing diffuse or focal effects on the CNS. The PNS is not protected by a BBB and therefore is susceptible to consequences of circulating autoantibodies, immune complexes, and other inflammatory molecules.

Box 28-1

Locations of NPSLE Pathophysiology

Vasculature

Brain parenchyma

Peripheral nerve

Not all neurologic manifestations experienced by patients with lupus arise from lupus, and it is exceedingly important to correctly differentiate lupus from nonlupus causes of neurologic symptoms. CNS lupus can exhibit manifestations similar to those of thrombotic thrombocytopenic purpura, posterior reversible encephalopathy syndrome, and infectious (bacterial, viral, and fungal), metabolic, and hormonal disturbances. Secondary effects of medications, particularly corticosteroids, are an additional possibility that must be considered, especially in the evaluation of emotional and cognitive complaints. Approximately two thirds of neuropsychiatric events occurring in patients with lupus are attributable to other causes.

Vascular Mechanisms

Vascular injury is common in SLE. Postmortem examination of human lupus brain tissue typically shows evidence of microvascular injury with microinfarcts, perivascular lymphocytic infiltrates, and endothelial cell proliferation.¹^–³ Microvascular injury leading to ischemia may result in cortical atrophy and ischemic patchy multiple sclerosis–like demyelination observed in lupus brains. Actual vasculitis with an inflammatory infiltrate and fibrinoid necrosis within vessel walls in the brain is rare, although more commonly seen in the PNS.^2,³ Gross infarcts do occur and can stem from the accelerated atherosclerosis associated with lupus or from thrombosis occurring in the context of antiphospholipid antibodies. These autoantibodies—anticardiolipin, anti–beta 2 glycoprotein I (anti–β₂ GPI), and/or the lupus anticoagulant—are associated with a hypercoagulable state that, in combination with a “second hit” such as infection or an inflammatory insult from lupus itself, gives rise to an intravascular clot. Tissue infarction, hemorrhage, or more limited focal neuron injury results from impaired blood flow, and the actual clinical symptoms that develop from the ischemic insult depend on the location, duration, and degree of vascular compromise. Stroke, transient ischemic attacks, and cognitive decline in association with recurrent microvascular ischemia are manifestations of NPSLE associated with antiphospholipid antibodies. Mechanistically, antiphospholipid antibodies may block β₂ GPI–mediated inhibition of von Willebrand factor–dependent platelet adhesion and aggregation and thus inhibit a physiologic anticoagulant property of β₂ GP1.⁴ Antiphospholipid antibodies also contribute to the vascular damage of NPSLE by promoting the development of atherosclerosis independent of the other mechanisms accelerating atherosclerosis in lupus. Antiphospholipid antibodies potentiate the formation of foam cells by facilitating uptake by macrophages of oxidized low-density lipoprotein (LDL).⁵ Additionally, they upregulate endothelial cell expression of adhesion molecules, facilitating the egress of circulating monocytes from the blood into the vessel walls, where they subsequently transform into LDL-uptaking macrophages.⁶

Central Nervous System Mechanisms

The brain parenchyma may be the target of autoantibodies, cytokines, and infiltrating cells, resulting in either diffuse or focal injury. Behavioral, cognitive, or mood disorders, psychosis, and an acute confusional state are examples of syndromes attributed to diffuse pathophysiology; focal injury is associated primarily with vascular disease, but focal seizures may also result from parenchymal disease. Brains of young MRL/lpr mice show mononuclear cell infiltrates within the choroid plexus, hippocampus, meninges, and cerebellum.^7,⁸ As these mice age, CD19⁺ B cells and CD138⁺ plasma cells are present, and the brain tissue shows atrophy and decreased branching of neuronal dendritic spines. Cerebrospinal fluid (CSF) from both MRL/lpr mice as well as from patients with SLE may be toxic to neurons.^9,¹⁰ However, many of the CNS NPSLE syndromes are not permanent, raising the possibility that neuronal injury may not always be lethal and that neural reparative mechanisms are operative.

