Behavioral Changes in Systemic Lupus Erythematosus are of an Autoimmune Nature

Rael D Strous; Yehuda Shoenfeld

Disclosures

Nat Clin Pract Rheumatol. 2007;3(11):592-593. 

Neuropsychiatric manifestations are present in approximately 70% of patients with systemic lupus erythematosus (SLE). Some patients also demonstrate signs of central nervous system (CNS) involvement, identified by neuroimaging and post-mortem.[1] Approximately 20 different manifestations of behavioral disorders have been described in SLE. Although the precise nature and pathophysiology of these neuropsychiatric manifestations remain unknown, they might be associated with SLE disease-specific features and medication, as well as primary neurological and psychiatric disorders. Since many of the signs and symptoms of SLE can be attributed to the large number of identified autoantibodies, it would be reasonable to expect the same in neuropsychiatric SLE (NPSLE).[1] Thus, increasing evidence suggests a role for autoimmune factors in contributing to neuropsychiatric expressions via direct and indirect autoantibody-induced neuronal damage.

Our group has recently identified a number of autoantibodies reported to be associated with, or specific to, NPSLE.[2] Overall, 20 autoantibodies have been identified, but no specific neuropsychiatric manifestation has been associated with the full autoantibody list. Various autoantibody subtypes have been identified that target brain-specific antigens, including neuronal, N-methyl-D-aspartate (NMDA) receptor and lymphocytotoxic subtypes. Systemic antigens consist of subtypes specific to nuclear, cytoplasmic, phospholipid, and endothelial cell substrates. The most common behavioral expressions associated with these autoantibodies are cognitive impairment, psychosis, and depression (see supplementary online information). Specifically, psychosis has been associated with 8 autoantibodies. Although there does not seem to be any specificity among autoantibodies for any single behavioral manifestation, detection of autoantibodies could be helpful for the diagnosis of NPSLE.

Hypothetical mechanisms of the involvement of autoantibodies in NPSLE, based on experimental models, include vascular occlusion and local injury caused by pathogenic autoantibodies.[3] Vascular occlusion contributing to CNS-related ischemia is mediated by thrombotic capillary occlusion in combination with mild inflammation, endothelial activation and prothrombotic states and atherosclerosis.[2] Many of these autoantibodies might contribute to NPSLE pathogenesis by non-ischemic mechanisms, including the inhibition of astrocyte proliferation and nonspecific permeabilization and depolarization of synaptoneurosomes. A further mechanism includes cerebrovascular endothelial injury, whereby blood-brain-barrier (BBB) permeability is increased, enabling access of pathogenic autoantibodies into the brain, an area usually sheltered from harmful immune-response effects.[3] These autoantibody-mediated CNS lesions lead to NPSLE behavioral symptoms similar to other CNS disorders with autoimmune phenomena.

Specific attention has focused upon the prominent role that autoantibodies against ribosomal P proteins have in NPSLE. The anti-ribosomal P antibodies are members of a polyspecific population of autoantibodies that target three highly conserved ribosomal phosphoproteins. The anti-ribosomal P antibody is specific to SLE with a prevalence of 6-36% and is detected predominantly during active disease.[4]

High anti-ribosomal P titers in SLE have been observed particularly with psychosis and depression.[5] Since passive transfer of anti-ribosomal P might assist in determining whether an autoantibody can directly induce behavioral changes, we recently injected mice intracerebroventricularly with anti-ribosomal P in a forced swimming depression-paradigm.[6] This allowed examination of antibody behavioral effects and the specificity of these effects to pharmacologic and immunologic treatments. Results indicated that anti-ribosomal P induces depression-like behavior that was blocked by a specific anti-idiotypic antibody. The anti-ribosomal P staining pattern localized to the limbic system is highly suggestive of the autoantibody's causative role in inducing affective changes since these are areas prominently implicated in depression. Long-term administration of the antidepressant fluoxetine averted depression; however, when administered for nontherapeutic lengths of time, this failed to provide such protection.

Interestingly, the anti-P antibody localized to regions is associated with olfaction. This is particularly significant since one of the principal animal models used in depression research is rodent olfactory bulbectomy, which mimics biological and behavioral aspects of depression including immunological perturbations.[7] The observation that an autoantibody commonly found in SLE specifically binds the olfactory cortex, which is associated with depression, corroborates the role of the limbic-olfactory pathway in depression. Whether this association might have value in the management of comorbid depression and NPSLE remains to be validated. Many complex connections exist between the immune and nervous systems, and there seem to be novel features of the olfactory system that are linked to immunologic function and autoimmune conditions. Furthermore, olfactory dysfunction is often prominent at early stages in various neurological conditions (e.g. multiple sclerosis, Alzheimer's disease, Parkinson's disease, schizophrenia).[8] Although olfactory function is impaired in varying degrees in NPSLE (Y Shoenfeld, unpublished data), the precise origin of this dysfunction is unclear and might be a manifestation of direct or indirect illness effects. The possibility exists that it is a secondary outcome of other limbic area involvement, such as the amygdala, where recent research has indicated selective damage in SLE models mediated via anti-NMDA autoantibodies.[9] This amygdala neuronal loss would also lead to abnormalities in emotion regulation in SLE, including modulation of stress, fear, and depression. This is exciting data because it indicates autoantibody effects on the limbic system that alter emotions. It might alternatively be suggested that altering emotions with stress affects the BBB, increasing its permeability by means of catecholamine release. This would lead to increased vulnerability of specific CNS structures to various autoantibodies because of a breached BBB, resulting in NPSLE. Incidentally, a parallel process of amygdala "degeneration" in stress might be mediated via increased corticosteroids, either by direct or indirect effects. Since the amygdala is clearly linked anatomically and physiologically to olfactory function,[10] such amygdala damage might also lead to impaired olfactory function.

Although the mechanism of anti-ribosomal-P-antibody-induced depression at the molecular level is unknown, it might be mediated via binding to cells (not to ubiquitous intracellular ribosomal P protein but rather to surface antigens) followed by penetration in a process that is Fc-independent (Fab-mediated). The surface antigen acts as a receptor, and its modulation by autoantibodies would influence limbic structures, potentially inducing depression. This process, ultimately resulting in inhibition of protein synthesis and apoptosis, would predict selective neuronal loss in the piriform, cingulate, and hippocampus. Evidence from the above study yields potentially vital information, since it reflects the first evidence of an experimental depression induced by a specific autoantibody involving the olfactory and limbic regions related to NPSLE. The process is important, since revealing how anti-ribosomal P induces behavioral changes might assist in the development of novel treatments for conditions involving the CNS in SLE.[8]

The importance of optimally managing NPSLE illness cannot be overstated. This applies not only to factors regarding quality of life; recent research suggests that depression severity is associated with SLE disease activity, which implies that management of depression might mitigate SLE severity. Further research is warranted in order to further our understanding of NPSLE and, more importantly, to alleviate illness in this long-suffering patient population.


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