A novel experimental approach in treating central nervous system lupus: Kudos and Kicks

Abstract

More than 1 million North Americans are affected by the autoimmune disease systemic lupus erythematosus (SLE) (1). Up to 70% of patients with SLE experience central nervous system (CNS) manifestations that differ in onset, severity, and presentation (2). Despite advances in diagnosis and classification, little is known about the pathogenic mechanisms that account for the high rates of depression, anxiety, psychosis, and neurologic and cognitive deficits (3). Animal models have been shown to be an indispensable tool for understanding the nature of SLE in general, and of CNS lupus in particular (4). Some recent experimental findings relevant for the development of novel diagnostic/ treatment modalities include cerebrospinal fluid cytotoxicity, vulnerability of limbic structures, and the role of brain-reactive antibodies in the induction of brain damage (5–7). In this issue of Arthritis & Rheumatism, Lapter and colleagues (8) report that immunization with the synthetic tolerogenic peptide hCDR1 (human first complementarity-determining region) prevents CNS pathology and behavioral dysfunction in the NZB/NZW mouse model of CNS lupus. A series of dependent measures were taken at the level of central cytokine production, brain histology, and behavioral performance. Consistent with the results of a study that examined kidney pathology in mice with lupus (9), the overall conclusion was that repeated immunization with the hCDR1 peptide over 10 weeks led to the amelioration of central manifestations induced by SLE-like disease. In particular, this treatment reduced infiltration of CD3 T cells and immune complex deposition in the brains of lupus-afflicted mice. It also reduced diseaseinduced gliosis, as revealed by reduced glial fibrillary acidic protein expression in the hippocampus. More importantly, diseased NZB/NZW mice showed a significant loss in neuronal nuclei immunoreactivity, which was fully restored after sustained hCDR1 treatment. The expression of messenger RNA (mRNA) for interleukin-1 (IL-1), IL-6, interferon-, IL-10, and transforming growth factor was elevated in the hippocampi of diseased mice but was significantly downregulated in the peptide-treated group. Increased TUNEL staining has previously been documented in the brains of lupus-prone MRL/lpr mice, suggesting enhanced apoptotic cell death during disease development (10). Consistent with this hypothesis, the present study revealed increased mRNA and protein levels of caspase 8 and reduced expression of the antiapoptotic molecule Bcl-xL in the brains of lupusaffected NZB/NZW mice. As observed for other measures, the expression of these apoptosis-related molecules was normalized after immunizations with hCDR1. At the behavioral level, performance in anxiety-related and memory-dependent tasks was improved in immunized mice, further supporting the notion that preserved structural integrity is accompanied by functional CNS recovery. The authors hypothesize that beneficial mechanisms involve inhibition of T cell receptor signaling following peptide binding to class II major histocompatibility complex, induction of CD4CD25 regulatory T cells, and reduction of apoptosis. Taken together, the results obtained implicate a cascade of pathologic events involving an imbalanced local cytokine network, T cell infiltration, and complement system activation. One may infer that these events jointly result in enhanced apoptosis, which is preventable by repeated immunizations with hCDR1. Although such an interpretation is consistent with the current state of knowledge, it can be challenged by novel develop