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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a wide spectrum of autoantibodies, among which anti-ribosomal P (anti-P) antibodies are considered to be closely related to the neuropsychiatric SLE (NPSLE). Hydroxychloroquine (HCQ) has been proven to be effective against a variety of autoimmune diseases and is an essential drug for the treatment of SLE. In this study, we investigated the effects of anti-ribosomal P (anti-P) antibodies on neural cells and determined whether hydroxychloroquine (HCQ) influenced the anti-P antibodies-induced changes. The results showed that the binding of anti-P antibodies with mouse neuroblastoma- 2a (N2a) cells and rat primary neurons resulted in elevated intracellular calcium levels, inducing decreased cell viability and cell apoptosis. These inhibitory effects were alleviated by HCQ in a concentration-dependent manner by reducing the intracellular calcium levels and modulating the expression of apoptotic proteins. In summary, our study demonstrates that anti-P antibodies induce neural cell damage. HCQ could ease the damage effects and may play a neuroprotective role in NPSLE.

Background Anti-ribosomal P (anti-Rib-P) antibody is a specific serological marker for systemic lupus erythematosus (SLE) and routinely tested by targeting the common epitope of three ribosomal proteins of P0, P1 and P2. This study aimed to investigate if testing antibodies against individual ribosomal protein, but not the common epitope, is required to achieve the best diagnostic benefit in SLE. Methods The study included 82 patients with SLE and 22 healthy donors. Serum antibodies were determined by ELISA and immunoblot. Results The prevalence of each antibody determined by ELISA was 35.4% (anti-Rib-P), 45.1% (anti-Rib-P0), 32.9% (anti-Rib-P1) and 40.2% (anti-Rib-P2) at 99% specificity, respectively. Of 53 patients with negative anti-Rib-P antibody, 21 (39.6%) were positive for anti-Rib-P0, 9 (17.0%) for anti-Rib-P1 and 12 (22.6%) for anti-Rib-P2 antibody. The positive rate of anti-Rib-P antibody detected by ELISA was close to the results by immunoblot (33.4%). Patients with any of these antibodies were featured by higher disease activity and prevalence of skin rashes than those with negative antibodies. Moreover, each antibody was particularly related to some clinical and laboratory disorders. The distribution of subclasses of IgG1–4 was varied with each antibody. Anti-Rib-P0 IgG1 and IgG3 were strongly correlated with disease activity and lower serum complement components 3 and 4. Conclusions Anti-Rib-P antibody is not adequate to predict the existence of antibodies against ribosomal P0, P1 and P2 protein. The examination of antibodies against each ribosomal protein is required to achieve additional diagnostic benefit and to evaluate the association with clinical and serological disorders as well.

We report the case of a 25-year-old woman who developed temporal lobe epilepsy associated with systemic lupus erythematosus (SLE). Serum and cerebrospinal fluid samples showed high titers of anti-ribosomal P (anti-P) antibodies with negative anti-NMDAR antibodies. She was receiving prednisone and azathioprine, with normalization of SLE serum markers, but without changes in titers of anti-P antibodies. No seizure control was achieved using valproic acid, levetiracetam and lamotrigine. However, she had a selective response to topiramate, an AMPAR blocker, maintained during 6 years of follow-up. We discuss the pathophysiology of this autoimmune epilepsy associated with high titer anti-P antibodies.

Autoimmune disorders result from the attack of the immune system against self, since patients with these diseases have lost a major characteristic of the immune system, the immune tolerance (ability not to react against self). They can affect one organ (organ-specific) or many organs (systemic). The majority of autoimmune rheumatic diseases are systemic. The disorders occur in genetically predisposed individuals (associated with major histocompatibility antigens and other immunoreactive molecules) when they come across with chemical, physical, or microbial agents in the context of a particular hormonal background (majority are females) and under circumstances that create an incompetence to cope with life stressful events. The autoimmune attack can be mediated by autoantibodies, immune complexes, or T lymphocytes and can result in organ hyperfunction (e.g., hyperthyroidism), hypofunction (e.g., myasthenia gravis), or destruction of the affected organ (e.g., synovium in rheumatoid arthritis). The presence of leukocytosis and acute-phase proteins (C-reactive protein) characterizes the autoimmune disorders as inflammatory (e.g., vasculitis), while their absence as not inflammatory (e.g., systemic lupus erythematosus, SLE). B-lymphocyte hyperactivity, as attested by hyperglobulinemia and a plethora of circulating or tissue-deposited autoantibodies, is a common manifestation in the majority of autoimmune diseases, while different types of T-helper lymphocytes (Th1,Th2, and Th17) operate in different autoimmune diseases. The autoantibodies can be diagnostic (high specificity for a disease, e.g., anti-Sm for SLE), pathogenetic (e.g., DNA-anti-DNA immune complexes activate the complement cascade and induce tissue injury), or predictive for disease development (e.g., rheumatoid factors and anti-cyclic citrullinated autoantibodies).