Cytokines and Chemokines

Cytokines and chemokines are small molecules which may play a role in the pathophysiology of CNS NPSLE. Elevations of these proteins have been demonstrated within the CSF of patients with CNS NPSLE. They may gain access to the CNS from the peripheral circulation through a permeabilized BBB or be produced within the CNS by astrocytes and microglia. Cytokines have directs effects on endothelial cells and neurons, causing dysfunction and apoptosis. In mice, proinflammatory cytokines are linked to depression, anhedonia, social isolation, and lethargy; in humans, similar associations exist.¹¹^–¹⁴

Examination of CSF of patients with NPSLE has shown the presence of multiple proinflammatory cytokines, including interleukin-6 (IL-6), IL-1, tumor necrosis factor (TNF), interferon alpha (IFN-α), B cell–activating factor (BAFF), and APRIL (a proliferation-inducing ligand ) (reviewed in reference 15). Intrathecal elevation of IL-6 is consistently reported in studies of NPSLE and is present in studies of patients with central NPSLE syndromes. Numerous inflammatory conditions, autoimmune diseases, and neurologic conditions, such as CNS infections, cerebrovascular events, and myelitis, also cause increased levels of intrathecal IL-6 and must be clinically excluded before a CSF IL-6 elevation is attributed to NPSLE. Intrathecal IL-6 in NPSLE is associated with the CSF IgG Index, a measurement of intrathecal immunoglobulin (Ig) G production suggesting that IL-6 in concert with BAFF and APRIL, which are also elevated in CSF from patients with diffuse NPSLE, may increase B-cell activation within the CNS.^16,¹⁷ BAFF is a potent B-cell activator that plays a role in the regulation of B-cell proliferation and differentiation.

IFN-α, also demonstrated in the CSF of patients with NPSLE, is of particular interest in the pathophysiology of NPSLE, given its ability to promote an autoimmune response and its recognized role in the etiopathogenesis of SLE.^18,¹⁹ Immune complexes created with NPSLE CSF in combination with nucleic acid–containing antigen stimulate release of IFN-α and other proinflammatory molecules (IFN-γ–induced protein 10 [IP-10], IL-8, and monocyte chemoattractant protein-1 [MCP-1]) ex vivo.¹⁹ Indirect support for the role of IFN-α in NPSLE comes from the untoward side effects of this cytokine when used as a therapeutic modality for treatment of hepatitis or malignancy; approximately one third of patients receiving IFN-α exhibit CNS symptoms.²⁰ The most common feature is depression, but psychosis, confusion, mania, and seizures have also been reported. Of note, IL-6 may potentiate the depressive propensity of IFN-α because high serum levels of IL-6 prior to administration of IFN-α predict the development of depression.²¹

Levels of chemokines such as IL-8, IP-10, fractalkine, RANTES (regulated upon activation, normal T-cell expressed, and secreted), MCP-1, and matrix metalloproteinase 9 (MMP-9) are additionally elevated in NPSLE CSF.^16,²²^–²⁴ Although these molecules are all capable of triggering inflammatory responses, the pathophysiologic mechanism(s) by which they cause CNS symptoms remains to be elucidated. The intrathecal ratio of IP-10 to MCP-1 is significantly higher in patients with NPSLE than in patients with SLE without CNS symptoms and may be a useful marker of NPSLE.²⁵ Because multiple cytokines and chemokines are present in the CSF of patients, studying the effects of a single mediator is difficult and may, in fact, not be as informative as the examination of various combinations.

Autoantibodies

Tissue injury in SLE is generally initiated by autoantibodies; thus, the role of autoantibodies in the pathogenesis of CNS NPSLE syndromes continues to be an area of interest. Pathology may potentially result from direct binding of antibodies to cells, from effects of activation of complement and the inflammatory cascade, or from antibody-dependent cellular cytotoxicity. It is likely that numerous antibodies are involved in the pathogenesis of NPSLE.

Antineuronal antibodies were the first autoantibodies identified and studied for a potential pathophysiologic role in NPSLE. However, NPSLE symptoms do not correlate with serum titers of these antibodies, and there are no identified functional effects of antibody binding to neurons in vitro. Immunoproteomic assays that have been used with neuroblastoma lines or brain to probe for specific brain antigens recognized by autoantibodies in lupus sera have identified several neuronal targets.^26,²⁷ Sera from patients with and without NPSLE react with neuronal antigens; however, the specificities of these antineuronal antibodies in the two clinical groups are different.²⁷ These data suggest that some antineuronal autoantibodies are associated with neuropathology and others are not.

