Cognitive impairment occurs in 40-90% of patients with systemic lupus erythematosus (SLE), which is characterized by autoantibodies to nuclear antigens, especially DNA. We discovered that a subset of anti-DNA antibodies, termed DNRAbs, cross reacts with the N-methyl-d-aspartate receptor (NMDAR) and enhances NMDAR signaling. In patients, DNRAb presence associates with spatial memory impairment. In a mouse model, DNRAb-mediated brain pathology proceeds through an acute phase of excitotoxic neuron loss, followed by persistent alteration in neuronal integrity and spatial memory impairment. The latter pathology becomes evident only after DNRAbs are no longer detectable in the brain. Here we investigate the mechanism of long-term neuronal dysfunction mediated by transient exposure to antibody. We show that activated microglia and C1q are critical mediators of neuronal damage. We further show that centrally acting inhibitors of angiotensin-converting enzyme (ACE) can prevent microglial activation and preserve neuronal function and cognitive performance. Thus, ACE inhibition represents a strong candidate for clinical trials aimed at mitigating cognitive dysfunction.

Objective. To define the antiphospholipid score (aPL-S) by testing multiple antiphospholipid antibodies (aPL) and to evaluate its efficacy for the diagnosis of antiphospholipid syndrome (APS) and predictive value for thrombosis.Methods. This study comprised 2 independent sets of patients with autoimmune diseases. In the first set of patients (n ‫؍‬ 233), the aPL profiles were analyzed. Five clotting assays for testing lupus anticoagulant and 6 enzyme-linked immunosorbent assays (IgG/ IgM anticardiolipin antibodies, IgG/IgM anti-␤ 2 -glycoprotein I, and IgG/IgM phosphatidylserine-dependent antiprothrombin antibodies) were included. The association of the aPL-S with a history of thrombosis/ pregnancy morbidity was assessed. In the second set of patients (n ‫؍‬ 411), the predictive value of the aPL-S for thrombosis was evaluated retrospectively. Two hundred ninety-six of these patients were followed up for >2 years. The relationship between the aPL-S and the risk of developing thrombosis was analyzed.Results. In the first set of patients, the aPL-S was higher in those with thrombosis/pregnancy morbidity than in those without manifestations of APS (P < 0.00001). For the aPL-S, the area under the receiver operating characteristic curve value was 0.752. In the second set of patients, new thromboses developed in 32 patients. The odds ratio (OR) for thrombosis in patients with an aPL-S of >30 was 5.27 (95% confidence interval [95% CI] 2.32-11.95, P < 0.0001). By multivariate analysis, an aPL-S of >30 appeared to be an independent risk factor for thrombosis (hazard ratio 3.144 [95% CI 1.383-7.150], P ‫؍‬ 0.006).Conclusion. The aPL-S is a useful quantitative index for diagnosing APS and may be a predictive marker for thrombosis in autoimmune diseases.

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Patients with demyelinating NPSLE should be tested for IgG antibodies to AQP-4, MOG, and DWEYS. IgG anti-AQP-4 can be considered diagnostic for NMOSD, whereas none of these antibodies appear to be diagnostic for demyelinating NPSLE. Moreover, IgG anti-dsDNA are present in patients with NMOSD but are not cross-reactive with IgG anti-DWEYS, indicating that the antigenic stimulus and mechanisms of tissue damage are potentially different between demyelinating NPSLE and NMOSD.

The brain is normally sequestered from antibody exposure by the blood brain barrier. However, antibodies can access the brain during fetal development before the barrier achieves full integrity, and in disease states when barrier integrity is compromised. Recent studies suggest that antibodies contribute to brain pathology associated with autoimmune diseases such as systemic lupus erythematosus and neuromyelitis optica, and can lead to transient or permanent behavioral or cognitive abnormalities. We review these findings here and examine the circumstances associated with antibody entry into the brain, the routes of access and the mechanisms that then effect pathology. Understanding these processes and the nature and specificity of neuronal autoantibodies may reveal therapeutic strategies toward alleviating or preventing the neurological pathologies and behavioral abnormalities associated with autoimmune disease.