The pathogenesis of neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE) is multifactorial and can involve various inflammatory cytokines, autoantibodies such as anti-neuronal antibodies, anti-ribosomal P antibodies, anti-NR2 glutamate receptor binding antibodies, anti-Sm antibodies, anti-U1-RNP antibodies and anti-phospholipid antibodies, and immune complexes (IC). Disruption of the blood-brain barrier (BBB) is integral to the neuropathology of SLE. Recently the possibility has been reported that aforementioned autoantibodies in the circulation may be strongly associated with disruption of the BBB. Each of these mechanisms might contribute to the pathogenesis of focal NPSLE (for example, cerebrovascular disease, movement disorders, myelopathy, seizures and cranial neuropathy) or diffuse NPSLE (for example, acute confusional state, psychosis and cognitive dysfunction) to varying degrees. In this review we focus on how the aforementioned autoantibodies, the BBB, IC and cytokines as well as chemokines are associated with the appearance of NPSLE.

This study compares the effects of human antiphospholipid (aPL) and anti-P-ribosomal (anti-P) IgG and control IgG on the brain. Intracerebroventricular (ICV) injected aPL mice (exAPS) displayed specific hyperactivity compared to anti-P-injected (exSLE) and control mice. In contrast ICV injected anti-P-injected mice specifically displayed depression-like behavior and olfactory impairment compared to the other 2 groups. Both anti-P and aPL injected mice were impaired in the passive avoidance test compared to controls. The distinct cognitive effects of the 2 pathogenic antibodies argue for a specific and differential direct action of these autoantibodies on the brain in clinical disease.

Anti-P antibodies have been associated with organ involvement in SLE, such as in autoimmune hepatitis, and have been suggested to be directly pathogenic. Neuropsychiatric lupus, lupoid hepatitis, autoimmune hepatitis, lupus nephritis, and Chagas' disease have been associated with the presence of anti-P antibody. This review seeks to look into the current literature on anti-P antibody and the association between SLE and non-SLE autoimmune connective tissue disorder.

Neuropsychiatric lupus affects above 50% of patients with systemic lupus erythematosus and may span from mild symptoms to acute devastating life-threatening ones. Owing to the clinical variability, most pharmacological data rely on small, uncontrolled trials and case reports. The mainstay of therapy relies on immune-suppression by glucocorticoids, in adjunction with cyclophosphamide or anti-B-cell therapy, in moderate to severe cases. In selected scenarios (e.g., chorea) intravenous immunoglobulin or plasmapheresis may be effective. Anticoagulation is warranted if anti-phospholipid antibodies are present. In parallel there may be a need for symptomatic treatment such as anti-epileptic or anti-depressive treatments, etc. In the future, more studies addressed to assess pathogenesis and preferred treatments of specific manifestations are needed in order to personalize treatments. © 2015 Taylor and Francis.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most difficult manifestations of lupus to diagnose. Measurement of serum brain antibodies has contributed to early diagnosis and management of NPSLE before development of a debilitating disease. We aimed to assess the value of serum anti-ganglioside M1 antibodies in prediction of NPSLE, in comparison to other antibodies used in routine laboratory diagnosis of NPSLE. In addition, we are the first to study the relationship between these antibodies and cognitive function in lupus patients. Serum anti-ganglioside M1, anti-ribosomal P protein and anti-cardiolipin antibodies were measured in 30 lupus patients without clinical evidence of NPSLE, aged 8–16years, and 30 healthy matched-subjects. Patients were followed-up clinically by monthly neuropsychiatric evaluation and assessment of cognitive function for 12months. Twelve patients developed neuropsychiatric manifestations during follow-up. Of those patients, 83.3%, 50% and 16.7% were seropositive for anti-ganglioside M1, anti-ribosomal P and anti-cardiolipin antibodies, respectively at the time of initial evaluation before clinical presentation of NPSLE. There was a significant positive association between anti-ganglioside seropositivity and cognitive dysfunction (P

