Association of psychiatric manifestations with antibodies to ribosomal p proteins in systemic lupus erythematosus

142

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.

Section: Discussionsupporting

confidence: 89%

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

Arnett

Reveille

Moutsopoulos

et al. 1996

142

“…Ribosomal P proteins share a common linear determinant that is present in the carboxyl-terminal 22-amino acid sequence (1). Previous and recent studies have disclosed the association of anti-P antibodies with neuropsychiatric disease in SLE (2,3). Moreover, it was recently shown that antiribosomal P is strongly associated with hepatitis and nephritis in SLE (4).…”

Section: Fragments Of Anti-p Antibodies Which Do Not Results In Fc␥ Rmentioning

confidence: 99%

Anti–ribosomal P protein antibody in human systemic lupus erythematosus up‐regulates the expression of proinflammatory cytokines by human peripheral blood monocytes

Nagai¹,

Arinuma²,

Yanagida³

et al. 2005

Objective. Autoantibodies to ribosomal P proteins (anti-P antibodies) are detected in 12-16% of patients with systemic lupus erythematosus (SLE) and have been found to be associated with some manifestations of the disease, including lupus psychosis and hepatitis. Recent studies have disclosed that anti-P antibodies react with activated T cells but not with B cells, suggesting possible direct effects of anti-P antibodies on immune regulation. The present study was designed to explore the presence of the epitope recognized by anti-P antibodies on human peripheral blood monocytes.Methods. Highly purified peripheral blood monocytes obtained from healthy donors were cultured with or without interferon-␥ (IFN␥) in the presence of either anti-P antibodies purified by affinity chromatography from the sera of patients with SLE or control IgG.Results. Flow cytometry analysis disclosed that fresh (day 0) monocytes did not express the ribosomal P epitope, whereas expression of the ribosomal P epitope was induced on annexin V-negative monocytes after activation through plastic adherence for 48 hours. More important, anti-P antibodies (compared with normal IgG or IgG from SLE patients devoid of anti-P antibodies) enhanced the production of tumor necrosis factor ␣ (TNF␣) and interleukin-6 (IL-6) by activated monocytes. Accordingly, anti-P antibodies also up-regulated the expression of TNF␣ and IL-6 messenger RNA in activated monocytes. Of note, F(ab ) 2 fragments of anti-P antibodies, which do not result in Fc␥ receptor (Fc␥R) crosslinking, also effectively up-regulated the expression of TNF␣ and IL-6.Conclusion. These results indicate that human peripheral blood monocytes express the ribosomal P epitope upon activation, irrespective of induction of apoptosis. Moreover, the data suggest that anti-P antibodies might modify a variety of inflammatory responses through up-regulation of the expression of proinflammatory cytokines in monocytes, in a manner that does not involve Fc␥R crosslinking.Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the expression of a variety of autoantibodies. Autoantibodies to ribosomal P proteins (anti-P antibodies) are detected in 12-16% of patients with SLE (1). Anti-P antibodies are directed to 3 phosphoproteins (P0, P1, and P2), which are located on the larger 60S subunit of eukaryotic ribosomes and have molecular weights of 38 kd, 19 kd, and 17 kd, respectively (1). Ribosomal P proteins share a common linear determinant that is present in the carboxyl-terminal 22-amino acid sequence (1). Previous and recent studies have disclosed the association of anti-P antibodies with neuropsychiatric disease in SLE (2,3). Moreover, it was recently shown that antiribosomal P is strongly associated with hepatitis and

“…A number of studies have attempted to determine whether there might be suitable antibody markers for detecting the group of patients with SLE who have or might develop neuropsychiatric complications (15)(16)(17)(18)(19)26,27). The majority of these studies have been directed at SLE patients, with normal patients serving as controls.…”

Section: Discussionmentioning

confidence: 99%

“…Various methods have been utilized to detect central nervous system lesions in patients with SLE, including lumbar puncture and cerebrospinal fluid examination, electroencephalography, cerebral angiography, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography, brain imaging with 99m Tc-hexamethylpropylene amine oxime, and 99m Tc-ethyl cysteinate dimer brain single-photon-emission CT (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Immunologic tests which have been used to detect central nervous system involvement in SLE patients have included assays for serum and cerebrospinal fluid antineuronal antibodies (15), serum anti-ribosomal P antibodies (16,17), and serum antiphospholipid antibodies (aPL) (18,19). In some studies, antineurofilament antibodies have also been examined in SLE patients with central nervous system lesions and were found to be elevated, particularly in patients with diffuse subcortical white matter lesions detected by MRI (20).…”

mentioning

confidence: 99%

Antibodies to microtubule‐associated protein 2 in patients with neuropsychiatric systemic lupus erythematosus

Williams¹,

Sugiura²,

Tan³

2004

Objective. Microtubule-associated protein 2 (MAP-2), a cellular protein restricted to neurons, is important in the control of cytoskeletal integrity and other neuronal functions. We undertook this study to examine the presence of autoantibodies to MAP-2 in neuropsychiatric systemic lupus erythematosus (NPSLE).Methods. Sera from 100 patients with SLE, 74 patients with other neurologic disorders and injuries (including cerebrovascular accidents, brain trauma, brain tumors, and demyelinating disorders), and 60 normal controls were examined both by enzyme immunoassays and by Western immunoblotting for autoantibodies to MAP-2. Sera designated positive for antibodies to MAP-2 were required to be positive in both assays.Results. Seventeen percent of SLE patients had autoantibodies to MAP-2, in contrast to 4% of neurologic injury/disease control patients (P ‫؍‬ 0.028) and 1.7% of normal controls. In SLE, anti-MAP-2 positivity in both assays was associated with neuropsychiatric symptoms in 76.5% of patients, whereas the absence of anti-MAP-2 was associated with neuropsychiatric symptoms in 19.7% of patients (P ‫؍‬ 0.0002). The neuropsychiatric symptoms in the former group included psychosis, seizure, neuropathy, and cerebritis.Conclusion. Autoantibodies to MAP-2, a neuronrestricted cytoskeletal protein, appear to be another immune marker for NPSLE.