Alpha-tubulin has been recognized as a targeted autoantigen in SLE, particularly in patients with severe CNS manifestations of NPSLE.²⁸ Longitudinal observational studies of patients with and without these autoantibodies remain to be conducted.

In addition to their prothrombotic properties, earlier studies suggested that antiphospholipid and anti–β₂ GPI antibodies have direct effects on brain parenchyma and may influence neuronal function (reviewed in reference 29). In one study, binding of these antibodies to neuronal cell membranes had depolarizing and permeabilizing effects on synaptosomes.³⁰ However, these reports have not been confirmed or extended, and whether antiphospholipid antibodies are directly neurotoxic remains unclear.

Serum and CSF anti–ribosomal P (anti-P) antibodies occur infrequently in SLE. When first described, they were reported to be associated with lupus psychosis.³¹ They are now recognized to occur with multiple features of lupus, including, in some but not all reports, thought and mood disorders.^32,³³ Anti-P antibodies have also been shown to disrupt olfaction and cause depression in a mouse model of direct intrathecal injection of the antibodies.^34,³⁵ In these studies, autoantibodies bound to neurons in the hippocampus, cingulate cortex, and olfactory piriform cortex. It is noteworthy that in humans, an impaired sense of smell is associated with lupus disease activity as well as a past history of NPSLE.³⁶ In vitro, anti-P antibodies are toxic to neurons. They bind a neuronal integral membrane protein, resulting in a rapid and sustained influx in calcium into the neuron with subsequent apoptotic cell death.

Antibodies to the N-methyl-D-aspartate receptor (NMDAR) are likely to play a pathophysiologic role in cognitive and emotional dysfunction in SLE. Anti-NMDAR autoantibodies are a subset of anti–double-stranded DNA (dsDNA) autoantibodies that cross-react with the NR2A and B subunits of the glutamate receptor.³⁷ Binding of anti-DNA, anti-NMDAR antibodies to neurons can lead to excitatory, apoptotic, and noninflammatory cell death, but the effects of anti-NMDAR antibody binding are concentration dependent. Lower antibody concentration affects synaptic plasticity and results in temporary neuronal dysfunction without death.³⁸ The NMDAR is found throughout the brain but is most dense in the hippocampus and amygdala, areas associated with learning and affective responses, respectively. Nonautoimmune mice that are immunized to produce anti-DNA, anti-NMDAR antibodies display no behavioral abnormalities and show no neuronal loss despite the presence of circulating anti-NMDAR antibodies.³⁹ Although seemingly counterintuitive, this observation is consistent with our knowledge of the BBB, which protects the brain parenchyma against potentially toxic substances in the bloodstream (see later). Breach of the BBB in either the hippocampus or the amygdala of these immunized, nonautoimmune mice results in regional loss of neurons in the hippocampus or amygdala, respectively, and leads to associated behavior abnormalities (impaired learning in mice with a breach of the BBB in the hippocampus and attenuated responses to a fear-conditioning paradigm in mice with a breach in the BBB in the amygdala).^39,⁴⁰ Approximately 25% to 50% of patients with lupus exhibit elevated titers of anti-NMDAR antibody. Although cross-sectional studies have not shown a consistent correlation between serum anti-NMDAR antibodies and cognitive impairment or depression, the antibodies have been detected in CSF of patients with lupus and have been eluted from lupus brain tissue.^37,⁴¹^–⁴⁵ Several studies of CSF anti-NMDAR antibody titers show a significant correlation between antibody titers and central, diffuse NPSLE syndromes (seizures, acute confusional state, mood and anxiety disorders, psychosis, severe cognitive dysfunction).⁴⁶ Titers subside concomitant with a decrease in symptoms. Furthermore, the presence of CSF anti-NMDAR antibody helps distinguish patients with diffuse NPSLE from patients without NPSLE.