Association of cerebrospinal fluid anti-ribosomal P protein antibodies with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus

Abstract

We explored the relationship of antibodies to the whole ribosomal P proteins (P0, P1, and P2) in cerebrospinal fluid (CSF) with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus (SLE). CSF samples were obtained from 71 SLE patients (52 patients with diffuse psychiatric/neuropsychological syndromes [diffuse NP-SLE] and 19 patients with neurological syndromes or peripheral neuropathy [focal NP-SLE]) as well as from 24 patients with non-inflammatory neurological disease. Immunoglobulin G (IgG) antibodies to the C-terminal 22-amino acid ribosomal P synthetic peptide (anti-P C22 ) and those to purified bovine ribosomal P proteins (P0, P1, and P2) (anti-whole P) were determined by enzyme-linked immunosorbent assay; affinitypurified IgG anti-P C22 were used as the standard. The concentrations of antibodies to epitopes other than the Cterminal 22 amino acids of ribosomal P proteins were calculated by subtracting anti-P C22 from anti-whole P (anti-P EX.C22 ). CSF anti-whole P levels were significantly elevated in diffuse NP-SLE compared with focal NP-SLE or control patients. By contrast, there were no significant differences in CSF anti-P C22 levels among the three groups. Of note, CSF anti-P EX.C22 levels were significantly elevated in diffuse NP-SLE compared with the other two groups. CSF anti-P EX.C22 levels were not significantly correlated with CSF anti-P C22 levels, but with CSF antibodies against the recombinant ribosomal P0 protein lacking the Cterminal 22 amino acids (C22-depleted rP0). Moreover, levels of CSF anti-P EX.C22 or CSF anti-C22-depleted rP0, but not CSF anti-P C22 , were significantly correlated with CSF anti-neuronal cell antibodies (anti-N). These results indicate that CSF IgG antibodies to the epitopes other than the C-terminal 22 amino acids of ribosomal P proteins, which might contain one of the major targets of CSF anti-N, are associated with the development of diffuse NP-SLE.

Differences in Regional Brain Activation Patterns Assessed by Functional Magnetic Resonance Imaging in Patients with Systemic Lupus Erythematosus Stratified by Disease Duration

“…This result reinforces our hypothesis that antibody-mediated neuronal damage in SLE requires interruption of the BBB; as a validated measure of organ damage in SLE, most of which is mediated by circulating inflammatory cytokines or autoantibodies, the DI would not be expected to reflect damage in an organ protected by the BBB. This result is supported by previous studies that have reported correlations between NPSLE and antibrain antibodies or cytokines in cerebrospinal fluid, as opposed to peripheral blood (6)(7)(8)(9) and studies showing that the progression of cognitive impairment is independent of disease activity.…”

“…However, these mechanisms do not account for the majority of symptom complexes associated with NPSLE-in particular, the insidious cognitive decline manifested by up to 80% of lupus patients and the common mood disorders. Recent studies have demonstrated direct neurotoxic effects of lupus autoantibodies; antibodies to n-methyl-D-aspartate receptor (NMDAR), ribosomal P (anti-P), α-tubulin and phospholipid have been shown to bind neurons ex vivo with harmful effects (1)(2)(3)(4)(5) and all have been identified in the cerebrospinal fluid of SLE patients with CNS symptoms attributable to SLE (6)(7)(8)(9). In murine studies, circulating antibrain antibodies can cause neuronal dysfunction and apoptosis after breach of the BBB (5,(10)(11)(12), resulting in functional impairment on cognitive and behavioral tasks, as can antibodies directly injected intraventric- …”

Utility of Autoantibodies as Biomarkers for Diagnosis and Staging of Neurodegenerative Diseases

“…Binding of ANAs to these proteins can generate immune complexes capable of triggering complement activation, eventually leading to extensive tissue inflammation. In addition to ANAs, anti-N-methyl-D aspartate receptor (anti-NMDAR) autoantibodies have also been associated with SLE and neuropsychiatric systemic lupus erythematosus (NPSLE) (Hanly et al, 2011;Hirohata, Arinuma, Takayama, & Yoshio, 2007;Yaniv et al, 2015;Yoshio, Hirata, Onda, Nara, & Minota, 2005). A study by DeGiorgio et al demonstrated cross-reactivity between the NR2A and NR2B subunits of NMDARs and antidouble-stranded (ds)DNA autoantibodies, leading to the loss of neurons both in vivo and in vitro models (DeGiorgio et al, 2001).…”

Pathogenesis of neuropsychiatric systemic lupus erythematosus and potential biomarkers

“…Recently, Hirohata et al [32] noted elevations in anti-ribosomal P levels with diffuse NPSLE, while others studies have demonstrated a more specific association with the NPSLE syndromes of psychosis and depression [24,26,27,33].…”