Antibodies and Brain Disease: A Convergence of Immunology and Physiology

I ncreasingly, patients with systemic lupus erythematosus (SLE) are recognized to have central nervous system (CNS) manifestations. Overt infl ammation in the CNS is rare, but impairment of cognition or mood disturbance is common. Treatment of infl ammation is directed at the underlying autoimmune disorder; treatment of other manifestations, including mood disorder, often focuses on symptom alleviation. Cognitive impairment in particular appears to be progressive and unrelated to disease activity, and, at the present time, untreatable. One interesting aspect of neuropsychiatric lupus is that symptoms may remit as well as progress. With no known pathophysiology for the cognitive impairment or mood disturbance seen in SLE, and no ability to track the dynamic state of either of these symptom complexes, it has been diffi cult to develop a meaningful classifi cation of neuropsychiatric SLE or a mechanistic understanding of these aspects of the disease process. There is possible mechanistic precedent for neuropsychiatric lupus in a number of disease syndromes in which anti-neuronal antibodies cause damage in the CNS. Often these antibodies arise as a consequence of microbial infection and cross-react with microbial antigens, as in post-streptococcal movement disorders [1], post-infectious polyradiculopathies [2], and tropical spastic paraparesis [3]. Recently, a novel pathophysiology for cognitive decline and mood disorder in SLE has been proposed: cross-reacting anti-DNA, anti-N-methyl-D-aspartate receptor (NMDAR; see Glossary) antibodies mediating neuronal damage or death. These antibodies bind a 5–amino acid epitope D/E W D/E Y S/G in the extracellular domains of the NR2A and NR2B subunits of the NMDAR [4–9]. Emerging clinical information about the frequency of these anti-DNA, anti-NMDAR antibodies in patients with SLE suggests that 30%–50% of patients have these antibodies [10–14]. In one longitudinal study, brain dysfunction correlated with the presence of antibody to DWEYS peptide in the cerebrospinal fl uid, and symptom severity correlated with antibody titer [10]. But cross-sectional analyses of neuropsychological function and serum anti-NMDAR antibody levels have yielded confl icting data [11–13]. Two studies found a signifi cant correlation between anti-NMDAR antibodies and depression [12,13] and one study found a correlation with neuropsychiatric disease manifestations [10]. Another study failed to show a correlation between anti-NMDAR antibodies and disease manifestations [11]; however, these investigators required more extensive cognitive impairment for diagnosis. In a new study in PLoS Medicine, Emmer and colleagues attempted to test whether the presence of the anti-NMDAR antibody correlates with brain abnormality [15]. The abnormality was assessed by an emerging quantitative …