Symptoms originating from the central nervous system (CNS) occur frequently in patients with systemic lupus erythematosus (SLE), and CNS involvement in lupus is associated with increased morbidity and mortality. We recently showed that neurones and astrocytes are continuously damaged during the course of CNS lupus. The matrix metalloproteinases (MMPs) are a group of tissue degrading enzymes that may be involved in this ongoing brain destruction. The aim of this study was to examine endogenous levels of free, enzymatically active MMP-2 and MMP-9 in cerebrospinal fluid from patients with SLE. A total of 123 patients with SLE were evaluated clinically, with magnetic resonance imaging of brain and cerebrospinal fluid (CSF) analyses. Levels of free MMP-2 and MMP-9 were determined in CSF using an enzymatic activity assay. CSF samples from another 22 cerebrally healthy individuals were used as a control. Intrathecal MMP-9 levels were significantly increased in patients with neuropsychiatric SLE as compared with SLE patients without CNS involvement (P < 0.05) and healthy control individuals (P = 0.0012). Interestingly, significant correlations between MMP-9 and intrathecal levels of neuronal and glial degradation products were noted, indicating ongoing intrathecal degeneration in the brains of lupus patients expressing MMP-9. In addition, intrathecal levels of IL-6 and IL-8 two cytokines that are known to upregulate MMP-9 both exhibited significant correlation with MMP-9 levels in CSF (P < 0.0001), suggesting a potential MMP-9 activation pathway. Our findings suggest that proinflammatory cytokine induced MMP-9 production leads to brain damage in patients with CNS lupus.
Central nervous system (CNS) involvement has been reported to occur in 1475% of all systemic lupus erythematosus (SLE) patients. However, frequency rates vary considerably, depending on the diagnostic criteria applied. CNS lupus can occur at any time during the course of SLE, and its symptoms are diverse. The features of this condition can include seizures, stroke, depression, psychoses and disordered mentation. Neuropsychiatric involvement in SLE (NPSLE) has been shown to predict a high frequency of flares, and it is considered a major cause of long-standing functional impairment as well as a cause of mortality. Over the past decade CNS lupus has been treated with cytotoxic drugs, which improve disease outcome.
Because of the multiple pathogenic mechanisms that cause manifestations of CNS lupus, no single confirmatory diagnostic test is available. Several clinical, laboratory and radiographic test findings are reported to be abnormal in some but not all patients with CNS lupus. Magnetic resonance imaging (MRI) of brain has been shown to be valuable in detecting even minor lesions caused by CNS lupus, and these correlate with CNS manifestations in SLE. Pleocytosis and elevated protein levels are found in some but not all patients with CNS lupus. Elevated concentrations of IgG in cerebrospinal fluid (CSF), IgG:albumin ratio and IgG index, and the presence of oligoclonal bands have all been described with varying frequencies in patients with NPSLE. Few studies have demonstrated elevated IL-6 levels in CSF from patients with CNS lupus. Some other reports have described increased levels of IL-1, IL-8 and interferon-γ in CSF from patients with CNS lupus. We recently reported neuronal damage, astrogliosis and formation of toxic metabolic products such as Aβ42 in patients with NPSLE.
One of the prototypical destructive events in the human brain, initiated by the release of inflammatory cytokines and ending with tissue destruction, is production of matrix metalloproteinases (MMPs). The MMPs are a family of endopeptidases produced by a variety of inflammatory cells. All of the cell types that exist in the CNS are potential sources of MMPs. In vitro, neurones, astrocytes, microglia and oligodendrocytes express various MMP family members, and production of MMPs by neuronal cells can be upregulated by several inflammatory cytokines. MMPs have a multitude of regulatory functions, including control of influx of inflammatory mononuclear cells into the CNS, participation in myelin destruction and disruption of the integrity of the bloodbrain barrier. With respect to MMP-9, it was recently shown that CSF levels of this enzyme increase during bacterial meningitis and that it is associated with brain damage. The aim of the present study was to measure levels of free active MMP-2 and MMP-9 in CSF of SLE patients with CNS lupus, and to relate these data to clinical and laboratory measures of brain parenchymal degradation. Our results suggest that MMP-9 but not MMP-2 actively participates in brain destruction in CNS lupus.