Neurolupus is associated with anti-ribosomal P protein antibodies: An inception cohort study
Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a broad spectrum of clinical manifestations. Central nervous system (CNS) involvement occurs in up to 80% of SLE patients [1], [2], [3], [4], [5] the large difference in frequency mostly depending on the diagnostic criteria [6], [7], [8], the considered population, the study design, and antibody assay used.
Neuropsychiatric SLE (NPSLE) includes neurological syndromes of central, peripheral, and autonomic nervous system observed in patients with SLE not due to infections, hypertension, metabolic abnormalities or drug toxicity. These manifestations may precede the onset of SLE or occur at anytime during the course of the disease. In 1999, the American College of Rheumatology (ACR) proposed a standard nomenclature for NPSLE, with case definitions of 19 neuropsychiatric syndromes including seizures, stroke, headache, polyneuropathy, mononeuropathy, depression, and psychosis [9].
The pathogenesis of NPSLE is still unknown, but several autoantibodies (Abs) directed to nuclear as well as cytoplasmic antigens have been suggested to play a role [10], [11], [12], [13].
Phosphorylated ribosomal (P ribosomal) proteins are three ubiquitous, highly conserved acidic phosphoproteins (P0, P1, P2) of different molecular weights (38 kDa, 17 kDa, and 15 kDa) forming the stalk of the 60S ribosomal subunit, where they play a role in protein synthesis. They share a 22 amino acid carboxyl-terminus which contains an immunodominant epitope. The ribosomal protein P0 immunolocalizes on the membrane surface of neuronal, hepatic, and endothelial cells, in an immunological accessible way [14].
Abs to the P ribosomal proteins are considered a highly specific marker of SLE and appear to correlate with disease activity, liver, kidney as well as with CNS involvement [15].
Abs to P ribosomal proteins were first reported to be associated with NPSLE in 1987, when Bonfa et al. described serum IgG to P ribosomal proteins in 18 of 20 patients with neuropsychiatric manifestations. In 2 cases the Abs serum level correlated with disease activity [16]. Subsequent studies gave, however, inconsistent results [17], [18], [19], [20]. Two recent international multicentre studies, carried out on a very large number of SLE patients, led to opposite results [21], [22].
Interestingly, an animal model of autoimmune depression has recently been developed by injecting anti-P ribosomal Abs in cerebral ventriculi of mice [23]. In addition it has been suggested that anti-P ribosomal mediated damage could derive from neuronal apoptosis [24].
The objective of our study was to investigate whether the presence of serum Abs to ribosomal P proteins in SLE patients correlates with NPSLE manifestations using a large inception cohort of patients followed in a single centre. Moreover, in a subgroup of patients we also analyzed whether Abs to P ribosomal proteins were detectable in the cerebrospinal fluid (CSF) and whether their presence was related to blood–brain barrier alterations.
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Patients
We considered an inception cohort of 219 consecutive patients affected with SLE recruited in a single Rheumatologic Unit of the University of Padua, and followed-up from 1986 to October 2004. They were all Caucasian, 185 women and 34 men, mean age at diagnosis 28 ± 10.4 years (range 10–66). The median follow-up was 110 months (range 1–18 years).
All patients fulfilled at least four of the ACR criteria for SLE classification.
SLE-associated clinical manifestations, occurring anytime during the
Serum Abs to ribosomal P proteins and clinical and serological correlations
IgG Abs to P ribosomal proteins were present anytime in 45 (21%) of the 219 SLE patients (Fig. 1B). The SLE age at onset was significantly younger in patients with Abs to P ribosomal proteins than in those without (23.2 ± 7.4 vs 26.7 ± 10.5 years, p = 0.04). Of the 45 patients with Abs to P ribosomal proteins, 23 (51%) had neurological manifestations: 19 (42%) CNS involvement including 8 (17%) headache, 4 (8%) cerebrovascular disease, 4 (8%) psychiatric disorders (3 depression, one psychosis), one
Discussion
The results of our study confirm the association between NPSLE and Abs to P ribosomal proteins using an inception cohort of patients, homogeneous in respect to race, followed-up in a single centre for a median period of 10 years. Moreover, our results suggest that even peripheral nervous system manifestations attributable to SLE may be related to Abs to P ribosomal proteins.
Firstly described by Bonfa et al. [16] the relationship between psychosis and Abs to P ribosomal proteins became
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2023, Brain, Behavior, and Immunity - HealthHydroxychloroquine alleviates the neurotoxicity induced by anti-ribosomal P antibodies
2021, Journal of NeuroimmunologyCitation Excerpt :Anti-P antibodies have been reported to be associated with severe clinical phenotypes of SLE, such as autoimmune hepatitis (Calich et al., 2013), lupus nephritis (Hirohata, 2011; Kang et al., 2019), and neuropsychiatric SLE (NPSLE) (Abdel-Nasser et al., 2008; Arinuma et al., 2019; Diamond et al., 2009). Anti-P antibodies were detected in both the peripheral blood and cerebrospinal fluid of patients with NPSLE, indicating blood–brain barrier permeation (Bonfa et al., 1987; Briani et al., 2009; Hirohata et al., 2007). Studies have reported that an injection of anti-P antibodies into the lateral ventricle of mice provoked olfactory dysfunction and depression-like behavior (Katzav et al., 2008; Katzav et al., 2007).
Seizures as a clinical manifestation in somatic autoimmune disorders
2019, SeizureCitation Excerpt :A meta-analysis suggested that headache (28%); followed by mood disorders (20%), cognitive dysfunction (20%), and seizures (10%) were the commonest neuro-psychiatric symptoms in SLE [35]. Various reports indicated a high prevalence of seizures among people with SLE (prevalence:1.6%–16%) [3,8,36–41]; and from studies including controls they seem higher than in the general population [8,38–41]. A recent cross sectional study with over 5000 people with SLE and over 25,000 controls found epilepsy 4.7 times more likely in the SLE cohort (95% CI: 3.9–5.8%) [39].
The role of ophthalmic imaging in central nervous system degeneration in systemic lupus erythematosus
2018, Autoimmunity ReviewsCitation Excerpt :Anti-ribosomal P were related to hippocampal atrophy and memory impairment in these patients [28] [29]. Elevated anti-ribossomal P, both in serum and cerebrospinal fluid, was also reported to have a strong association with lupus related psychosis [30,31]. Antibodies against NMDA receptor, which is responsible for activity-dependent synaptic plasticity and long-term potentiation that underlie memory and learning [32,33], are significantly augmented in the serum of NPSLE patients [34].