To analyse prospectively the diagnostic sensitivity and specificity as well as the clinical relevance of ribosomal P (anti-P) autoantibodies in a large cohort of SLE patients.The anti-P autoantibodies were evaluated in the serum of 200 Tunisian SLE patients at disease onset and 130 various control subjects by a sensitive immunodot assay. A complete laboratory evaluation and clinical examination were performed in each SLE patient. During the follow-up, the patients were regularly monitored for clinical parameters. Global SLE activity was measured by the ECLAM.The sensitivity and specificity of anti-P testing for SLE were 23.5 and 98.4%, respectively. The anti-P-positive samples 14/47 (29.8%), 27/47 (57.4%) and 5/47 (10.6%) were negative for anti-dsDNA, anti-Sm or both antibodies, respectively. The anti-P-positive patients showed more active disease activity and a much higher prevalence of arthritis. An association between IgG aCLs and anti-P antibodies was also found. However, anti-P antibodies were not associated with neuropsychiatric manifestations or lupus nephritis.This study does not seem to confirm the described association of anti-P antibodies with neuropsychiatric manifestations of SLE. However, it supports the anti-P antibody association with arthritis and disease activity as well as the presence of aCL. Based on our study and other related studies, we propose that, akin to anti-Sm and anti-dsDNA, anti-P antibodies detected by one agreed method may be considered for inclusion as a criterion for the classification of SLE.

In the present study, anti-ribosomal P antibody in sera of patients with systemic lupus erythematosus was assayed using an enzyme-linked immunosorbent assay, and its association with clinical symptoms of the patients was analyzed. The presence of anti-ribosomal P antibody was associated with increased frequency of lupus nephritis in the presence of anti-DNA antibody, and was associated with increased frequency of vascular thrombosis in the presence of anti-beta2 glycoprotein I antibody and/or lupus anticoagulant. The level of anti-ribosomal P antibody correlated inversely with the peripheral lymphocyte counts.

Patients with systemic lupus erythematosus, with and without nephritis, were studied for their serological profiles. Patients were stratified into two groups defined by the presence or the absence of precipitating antibodies to ribosomal P proteins. It was found that 27 patients were positive for anti-P precipitins and the remaining 34 patients were studied for the presence of lesser amounts of anti-P antibodies by Western blot and ELISA tests. The nephritic patients were characterized most frequently by the presence of both autoantibodies to dsDNA and the ribosomal P proteins. In the group with anti-P precipitins, anti-dsDNA titers were much higher in the patients with nephritis than in those without nephritis. Thus, over a wide range of anti-ribosomal P antibody concentrations, the mutual occurrence of anti-P antibodies with anti-dsDNA antibodies was strongly associated with lupus nephritis.

Objective The objective of this paper is to analyze the relationship of anti-protein ribosomal P (RibP) antibodies with circulating levels of IFNα, TNFα, IFNγ, IL-17 and IL-10 in SLE. Disease activity and other systemic lupus erythematosus (SLE) features were also analyzed. Methods Anti-RibP and other SLE-related antinuclear antibodies (ANA) were determined by fluoro-enzyme immunoassay in the sera of 107 SLE patients. Circulating cytokines were quantified by flow cytometry (IFNα, IL-10 and IL-17) or ELISA (TNFα and IFNγ). Results Anti-RibP-positive patients (14.9%) displayed significantly higher serum levels of IFNα ( p = 0.023) and IL-10 ( p = 0.016) than their negative counterparts. This cytokine upregulation was independent of the presence of other ANA even though, in our patient cohort, anti-dsDNA was found to be associated with anti-RibP (OR, CI 95%: 6.03, 1.32–27.93, p = 0.021) and to correlate with IL-10 levels ( r = 0.204, p = 0.036). In fact, patients positive for anti-RibP but negative for anti-dsDNA exhibited the highest amounts of both IL-10 and IFN-α that were not related to disease activity since these patients showed lower SLEDAI than patients also positive for anti-dsDNA ( p = 0.018). Anti-RibP positivity was also associated with early diagnosis, hypocomplementemia and leukopenia. Conclusions Presence of anti-RibP was found to be related to increased serum IFNα and IL-10 levels independently of both antibody status and disease activity.

