Clinical and biological aspects of anti-P-ribosomal protein autoantibodies

Abstract

Among the many clinical manifestations of systemic lupus erythematosus (SLE), central nervous system (CNS) involvement is of a prognostic importance. In this respect, anti-ribosomal P protein antibodies were shown by many to occur in association with SLE neuropsychiatric manifestations, mainly psychosis. The prevalence of anti-P antibodies was strongly related to disease activity wherein disease remission was associated with the disappearance of these antibodies. In addition to its association with CNS involvement, the occurrence of liver and kidney disease in SLE patients with anti-P antibodies was widely reported. Anti-P antibodies are able to bind T cells, monocytes, neurons and hepatocytes thereby enhancing the production of pro-inflammatory cytokines and both CNS and liver damage. Similar to the ability of anti-dsDNA antibodies, anti-P antibodies were shown to penetrate into living cells, leading to cell dysfunctions such as cell apoptosis. These biological aspects may play an important role in the pathogenesis of SLE.

Introduction

Systemic lupus erythematosus (SLE) is a prototype of autoimmune diseases, where a wide spectrum of autoantibodies are associated with a great diversity of clinical manifestations [1]. Some of these autoantibodies such as anti-Sm antibodies are highly specific and of high diagnostic value [2]. Apart from being specific, high titers of anti-dsDNA were widely reported to be associated with increased SLE disease activity. However, remission in the course of SLE is usually associated with the reduction of anti-dsDNA antibodies [3], [4]. Among the other autoantibodies of importance in SLE are anti-ribosomal-P protein antibodies, which are directed against three proteins of molecular weight 38 (PO), 19 (P1), and 17 (P2) kDa. Other anti-ribosomal-P antibodies that are detected in patients with SLE, include anti-28S rRNA, anti-S10, and anti-L12 that are frequently directed against the P proteins and the shared conserved carboxyl terminus [5], [6].

Aiming to assess their specificity in SLE patients, anti-P antibodies were detected (using Western blot analysis) in the sera of patients with various autoimmune diseases [7]. In this early study, of 93 randomly selected patients, the frequency of anti-P antibodies was 7 out of 59 SLE patients (12%) and 0 out of 34 non-SLE patients. It was concluded that anti-P antibodies are specific serological markers for SLE and may be detected in the serum even when anti-dsDNA antibodies are not found. Later studies established again that in patients with other autoimmune diseases, such as rheumatoid arthritis, the level of anti-P antibodies was normal, which indicates that these antibodies are highly specific for patients with SLE [8], [9].

Some studies have shown that different ethnic backgrounds may influence the frequency with which anti-P antibodies occur in SLE patients, ranging from 6% to 46% [10]. In most of the ethnic groups (Whites, Blacks, and Hispanics) anti-P antibodies have been found in 6–20% of patients, in contrast to the Chinese group where 36% were reported to be positive [11].

In a group of Chinese SLE patients from Malaysia who have high prevalence of anti-P antibodies, an increased frequency of an HLA-DRB gene allele DR 16X was found [12]. This allele has only been found in the South East Asian population which could explain the high prevalence of anti-P antibodies in Chinese. In order to assess whether anti-P antibodies are associated with any major histocompatibility complex (MHC) class II alleles, sera from 394 SLE patients were studied [23]. The HLA-DR2, DQ6 haplotypes were increased in anti-P positive whites, blacks, and Mexican-Americans. A shared amino acid sequence in HLA-DQB1 was strongly associated with anti-P positivity (70%) vs anti-P negativity (42%) across ethnic lines. Although anti-P response in SLE patients is strongly influenced by certain MHC class II alleles, it is still unclear whether CNS involvement is really increased among various ethnic groups such as among Chinese.

The association between anti-Sm and anti-P antibodies (both highly specific in SLE) was determined in both human SLE and MRL/lpr mice [13]. Anti-P antibodies as detected by ELISA were found in 18/65 (28%) of sera from lupus patients with anti-Sm, but in only 6/55 (11%) of sera without anti-Sm (p < 0.05). The levels of anti-P were significantly higher in sera containing anti-Sm (0.37 ± 0.45) than in sera without anti-Sm antibodies (0.18 ± 0.2) (p < 0.05). Similarly, significantly higher proportion of anti-P positivity was found in autoimmune MRL/lpr mice positive for anti-Sm (11/53 = 21%) in comparison to mice without anti-Sm antibodies (3/53 = 6%) (p < 0.05). It has been reported that anti-P antibodies are more frequently detected in anti-dsDNA positive sera, and therefore the binding ability of anti-P antibodies towards polynucleotides and nucleosomes was assessed [14]. Purified anti-P antibodies from 8 SLE patients' sera were analyzed by ELISA on plates coated with DNA or nucleosomes. All the purified anti-P antibodies were bound to DNA and half of them were bound to nucleosomes. These data are in line with previous findings where immunization of C3H.SW female mice with a common human monoclonal anti-DNA idiotype (16/6 idiotype) was followed by the induction of high levels of murine anti-16/6 and anti-16/6 antibodies (associated with anti-DNA activity). Elevated titers of autoantibodies reacting with DNA, ribonucleo-proteins, P ribosomal proteins, autoantigens (Sm, Ro) and cardiolipin were also noted [15].

In this review we focus on the association between the presence of anti-P and SLE disease activity. We also summarize the evidence for the association between anti-P and CNS involvement, namely psychosis in SLE. Finally we discuss the important mechanistic issues related to the cellular effects of anti-P antibodies, such as apoptosis and antibody penetration to cells.