Antiribosomal P protein antibodies

INTRODUCTION — Autoantibodies directed against three phosphorylated protein ("P") components of ribosomes are present in a minority of patients with systemic lupus erythematosus (SLE) and are highly specific for this disease. Some studies have suggested that these antibodies may serve as markers for specific disease manifestations, including central nervous system (CNS) disease and hepatitis, but other studies have not confirmed these associations. (See 'Associations with specific manifestations of SLE' below.)

The specificity, clinical associations, and utility of measuring antiribosomal P antibodies are discussed here. An overview of antinuclear antibodies and the approach to the diagnosis of CNS disease in SLE are presented separately.

●(See "Measurement and clinical significance of antinuclear antibodies".)

●(See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus", section on 'Attribution of a clinical syndrome to SLE'.)

ANTIBODIES TO RIBOSOMAL P PROTEINS

Antigen specificity — The targets of antiribosomal antibodies found in the sera of some patients with systemic lupus erythematosus (SLE) are three highly conserved phosphorylated proteins ("P" proteins) located on the 60S subunit of ribosomes [1,2]. The P proteins, which exhibit molecular weights of 35, 19, and 17 kD, are designated P0, P1, and P2, respectively. The immunodominant epitope in patients with SLE is a shared sequence at the carboxy (C)-termini of the P proteins [3-5].

In their native form, the ribosomal P antigens form a pentamer consisting of one copy of P0 and two copies each of P1 and P2. This complex interacts with the 28S ribosomal RNA molecule to form the ribosomal stalk, including a guanosine triphosphatase (GTPase) domain involved in the elongation step of protein translation [6]. Monoclonal antibodies to P proteins inhibit binding of elongation factor (EF)-1 alpha and EF-2 to ribosomes and inhibit protein synthesis [7,8].

P proteins were initially identified on ribosomes in the cytoplasm [9]; subsequent studies have also detected epitopes recognized by antiribosomal P protein antibodies on the surface of neuronal, hepatoma, and activated T cells in vitro [10,11]. The binding of antibodies to these proteins on cell surfaces could have pathogenic significance, given evidence that such antibodies can be internalized, resulting in cellular dysfunction [6,12].

Antibody detection — Antibodies to ribosomal P proteins produce a finely speckled cytoplasmic staining pattern on a human epithelioma cell, type 2 (HEp-2) cell substrate using indirect immunofluorescence (picture 1). However, the sensitivity of indirect immunofluorescence for the detection of antiribosome P antibodies is less than 30 percent compared with commercially available, solid phase assays. In clinical practice, antiribosome P antibodies may be detected by immunoblot, enzyme-linked immunosorbent assay (ELISA), line immunoassay, or addressable laser bead assay. In these assays, antibodies are detected using purified native or recombinant antigen, synthetic peptides, or a combination of these antigenic targets. In some assays, a 22-amino acid peptide, which is shared by the three ribosomal P proteins and is the major autoantigenic epitope, is used to replace the full-length protein [3]. This peptide-based ELISA has been reported to provide the greatest discrimination between patients with SLE and controls [13,14]. However, it is possible that the lack of full-length ribosome P proteins decreases the sensitivity of some solid phase assays.

There are at least nine commercially available assays to detect antiribosome P antibodies: six ELISAs, one line immunoassay, and two addressable laser bead assays. The specificity and sensitivity of antibodies directed against ribosome P using these assays range from 10 to 25 percent (sensitivity) and 95 to 100 percent (specificity) [15]. Unfortunately, international standardization of assays to detect antibodies directed against ribosomal proteins has not yet been achieved, and there is no "gold standard" approach to detecting these antibodies.

DISEASE ASSOCIATIONS — The clinical significance of antiribosomal phosphorylated protein (P) antibodies is their specificity for the diagnosis of systemic lupus erythematosus (SLE) [16-18]. As indicated above, these antibodies have not been found in normal controls [13,17,19] and are rare in patients with other autoimmune diseases [13,20]. In a retrospective study of 487 SLE patients, the prevalence of antiribosomal P, anti-Sm, and anti-double-stranded DNA (anti-dsDNA) antibodies was 31.6, 20.7, and 45 percent, respectively [21]. It was reported that 27.9 percent of SLE patients had antiribosomal P antibodies and were negative for anti-Sm and anti-dsDNA antibodies. Antiribosomal P antibodies were considered to be most valuable in the diagnosis of SLE when other, specific autoantibodies are not detected.