Overt anti-ribosomal P (anti-P) autoantibodies are restricted to a subset of systemic lupus erythematosus (SLE) patients, and are potentially pathogenic. Covert anti-P are detected in all other individuals. An idiotype (Id) network is nonoperational in those with overt anti-P, whereas it is functional in all others. The aim of this study was to produce a murine monoclonal (mAb) anti-Id to characterize the anti-P Id network in SLE. BALB/c mice were immunized with F(ab')(2) fragments of IgG anti-P from a patient with a broadly cross-reactive Id. One mAb was chosen (mAb41) that reacted preferentially to the immunogen. This IgG1 mAb bound comparably in ELISAs to affinity-purified anti-P from 11 SLE patients with overt anti-P. This binding was partially inhibited with ribosomal P antigen. In contrast, it did not bind to affinity-purified control autoantibodies, nor to normal human IgG. mAb41 inhibited anti-P binding to ribosomal P antigen in immunoassays and on Jurkat cells. No change was detected in patients' anti-P antibodies over time when mAb41 was used in Id-specific ELISAs. We conclude that mAb41 is an anti-Id that recognizes a public idiotope within the antigen-combining site of anti-P antibodies. Thus, it is analogous to its human counterparts, and potentially, would modulate the pathogenicity of anti-P autoantibodies in vivo.

Autoantibodies to the 20-kDa ribosomal proteins (L12/S10) are not well studied, especially in juveniles with systemic lupus erythematosus (SLE). Randomly selected sera from American juveniles and adults with SLE were screened for antibodies to either 20-kDa protein and P proteins and then assayed for anti-L12 and anti-S10 by immunoblot assays. In a pilot study of patients with anti-P (Cohort 1), IgG antibodies to either 20-kDa protein and, specifically, to L12 were observed in 72 and 42% of juveniles and adults, respectively. IgG antibodies to S10 were detected less frequently. In Cohort 2 patients who were chosen irrespective of autoantibody status, twice as many juveniles as adults had IgG antibodies to either 20-kDa protein. Prevalences of IgG anti-L12 and IgG anti-S10 antibodies in the juveniles were 28 and 16% and in the adults were 13 and 12%, respectively. Anti-L12 were strongly but not invariably associated with anti-P, and usually arose temporally to these antibodies. Anti-S10 activity was due to anti-Sm antibodies. We conclude that IgG anti-L12 are more prevalent in SLE than previously reported, and are responsible for the majority of activity toward the 20-kDa ribosomal proteins, especially in juveniles.

Objective To determine the prevalence of anti-ribosomal P (anti-P) proteins in several groups of patients with juvenile-onset systemic lupus erythematosus (SLE) in comparison with the prevalence in adult SLE. Methods Serum samples were pooled together from 3 cohorts of patients with juvenile-onset SLE in 3 different medical centers and from a miscellaneous group of juvenile-onset SLE patients whose samples were sent by regional physicians. Sera were studied for the presence of anti-P using 2 assays: Western blot with ribosomes as antigen, and an enzyme-linked immunosorbent assay with the COOH-terminal 22 amino acids of the ribosomal P protein in a multiantigenic peptide format as antigen. Sera found positive by both tests were considered positive for anti-P antibodies. Findings from similar studies involving a large cohort of patients with adult-onset SLE from Oklahoma City were used for comparison. Results The prevalence of anti-P antibodies in the pooled sample of juvenile-onset SLE sera was 45 of 108, or 42%, while in the adult cohort from Oklahoma City, 20 of 260, or 7.7%, were positive for anti-P (odds ratio [OR] 9.6, P < 10−8 by Fisher's exact test). In addition, it was shown that 12 of 13 patients with both anti-P and anti–double-stranded DNA (anti-dsDNA) in the juvenile SLE cohort had nephritis, while only 8 of 22 patients without both antibodies were nephritic (OR 21.0, P < 10−8). It was also shown that in 9 illustrative cases, the levels of anti-P and anti-dsDNA antibodies usually varied together and in concordance with the clinical activity as measured by the SLE Disease Activity Index (SLEDAI). Finally, anti-P–positive and anti-P–negative patients had a similar prevalence of anti-dsDNA, anti-Ro/SSA, and anti-La/SSB antibodies, but patients with anti-P had a higher prevalence of anti–U1 RNP and anti-Sm (P = 0.041 and P = 0.0385, respectively, by Fisher's exact test). Conclusion Antibodies to ribosomal P protein are more prevalent in juvenile-onset SLE than in adult-onset SLE. Levels of antibodies to ribosomal P protein vary with the clinical disease activity as measured by the SLEDAI, often in concordance with the levels of anti-dsDNA. The presence of both anti-P and anti-dsDNA antibodies was powerfully associated with nephritis in the cohort of patients for whom comprehensive clinical and serologic data were available.

