Rheumatology Section, Medicine Department, LSU Health Sciences Center, New Orleans, LA 70112-2822, USA
SIR, We read with great interest the report by Gerli et al. [1] demonstrating in systemic lupus erythematosus (SLE) patients an association between anti-ribosomal P antibodies and anticardiolipin antibodies [anti-CL immunoglobulin (Ig) G isotype], as well as with a higher European concensus lupus activity measurement (ECLAM) score, photosensitivity, malar and discoid rash, and age of disease onset <33 yr old.
In agreement with the observations noted above are our findings. We studied the frequency and association of antiribosomal P-protein and anti-phospholipid antibodies in a large population of SLE patients. We also correlated the presence of these autoantibodies to clinical manifestations including neuropsychiatric SLE involvement and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). The study population was comprised of 131 patients (127 women and four men), and all fulfilled the American College of Rheumatology criteria for SLE. Sixty controls were also included. Anticardiolipin antibodies and anti-ß2-glycoprotein 1 (GPI) were evaluated by enzyme-linked immunosorbent assay (ELISA). All sera were tested for IgG, IgM and IgA isotypes.
Anti-dsDNA antibodies were performed by Critidia luciliae, ENA panel by double diffusion and anti-ribosomal P antibodies (P0, P1, P2) by ELISA. Two different ethnic groups were studied, including 34 African American and 97 Latin American SLE patients. Mean age at study was 33.5±13.7 yr (range 1693 yr), with a mean disease duration of 8.5±6.6 yr (range 133 yr). The prevalence of ribosomal-P antibodies was 23%. An association between the presence of anti-P and anti-CL antibodies was found in 24/30 (80%) SLE anti-ribosomal-P-positive sera (P=0.000002). The isotype distribution was significant for IgG (P=0.0017) and IgA (P=0.00011). In addition, the presence of anti-ß2-GPI among the 30 anti-P-positive patients was 19 (63%) (P=0.00005). The isotype distribution was significant for IgG (P=0.006) and IgA (P=0.0007).
We were unable to demonstrate any association between the presence of anti-P antibodies in the sera of SLE patients and any known clinical manifestation, including patients with neuropsychiatric, renal and/or hepatic manifestations and secondary antiphospholipid syndrome. However, a strong association was found between anti-P, anti-CL and anti-ß2-GPI antibodies. Both IgG and IgA isotypes of antiphospholipid antibodies were associated with anti-P antibodies. Our findings are also similar to those of Ghirandello et al. [2] and Schneebaum et al. [3]. These authors found an association between anti-P and anti-CL antibodies, but could not establish a correlation with clinical manifestations related to the antiphospholipid antibody syndrome, or with antinuclear antibodies, anti-dsDNA or with Sm antibodies. These data, however, are at variance with those of others. Tzioufas et al. [4] found an association between anti-P antibodies and active SLE and CNS involvement, especially in patients without anti-CL antibodies.
The exact mechanism(s) underlying the association of anti-P and antiphospholipid antibodies remains to be elucidated. Cross-reactivity between these two subsets of autoantibodies does not appear to exist, although the possibility that additional antibodies specific for conformational change(s) of P proteins may be cross-reactive with cardiolipin or other antiphosphlipid antibodies has not been excluded.
There is now compelling evidence that infectious agents including parasites such as Trypanosoma cruzi, and certain viruses and bacteria may trigger the formation of anti-P and antiphospholipid antibodies. Consideration has been given to antigenic spreading and autoantibody clustering as a result of disregulated apoptosis. Exposure of cryptic antigens and neoantigens of both ribosomal and antiphospholipid autoantigens during apoptosis may be the driving stimulus to the production of autoantibodies. In addition, infectious antigens can exert a wide spectrum of immune influences including stimulation of B cell mitogenesis, activation of macrophages with up-regulation and release of pro-inflammatory cytokines, co-stimulation of T and natural killer cells through cytokines such as interleukin-12, tumour necrosis factor (TNF)-, TNF-ß and interferon-
resulting in stimulation of antibody production to target sites that are specific for both infectious agent and host. Some of the mechanism(s), alone or in combination may explain the association between anti-P and antiphospholipid antibodies in SLE [57].
In conclusion, a prevalence of 23% and 12.1% for anti-P antibodies was found in both studies. More interesting was the finding of a strong association between anti-P and antiphospholipid antibodies. This association may indicate interplay between infectious agents and the known immune disregulation seen in SLE. Immunostimulatory sequences from infectious agents may play a role in the triggering or exacerbation of the disease and provide an explanation for the concomitant presence of these autoantibodies.
Notes
Correspondence to: R. Cuchacovich. E-mail: rcucha{at}hotmail.com or rcucha{at}lsuhsc.edu
References
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