Association of IgG anti‐NR2 glutamate receptor antibodies in cerebrospinal fluid with neuropsychiatric systemic lupus erythematosus

Yoshio, Taku; Onda, Koichi; Nara, Hiroyuki; Minota, Seiji

doi:10.1002/art.21547

Cited by 142 publications

(113 citation statements)

References 11 publications

(10 reference statements)

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“…Mice immunized with a multimerized configuration of DWEYS produce antidsDNA/NMDAR antibodies, display glomerular Ig deposition, and exhibit neuronal damage after a breach of the blood-brain barrier (BBB) that allows transit of these antibodies into the CNS (17). In humans, elevated titers of cross-reactive anti-dsDNA/ NMDAR antibodies are present in the serum of 40% of lupus patients and their presence in CSF of lupus patients correlates with CNS manifestations of neuropsychiatric lupus (NPSLE), which afflicts up to 80% of lupus patients (15,(18)(19)(20)(21)(22). Moreover, human anti-dsDNA/NMDAR antibodies have been eluted from postmortem brain tissue, and such antibodies isolated from lupus patient sera can cause brain damage (e.g., cognitive or behavioral dysfunction) in mice (23,24).…”

mentioning

confidence: 99%

Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity

Bloom

Cheng

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of pathogenic autoantibodies, many of which are directed against nuclear antigens, in particular double-stranded (ds) DNA. Both clinical studies and animal models have shown that anti-dsDNA antibodies contribute to kidney disease, which is present in 50% of lupus patients and is a major cause of mortality. We previously demonstrated that a subset of nephrotoxic anti-dsDNA antibodies also recognizes the pentapeptide consensus sequence D/E W D/E Y S/G (DWEYS) present in the NR2A and NR2B subunits of the N -methyl- d -aspartate receptor (NMDAR). Autoantibodies with this specificity are present in ≈40% of lupus patient sera and are both nephrotoxic and neurotoxic. Elevated titers are present in cerebrospinal fluid of patients with central nervous system manifestations of SLE. Administration of the nonnaturally occurring D form of the DWEYS pentapeptide prevents these antibodies from depositing in glomeruli and from mediating neuronal excitotoxicity. To craft a more useful therapeutic, we used the structural features of the DWEYS peptide to design a unique, selective, and potent small molecule peptidomimetic, FISLE-412, which neutralizes anti-dsDNA/NMDAR lupus autoantibodies and prevents their pathogenic interaction with tissue antigens. This compound, or others derived from it, may provide a unique strategy for the development of lupus therapeutics.

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confidence: 99%

Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity

Bloom

Cheng

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Of note, Yoshio et al have recently reported that CSF levels of anti-NR2 antibody were increased in SLE patients with neurologic syndromes involving the CNS, but not in those with diffuse psychiatric/neuropsychological syndromes alone, compared with SLE patients without neuropsychiatric involvement (15). Those investigators measured anti-NR2 using an ELISA with the synthetic DWEYSVWLSN peptide conjugated to BSA as antigen (15).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, subtracting the binding activity of these carrier proteins would be mandatory in order to determine specific activities of antibodies to peptides conjugated to carrier proteins, including BSA and HSA (16). However, Yoshio and colleagues did not subtract BSA binding activity (15), and it is thus highly likely that the presence of anti-BSA antibodies might have significantly influenced their results and conclusions. Therefore, it remained unclear from their study whether CSF anti-NR2 might be associated with diffuse or focal NPSLE.…”

Section: Discussionmentioning

confidence: 99%

Association of cerebrospinal fluid anti–NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus

Arinuma¹,

Yanagida²,

Hirohata³

2008

Arthritis & Rheumatism

221

130

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Results. Purified anti-NR2 bound to the surface of SK-N-MC cells. Levels of anti-NR2 antibodies in CSF were significantly elevated in patients with diffuse NPSLE compared with levels in control patients or those with focal NPSLE, whereas there were no significant differences in serum anti-NR2 levels among the 3 groups. In 31 of the 38 patients with diffuse NPSLE (81.6%) and 8 of the 18 patients with focal NPSLE (44.4%), CSF anti-NR2 levels were more than 3 SD above the mean level in the control patients (P ‫؍‬ 0.0120 by chi-square test). Conclusion.These results indicate that anti-NR2 is a constituent of antineuronal antibodies and, more importantly, that anti-NR2 antibodies in CSF, but not in serum, are associated with diffuse NPSLE.

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“…However, we did not store CSF samples from our NPSLE patients, and we are therefore unable to assess the presence of autoantibodies against the discriminant antigens in CSF or to compare serum and CSF self-IgG reactivities against MS and healthy brain tissues. CSF studies could help in elucidating the pathophysiologic mechanism of these antigenic targets (18), and we plan to collect both sera and CSF from all new patients with NPSLE. For the same reason, we were unable to assess levels of cytokines and chemokines in CSF.…”

Section: Discussionmentioning

confidence: 99%

“…However, while it is well established that autoantibodies can directly damage organs, especially the kidney (13), brain antigenic targets have not been fully identified in NPSLE. Several investigators have sought to identify autoantibodies that could bind directly to neurons and could serve as diagnostic markers in NPSLE (14)(15)(16)(17)(18)(19). Recently, sera collected from patients with SLE were tested for the presence of antibodies to microtubuleassociated protein 2 (MAP-2) and were detected in NPSLE patients in particular (20).…”

mentioning

confidence: 99%

Characterization of discriminant human brain antigenic targets in neuropsychiatric systemic lupus erythematosus using an immunoproteomic approach

Lefranc¹,

Launay²,

Dubucquoi³

et al. 2007

Arthritis & Rheumatism

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Objective. To characterize discriminant human brain antigenic targets in patients with neuropsychiatric systemic lupus erythematosus (NPSLE), using a standardized immunoproteomic approach.Methods. Self-IgG reactivity against normal and injured human brain tissues was studied by Western blotting of sera from 169 subjects, 16 patients with NPSLE, 12 patients with SLE without neuropsychiatric manifestations (non-NPSLE), 32 patients with Sjö-gren's syndrome with or without central nervous involvement, 82 patients with multiple sclerosis, and 27 healthy subjects. A proteomic approach was then applied to characterize discriminant antigens identified after comparisons of all patterns.Results. The serum self-IgG reactivity patterns against human brain tissue differed significantly between patients with NPSLE and the control groups. Four normal brain antigenic bands were specifically or preferentially recognized by sera from NPSLE patients (p240, p90, p77, and p24). Protein band p240 was characterized as microtubule-associated protein 2B (MAP-2B), p77 as Hsp70-71, and p24 as triosephosphate isomerase. Protein band p90 was not characterized. In contrast, 1 other protein band (p56, characterized as septin 7) was never recognized by sera from NPSLE patients but was recognized by a majority of sera from non-NPSLE patients.Conclusion. Our findings show that the immunoproteomic approach is a reliable method for assessing serum self-IgG reactivities against human brain tissue in NPSLE. Our characterization of some of the identified discriminant antigens, such as MAP-2B, triosephosphate isomerase, and septin 7, suggests that the stability of neuronal microtubules might be involved in the pathophysiology of NPSLE.

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Association of IgG anti‐NR2 glutamate receptor antibodies in cerebrospinal fluid with neuropsychiatric systemic lupus erythematosus

Cited by 142 publications

References 11 publications

Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity

Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity

Association of cerebrospinal fluid anti–NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus

Characterization of discriminant human brain antigenic targets in neuropsychiatric systemic lupus erythematosus using an immunoproteomic approach

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