Autoantibodies to anti-ribosomal P protein have been recognized in patients with systemic lupus erythematosus (SLE) in widely variable proportions of unselected patients. Presence of anti-ribosomal P antibodies was retrospectively studied in 69 patients with SLE during disease exacerbations and remissions or during continuously active disease. Anti-ribosomal P antibodies were positive in 21/69 patients during active disease, with an overall prevalence of 30.4%. Prevalence in patients with active nephritis was 75.0% (15/20), P value by Fisher's exact test of 8.39 × 10 −7 . In 12/13 patients (92.3%), anti-P disappeared during periods of disease remission, P = 0.0002. In 17/21 patients (81.0%) with anti-ribosomal P antibodies, anti-dsDNA antibodies were also positive. In 47 patients without anti-P, 23/47 (48.9%) were also positive for anti-dsDNA. In 9/12 patients (75.0%) titers of anti-dsDNA antibodies correlated with anti-P during disease exacerbations and remissions, P = 0.004. The higher prevalence of anti-P in patients with lupus nephritis with disappearance during disease remissions supports the hypothesis of an immunopathogenetic role of these antibodies in lupus nephritis. There was also a strong association between anti-dsDNA and anti-P antibodies.

Background Lupus nephritis is known to be associated with several antibodies including autoantibodies that target the DNA, C1q and histone, α-actinin, and the nucleosome. In addition, circulating anti-phosphoribosomal protein antibodies (anti-Ribos.P) were found to be associated with lupus nephritis. Study objective We have assessed the direct role of anti-Ribos.P in the development of glomerulonephritis in-vitro and in animal models. Study design NZBxW/F1 lupus prone mice were immunized with recombinant Ribos.P0 (rRibos.P). Evaluation of renal disease included mice evaluation for proteinuria and histologic analysis of the kidneys. Anti-Ribos.P monoclonal Ab was prepared from the rRibos.P immunized NZBxW/F1 mice by hybridoma technology. MAPKs expression was analyzed by MAPKs protein array and confirmed by real-time PCR and western blot. To elucidate whether anti-Ribos.P induce glomerulonephritis, naive C3H mice were immunized with recombinant rRibos.P and the glomerulonephritis was followed up as described above. Results The immunized NZBxW/F1 lupus prone mice developed anti-Ribos.P which was cross reactive with Sm and not dsDNA. The mice developed accelerated glomerulonephritis manifested by early proteinuria and immunoglobulin deposites in the mesangium of the kidneys. Anti-Ribos.P deposited in the glomerular mesangium were eluted from the kidney. The Ribos.P immunized naive C3H/Hen mice developed glomerulonephritis manifested by circulating autoantibodies directed to Ribos.P, dsDNA and Sm. The anti Ribos.P were cross reactive with Sm but not with dsDNA, and were deposited in the glomeruli. Interestingly these mice developed alopecia. In vitro. Primary mesangial cells exposed to mouse anti-Ribos.P mAb originated from the immunized lupus mice and to human anti-Ribos.P Abs, induced activation of mesangial cells via p38α, JNK, AKT and HSP27 MAPKs expression pathway. Conclusions Our data show for the first time that anti-Ribos.P are nephritogenic autoantibodies, as illustrated by in-vitro and in-vivo experiments: a) They accelerate the development of glomerulonephritis in lupus prone mice; b) They induce nephritis in naive mice. c) Anti-Ribos.P Abs trigger MAPKs expression in primary mesangial cells. These data contribute a direct mechanistic link between anti-Ribos.P and nephritis in lupus mice.

Systemic lupus erythematosus (SLE) is a chronic, multifaceted autoimmune disease that is characterized by the presence of autoantibodies predominantly directed against nuclear proteins and nucleic ...