As might be expected, given the variety of tests used to detect antiribosome P antibodies, the reported prevalence of antiribosomal P antibodies among patients with SLE is quite variable. Antiribosomal P antibodies were initially detected in 10 to 20 percent of patients with SLE [10,16,17,22]; however, other studies including adult SLE patients from China and Japan and children from the United States, Argentina, and Brazil have reported higher rates of prevalence (25 to 50 percent) [20,23-26]. As examples:

●An international study involving 11 centers, 947 patients with SLE, and 1113 controls used a mixture of three recombinant ribosomal P polypeptides as the antigenic target in an enzyme-linked immunosorbent assay (ELISA); the sensitivity and specificity of antiribosomal P antibodies for SLE were 21 and 99 percent, respectively [23]. The prevalence of antiribosomal P antibodies in patients with SLE at each individual center ranged from a high of 35 percent for patients from China to 8 percent for patients from Canada. None of 208 normal sera used as controls tested positive. The disease controls with positive tests included patients with rheumatoid arthritis (RA; 3 of 284 patients), patients with systemic sclerosis (SSc; 2 of 131), and one patient each with hepatitis C, mixed connective tissue disease (MCTD), and polymyositis.

●Another multicenter study, which employed an ELISA using the C22 epitope as the antigenic target, showed similar sensitivity and specificity for SLE (23 and 99 percent, respectively) [13]. Testing was negative in healthy blood donors and in patients with RA or Sjögren's disease (n = 135, 60, and 26, respectively). One patient each with MCTD, limited cutaneous SSc, ulcerative colitis, and polymyalgia rheumatica tested positive.

Several factors may be responsible for the variability of the prevalence of antiribosomal P antibodies in different populations of SLE patients, including differences in the techniques used to detect antibodies, variable ethnic or genetic composition of populations, and differences in regional practice and in patient selection [15,23].

ASSOCIATIONS WITH SPECIFIC MANIFESTATIONS OF SLE — The potential association between the presence of antiribosomal phosphorylated protein (P) antibodies and specific manifestations of systemic lupus erythematosus (SLE) is highly controversial. Antiribosomal P antibodies have been associated in different studies with SLE involving the central nervous system (CNS), liver, kidney, and skin. By contrast, other studies have not demonstrated such associations. Some studies have also suggested that these antibodies are markers for SLE disease activity.

The same factors that appear to account for differences in the prevalence of antiribosomal P antibodies among different groups of patients with SLE are likely to result in the variability in the associations with different clinical manifestations. Additionally, small sample sizes in many of the positive studies described below and differences in methods for detection of antibody may also be important.

Central nervous system disease — Based on the variable results from several studies, testing for antiribosomal P antibodies has limited diagnostic value for neuropsychiatric SLE and is not helpful in differentiating between clinical subtypes of neuropsychiatric SLE.

Some studies have suggested an association between the presence of antiribosomal P antibodies and neuropsychiatric manifestations of SLE, particularly psychosis [17,19,20,27,28]; however, other studies do not support such an association [13,22,29,30]. As examples:

●The lack of diagnostic utility of antiribosomal P antibodies for neuropsychiatric SLE is supported by a meta-analysis of observational data from 1537 patients with SLE from 14 centers in Europe, Asia, and South America [31]. The presence of antiribosomal P antibodies had an overall sensitivity and specificity for lupus of 26 and 80 percent, respectively. The sensitivity and specificity were similar for psychosis, mood disorder, or both (27 and 80 percent) and for other diffuse manifestations (24 and 80 percent). Positive testing did not distinguish between different manifestations of neuropsychiatric SLE, and results between different centers showed significant heterogeneity.

●In another study involving 116 patients with SLE, no association between the presence of antiribosomal P antibodies and neuropsychiatric SLE was observed; the sensitivity and specificity of antiribosomal P antibodies for neuropsychiatric disease were 21 and 13 percent, respectively [29].

Liver disease — An association between antiribosomal P antibodies and SLE-associated liver disease was suggested in several reports, including two small case-control studies, following an initial case report of a patient with lupus in whom antiribosomal P antibodies were produced soon after the development of chronic active hepatitis [32-34].

●One study found a higher number of patients with SLE-related liver disease among 20 patients with SLE and antiribosomal P antibodies than among controls with SLE but without such antibodies (7 of 20 patients versus 1 of 20 patients) [33]. Antibodies to ribosomal P were not found in the sera of 59 patients with autoimmune liver diseases, including chronic active hepatitis, primary biliary cholangitis (previously referred to as "primary biliary cirrhosis"), and sclerosing cholangitis in the absence of lupus, suggesting that the autoantibodies were not the result of immune-related hepatic injury.

●Another report found a higher number of patients with antiribosomal P antibodies among patients with SLE-related hepatitis compared with a control group of SLE patients without liver disease (6 of 6 patients versus 2 of 20 patients) [34]. Hepatitis was present in only 3 percent of the patients in the large lupus cohort, from which most of the patients for the study were drawn.

