Ribosomal P autoantibodies in systemic lupus erythematosus. Frequencies in different ethnic groups and clinical and immunogenetic associations

Abstract

Objective. To determine the frequencies and clinical associations of antiribosomal P antibodies (anti-P) in a large multiethnic cohort of patients with systemic lupus erythematosus (SLE), and to assess whether anti-P was associated with any major histocompatibility complex (MHC) class I1 alleles or shared amino acid sequences.Methods. Sera from 394 SLE patients were studied for anti-P using an enzyme-linked immunosorbent assay, and MHC class I1 alleles (HLA-DRB1, DQA1, and DQBl) were determined by DNA oligotyping.Results. Anti-P antibodies were found in 13-2W of patients in the majority of ethnic groups, but were perhaps more frequent in Chinese patients (36%) and less common in Bulgarian patients (6%). Neuropsychiatric lupus (psychosis and/or depression) was significantly associated with anti-P. The HLA-DR2, DQ6 haplotypes DRB1*1501 or *1503, DQA1*0102, and DQB1*0602 were increased in anti-P-positive whites, blacks, and Mexican Americans. The HLA-DQB1*0602 allele showed the strongest association with anti-P when these 3 ethnic groups were combined and compared with both race-matched anti-P-negative SLE patients and normal controls. The HLA-DQS specificity (DQB1*0302) was increased both in whites and in Mexican-Americans with anti-P who were negative for HLA-DQB1*0602, and perhaps also increased in Greeks, but not in blacks, in whom HLA-DQB1*0301 was increased. A shared amino acid sequence in HLADQBl (at position 26 of leucine and position 30 of tyrosine) was strongly associated with anti-P positivity (70%) versus anti-P negativity (42%) across ethnic lines.Conclusion. The anti-P response in SLE patients, occurring in -15% of patients, was strongly influenced by certain MHC class I1 alleles and was correlated with diffuse neuropsychiatric dysfunction.

Antibodies directed against ribosomal P proteins cross-react with phospholipids

“…Associations between anti-P and anti-CL antibodies have been reported recently [14,16,18], and we also observed the co-existence of anti-P and anti-CL in the same lupus sera [17]. At variance with our results, previous attempts to show that a cross-reactivity of anti-P purified antibody with CL had failed [16].…”

Autoantibodies and neuropsychiatric events at the time of systemic lupus erythematosus diagnosis: Results from an international inception cohort study

“…In general, the prevalence of autoantibodies was lower than that reported in other lupus cohorts (20,21,34,35). However, this was the first study to measure this complete panel of autoantibodies in a disease inception cohort, which, in combination with our efforts to minimize nonspecific antibody binding, is probably the explanation for the lower prevalence rates.…”

“…With regard to autoantibodies, the current data suggest that aPL cause focal NP disease (e.g., stroke, seizures) by promoting intravascular thrombosis (5). In contrast, anti-P antibodies (21,22), and possibly anti-NR2 antibodies (13,15), cause diffuse NP events (e.g., psychosis, depression, cognitive impairment) through a direct effect on neuronal cells; a critical factor in this is the ability of these antibodies to directly access neuronal cells either through intrathecal production or via passage from the circulation across a permeabilized blood-brain barrier.…”

“…The most direct evidence supporting the hypothesis of autoantibody involvement in NPSLE is derived from studies of animal models (13)(14)(15)(16)(17), whereas evidence from human studies is frequently conflicting or inconclusive (18)(19)(20)(21)(22). This may be due in part to methodologic difficulties involving, for example, selection of patients for study, lack of rigor in the characterization of NP events, and differences between laboratories in assay techniques.…”

“…The latter include antiphospholipid antibodies (aPL), antiribosomal P antibodies (anti-P), and autoantibodies that bind to neuronal antigens such as the recently described antibodies to the NR2 glutamate receptor (13). Although there is biologic plausibility and data from in vitro studies and animal studies to implicate these autoantibodies in the causality of nervous system disease (13)(14)(15)(16)(17), studies of humans with SLE have yielded inconsistent findings (18)(19)(20)(21)(22). Previous investigations have been limited by their cross-sectional study design, heterogeneity of study patients in terms of disease duration, and lack of standardization in both the classification of NP events and the methodology used for autoantibody detection.…”