Increasing attention has been paid to the relationship of autoantibodies to ribosomal P proteins (anti-P) with lupus nephritis. Several mechanisms of involvement of anti-P in lupus nephritis have been proposed, including cross-reactivity with anti-dsDNA and anti-endothelial cell antibodies (AECA). In addition, it is also suggested that anti-P might play a role in the development of lupus nephritis through induction of T helper 1 responses. Of note, recent studies have disclosed that the presence of isolated anti-P antibodies may discriminate patients with pure class V lupus nephritis, whereas the simultaneous presence of anti-dsDNA antibodies suggests class V disease with concomitant proliferative lesions. These observations lead to the hypothesis that anti-P and anti-dsDNA might result in membraneous changes and proliferative changes, respectively, although further investigation is required for confirmation.

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Anti-ribosomal P protein antibodies (anti-rib-P Abs) recognize three specific ribosomal proteins (P0, P1 and P2) located in the large ribosome's subunit. These autoantibodies (autoAbs) are restricted to systemic lupus erythematosus (SLE) during active disease and associated with neuropsychiatric, renal and hepatic involvement. A preferential association of anti-rib-P with anti-Sm and/or anti-DNA Abs are, possibly due, at least in part, to cross-reactivity. The prevalence of anti-rib-P Abs is influenced by ethnic variations and most common in Asians.

Autoantibodies to ribosomal P protein (anti-P) are a specific hallmark of systemic lupus erythematous (SLE). Several authors found significant associations of anti-P antibodies with neuropsychiatric, hepatic, and renal disease. We now report the isolation by phage display of human anti-idiotype (Id) monoclonal antibody fragments as single-chain Fv fragment (scFv) against anti-P antibodies. The V gene repertoires were derived from the RNA obtained from the B cells of a SLE patient. Affinity-purified anti-P antibodies were used for the selection of bacterial clones producing anti-P-specific scFv antibody fragments and little reactivity with normal IgG and other IgG antibodies. The anti-Id antibody recognizes a public idiotope broadly cross-reactive with polyclonal anti-P antibodies and inhibited binding of anti-P to ribosomal P antigen in immunoassays and on Jurkat cells. The anti-Id scFv antibody fragment may have therapeutic implications in SLE. They may also be used as probes in the study of the structure of the idiotype.

Sera from systemic lupus erythematosus patients that had antibodies to the ribosomal P proteins were compared in several different assays. The enzyme-linked immunosorbent assay (ELISA) method was compared to the Western immunoblotting method using either affinity purified human or bovine ribosomal P proteins. All 30 normal sera had no significant reactivity with these antigens. The most sensitive test was the ELISA using the human P protein, where 31/32 patients were positive (97%). The assay with bovine proteins in ELISA yielded 28/32 (88%) positive results. Immunoblotting with either bovine or human P protein was equally effective with 30/32 (94%) positive. An ELISA incorporating human P proteins is a more sensitive assay for clinical diagnosis than an ELISA with the bovine protein. Immunoblotting is a sensitive method, but is less convenient and is not quantitative. The ELISA with the human protein appears to be the method of choice.

Ninety one Japanese patients with systemic lupus erythematosus (SLE) were studied to determine the clinical significance of antibodies to ribosomal P protein (anti-P). Anti-P was detected by western blotting in 38 of 91 patients (42%). Clinical symptoms of SLE were compared between patients with and without anti-P. The occurrence of lupus psychosis was significantly higher in patients with anti-P than in those without anti-P (9/38 v 1/53). No significant association was found between anti-P and other symptoms of SLE. These data strongly support the suggestion proposed by previous workers that anti-P is a marker autoantibody for the development of lupus psychosis.

