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

Abstract

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

The TNFα locus is altered in monocytes from patients with systemic lupus erythematosus

“…Previous studies have determined that artificial histone acetylation at the TNFα locus is sufficient to increase the cells ability to respond to stimuli but does not lead in and of itself to transcription of TNFα [20]. Thus, we would hypothesize that the high serum levels of TNFα that are seen in SLE patients are due both to an increased competence to produce TNFα and to the presence of a stimulus, either or both of which may be a consequence of the disease process [43]. The immunology of SLE is extremely complex and there is evidence that histone acetylation at certain genetic loci may correlate with biochemical or phenotypic disease features while acetylation of other loci appears to be protective [35;44].…”

Association of cerebrospinal fluid anti–NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus

“…In contrast, anti-ribosomal P (anti-P) antibodies in the serum have been shown to be associated with diffuse NPSLE (4,16,19). We have recently demonstrated that anti-P antibodies up-regulate the expression of tumor necrosis factor ␣ protein and messenger RNA in human peripheral blood monocytes (20). Since tumor necrosis factor ␣ has been found to abrogate the integrity of the blood-brain barrier (21,22), it is likely that serum anti-P antibodies might also induce blood-brain barrier impairment and thus allow anti-NR2 in the systemic circulation to enter the CNS, leading to the development of neuronal damage.…”

Challenge of liver disease in systemic lupus erythematosus: Clues for diagnosis and hints for pathogenesis

“…As for the mechanism explaining this causal relationship, antiribosomal P positive sera from SLE patients were found to react strongly "in vitro" with a polypeptide antigenically related to a 38 kD ribosomal P0 protein present on the plasma membrane of hepatoma cells [28] , thus further strengthening the possibility that anti-ribosomal P antibodies could be directly detrimental in lupus patients by inducing hepatocellular lysis, and further transaminase release. Finally, anti-ribosomal P antibodies up-regulate the expression of proinflammatory cytokines by peripheral monocytes in SLE, which may be a contributing factor for hepatitis development [29] . Given that auto-antibodies directed against eukaryotic P proteins are highly specific to SLE, they can be used as diagnostic markers of the disease.…”