Several large studies have had too few patients with liver disease to draw any firm conclusions regarding this association, and further studies are required for confirmation [13,35].

Renal disease — Antiribosomal P antibodies have been associated with the presence and activity of lupus nephritis in several, mostly small, studies [33,36-38]; however, other reports have failed to confirm these observations [17,22,30,35]. As examples:

●An international multicenter study of 333 patients with SLE and 397 controls found no association between antiribosomal P antibodies and the presence of nephritis [13]. A single-center study from North Africa of 200 patients with SLE and 130 controls also found no association with renal disease [35].

●One study found a higher number of patients with SLE-related renal disease among 20 patients with SLE and antiribosomal P antibodies than among controls with SLE but without such antibodies (14 of 20 patients versus 4 of 20 patients) [33]. In other studies, levels of antiribosomal P antibodies fluctuated with the activity of renal disease and correlated with the anti-double-stranded DNA (anti-dsDNA) antibody titer [36,37]. In one report, antiribosomal P antibodies were primarily associated with membranous lupus [38].

Skin disease — Cutaneous manifestations of SLE have been associated with antiribosomal P antibodies in several studies [22,30,39]. As an example, in an Italian multicenter study of 149 consecutively seen patients with SLE, there was a significantly higher prevalence of both malar and discoid rashes among antibody-positive compared with antibody-negative patients at the time of the evaluation (61 versus 31 percent and 17 versus 2 percent, respectively) [30]. By contrast, other studies have not found this association [13,35].

Other associations — Other associations have been reported in some studies but not others [6,40], including associations with younger age [13], arthritis [35], increased disease activity [35,37], low levels of complement C3 or C4 [13], and increased prevalence of anti-dsDNA [3] and anticardiolipin antibodies [30,41].

CLINICAL UTILITY OF ANTIRIBOSOMAL P ANTIBODIES — Testing for antiribosomal phosphorylated protein (P) antibodies is most useful in helping to establish the diagnosis of systemic lupus erythematosus (SLE) in settings in which the diagnosis is uncertain; a role in diagnosis similar to that of anti-double-stranded DNA (anti-dsDNA) and anti-Sm antibodies is supported by the high specificity of these antibodies for SLE, while recognizing their mild to moderate sensitivity. (See 'Disease associations' above and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Laboratory testing'.)

Testing for antiribosomal P antibodies is generally not useful in the diagnosis or management of neuropsychiatric SLE, given the broad range of results for sensitivity and specificity that has been observed between patients in various studies. (See 'Associations with specific manifestations of SLE' above and 'Central nervous system disease' above and "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus", section on 'Attribution of a clinical syndrome to SLE'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Antinuclear antibodies".)

SUMMARY AND RECOMMENDATIONS

●The main targets of antiribosomal phosphorylated protein (P) antibodies found in the sera of some patients with systemic lupus erythematosus (SLE) are three highly conserved phosphorylated proteins located on the 60S subunit of ribosomes. Epitopes recognized by antiribosomal P antibodies are also present on the surfaces of some cells. (See 'Antigen specificity' above.)

●Antiribosomal P antibodies produce a finely speckled cytoplasmic staining pattern on a human epithelioma cell, type 2 (HEp-2) cell substrate using indirect immunofluorescence (picture 1). The sensitivity of indirect immunofluorescence for the detection of antiribosomal P antibodies is low. In clinical practice, these antibodies may be detected by immunoblot, enzyme-linked immunosorbent assay (ELISA), line immunoassay, or addressable laser bead assay. (See 'Antibody detection' above.)

●The clinical significance of antiribosomal P antibodies is their specificity for the diagnosis of SLE. These antibodies have not been found in normal controls and are rare in patients with other autoimmune diseases. The reported prevalence of antiribosomal P antibodies among patients with SLE is quite variable. (See 'Disease associations' above.)

●Antiribosomal P antibody testing has limited diagnostic value for neuropsychiatric SLE and is not helpful in differentiating clinical subtypes of SLE. Some studies have suggested a strong association between the presence of antiribosomal P antibodies and neuropsychiatric manifestations of SLE, while other studies do not support such an association. (See 'Central nervous system disease' above.)

●Various studies have also suggested that these antibodies are markers for SLE disease activity and various clinical or laboratory manifestations of SLE other than neuropsychiatric disease, but contradictory data have also been reported for these associations. (See 'Associations with specific manifestations of SLE' above and 'Liver disease' above and 'Renal disease' above and 'Skin disease' above and 'Other associations' above.)

●Testing for antiribosomal P antibodies is most useful in helping to establish the diagnosis of SLE in settings in which the diagnosis is uncertain, given the high specificity but low to moderate sensitivity of these antibodies for SLE. (See 'Clinical utility of antiribosomal P antibodies' above.)