purpose: The goal of this study was to determine whether elevated serum levels of antibodies to ribosomal P proteins (anti-P antibodies) are associated with neuropsychiatric manifestations in patients with systemic lupus erythematosus (SLE). Additional experiments examined characteristics of these antibodies that might be associated with pathogenicity. patients and methods: A large number of serum samples were collected from patients with SLE, control subjects with other rheumatic diseases, and normal individuals. At the time serum samples were obtained, patients with SLE were categorized according to the presence of psychosis, depression, and other manifestations of central nervous system (CNS) involvement. Serum anti-P antibody activity was quantitated by an enzyme-linked immunosorbent assay utilizing a synthetic peptide corresponding to the major P protein epitope. results: In a group of 79 normal individuals, mean (± SE) IgG anti-P activity was 0.01 ± 0.003 and no individuals had values greater than 3 SD above the mean. Similar results were obtained measuring IgM anti-P activity. Normal levels were found in all sera from 21 patients with rheumatoid arthritis. Of 119 patients demonstrating various patterns of antinuclear and anticytoplasmic antibody activity, elevated anti-P levels were found only in patients with SLE. Overall, 19% of 269 patients with SLE demonstrated elevated levels of IgG or IgM anti-P antibodies, including 14% of 187 patients without and 29% of 82 patients with neuropsychiatric manifestations. The frequency of positive test results varied greatly depending on the nature of the CNS involvement. The frequency in patients with severe depression (n = 8) and psychosis (n = 29) was 88% and 45%, respectively, compared with only 9% in patients with nonpsychiatric neurologic disease (n = 45). For the entire SLE group, the odds ratio for the association of anti-P antibodies and severe psychiatric manifestations was 7.63 with a 95% confidence interval of 3.61 to 16.14. In a review of 187 patients with SLE originally classified as not having severe psychiatric disease, seven of 10 patients being treated with antidepressant medications had elevated levels of anti-P antibodies. In serial studies, the serum level of anti-P antibodies appeared to correlate with the activity of psychiatric disease and did not correlate with the activity of other manifestations of SLE. Anti-P antibodies in nearly all patients were IgG and directed primarily to the C-terminal 11 amino acids of the P protein. No difference in these characteristics was observed when patients with and without psychiatric manifestations were compared. Paired serum and cerebrospinal fluid (CSF) samples were also obtained from eight patients with active neuropsychiatric disease. Even when expressed as a fraction of the total IgG present, anti-P activity was markedly lower in CSF than in serum. conclusions: Elevated levels of autoantibodies to the C-terminal region of ribosomal P proteins appear to be a specific marker for SLE, and are associated with both severe depression and psychosis in this disease. This assay is easily reproducible and may help distinguish SLE-induced psychiatric disease from that caused by other processes.

The characteristics of eukaryotic ribosomal proteins P0, P1, and P2 (P proteins) and their antigenic determinants were studied using the sera of patients with systemic lupus erythematosus (SLE). P0, P1, and P2 were isolated as a macromolecular complex by preparative isoelectric focusing and anion-exchange chromatography in the presence of 6 M urea. The apparent molecular size of the complex was 140 kDa as determined by gel filtration on a Sephadex G-200 column. P0 may, therefore, be the eukaryotic equivalent of Escherichia coli ribosomal protein L10. In addition, all three P proteins were detected in the postribosomal supernatant of HeLa cells, and P0 and P1 were found to be more acidic than their ribosome-bound counterparts. Partial proteolysis experiments revealed that SLE anti-P sera recognized one or both ends of the P2 equivalent protein from Artemia salina (eL12). Sixteen SLE sera containing antibodies to P0, P1, and P2 reacted with a carboxyl-terminal peptide 22 amino acids in length of eL12 and not with an amino-terminal peptide of 20 amino acids. Even though the carboxyl-terminal peptide completely inhibited the ability of the antiserum to react with all three proteins on an immunological blot, the same peptide produced only small decreases in binding of the SLE antibody to the native, nondenatured P proteins. These findings indicate that SLE anti-P antibodies react with a single sequential (linear) antigenic determinant on all three P proteins, but that additional antibodies recognize a conformational determinant(s).

In 18 of 20 patients with psychosis secondary to systemic lupus erythematosus (SLE), autoantibodies to ribosomal P proteins were detected by immunoblotting and measured with a new radioimmunoassay using a synthetic peptide as antigen. The frequency of anti-P was not increased in patients with other central nervous system manifestations of SLE (3 of 20, by radioimmunoassay), in patients with transient behavioral abnormalities due to SLE (none of 8), in patients with psychosis who did not have SLE (none of 13), or in normal controls (none of 20). In four of five paired serum samples, anti-P-peptide antibody levels increased 5-fold to 30-fold during the active phase of lupus psychosis. Longitudinal studies of anti-P activity in two patients with psychosis revealed that anti-P levels increased before and during the active phases of psychosis but not during sepsis or other exacerbations of SLE, and that the elevations were selective for anti-P antibodies, as opposed to anti-DNA antibodies. Longitudinal studies of anti-P activity in two patients with anti-P but without psychosis showed less than threefold changes in anti-P levels despite exacerbations of disease. We conclude that anti-P is associated with lupus psychosis and that synthetic peptide antigens may be useful for the detection and measurement of autoantibodies to intracellular proteins.