Discoveries in the pathophysiology of neuropsychiatric lupus erythematosus: consequences for therapy

To understand if the 16/6 Id IgG antibody is able to induce neurological effects, Kivity et al. compared the cognitive and behavioral performance of C3H female mice that had been injected with the human 16/6 Id IgG antibody (16/6 Id mice subset) and those injected with a commercial human IgG (control mice subset) [6]. Visual-recognition memory was assessed by using the novel-object recognition test. The authors found that there was a significant preference for attention to the new object compared with the old object by the control mice, but no difference in preference was found between the new and the old objects by the 16/6 Id mice. This result indicates impairment of visual-recognition memory in the 16/6 Id mice. In the Y-maze test, which assesses spatial memory, the 16/6 Id mice were also found to have impairment of spatial memory.

In addition, the brain pathology of these mice was examined to establish the potential mechanism by which the 16/6 Id IgG antibody is able to exert its neurological effects. In the brain tissue, increased microglial activation was seen in the hippocampus and amygdala, but not in the neurocortex or piriform cortex. In addition, the number of astrocytes in the hippocampus was found to be increased. Taken together, these results show that in mice, the 16/6 Id antibody causes impairment of both visual and spatial memory through hippocampal injury, and might selectively cross-react with some antigens in the hippocampus.

Kivity et al. also showed that, in addition to the anti-ribosomal P and anti-NR2 antibodies, another autoantibody, anti-16/6 Id antibody, can cross-react with human brain tissue and cause NPLE symptoms in SLE [6]. Brain tissue-reactive antibodies in NPLE are thought to be synthesized in the CNS or peripheral organs, such as the lymph nodes and bone marrow [10]. Therefore, if NPLE is associated with antibodies reaching the CNS through the BBB, treatments that not only eliminate brain-tissue-reactive antibodies but also protect the integrity of the BBB should be considered.

Therapy of NPLE is currently difficult. Although corticosteroids and immunosuppressive agents, such as cyclophosphamide, are broadly effective for NPLE, the condition is occasionally refractory to these treatments. Moreover, brain-tissue-reactive autoantibodies might cause irreversible neuronal degeneration via apoptosis. For instance, anti-ribosomal P antibody targets a neuronal surface protein, causing calcium influx and apoptosis [11]. These antibodies specifically bind to neurons in the hippocampus, cingulate cortex, and the primary olfactory piriform cortex, and, in mice, resulted in the induction of depression. These results implicate the olfactory and limbic areas in the pathogenesis of depression in SLE [12]. The anti-NR2 antibody also causes neuronal cell apoptosis, impairs the hippocampus-dependent memory function in mice, stimulates NMDA receptor-mediated synaptic responses and excitotoxicity through enhanced mitochondrial permeability [13]. and decreases cell viability through increased Ca²⁺ influx [5]. Kivity et al. showed that the anti-16/6 Id antibody hampers visual-recognition and spatial memory. Their hypothesis about the pathophysiology of anti-16/6 Id antibody-induced brain involvement was that brain inflammation induces modification of neuronal function and neuronal degeneration [6]. The authors also found increases in astrocyte number and microglial activation in the hippocampus of anti-16/6 Id antibody-injected mice. They suggested that increased astrocytes and activated microglial cells were involved in brain inflammation and therefore, an inflammatory process may affect cognitive impairment in mice injected with anti-16/6 Id antibody. By contrast, there was minimal local activation of astrocytes and microglial cells, and no lymphocytic inflammation in the brains of anti-NR2 antibody-injected mice [3].

It is plausible, therefore, that the wide variety of NPLE syndromes might be caused by differences in the recognition of brain tissue by lupus autoantibodies, such as anti-ribosomal P, anti-NR2, and anti-16/6 Id antibodies. Identification and evaluation of such differences would perhaps be useful in developing therapies for NPLE.

In the future, it is hoped that new agents will be developed to improve the prognosis for NPLE. The efficacy of such new agents should be determined through their ability to protect neuronal cells, modulate intracellular Ca²⁺, or regulate the deposition of autoantibodies in NPLE. Memantine is a drug used to treat Alzheimer’s disease, which modulates intracellular Ca²⁺ by blocking NMDA receptors. In addition, the DWEYS pentapeptide, which the anti-NR2 antibody recognizes as an antigen, prevents the anti-NR2 antibody from being deposited in tissues and mediating neuronal excitotoxicity in mice [14].

As Kivity et al. have shown, several autoantibodies against brain tissue are involved in NPLE. Given the differences in the cross-reactivity of each autoantibody with the nervous system, this may explain the difference and diversity of the clinical features in NPLE. Investigators and clinicians should consider not only inhibition of autoantibody synthesis but also protection of neuronal cells when investigating treatment strategies for NPLE.