An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus.

An unknown environmental agent has been suspected to induce systemic lupus erythematosus (lupus) in man. Prompted by our recent immunochemical findings, we sought evidence for an association between Epstein-Barr virus infection and lupus. Because the vast majority of adults have been infected with Epstein-Barr virus, we chose to study children and young adults. Virtually all (116 of 117, or 99%) of these young patients had seroconverted against Epstein-Barr virus, as compared with only 70% (107 of 153) of their controls (odds ratio 49.9, 95% confidence interval 9.3-1025, P < 0. 00000000001). The difference in the rate of Epstein-Barr virus seroconversion could not be explained by serum IgG level or by cross-reacting anti-Sm/nRNP autoantibodies. No similar difference was found in the seroconversion rates against four other herpes viruses. An assay for Epstein-Barr viral DNA in peripheral blood lymphocytes established Epstein-Barr virus infection in the peripheral blood of all 32 of the lupus patients tested, while only 23 of the 32 matched controls were infected (odds ratio > 10, 95% confidence interval 2.53-infinity, P < 0.002). When considered with other evidence supporting a relationship between Epstein-Barr virus and lupus, these data are consistent with, but do not in themselves establish, Epstein-Barr virus infection as an etiologic factor in lupus.

Lupus autoantibodies to native DNA cross-react with the A and D SnRNP polypeptides.

Antibodies to native DNA (nDNA) in sera from patients with systemic lupus erythematosus have been found to frequently correlate with antibodies to the A and D SnRNP proteins measured in Western blot assays. 40 of 54 SLE (74.1%) sera with anti-nDNA bound to A and D proteins, while 9 of 113 sera (8%) without anti-nDNA bound the A and D proteins, P < 10(-8) by Fisher's exact test. Antibodies to nDNA correlated closely with anti-A and anti-D in seven of eight patients followed sequentially, r = 0.7865. Nine human polyclonal anti-nDNA populations were isolated from DNA cellulose columns. Seven reacted equally with A and D, and two reacted predominantly with D. Two of three murine monoclonal anti-DNA antibodies isolated from NZB/NZW F1 hybrid mice bound A and D equally in Western blot with a titer > 1/40,000. These reactions were directed to the unfolded A and D proteins measurable in Western blot since these monoclonals (and several of the human anti-nDNA populations) failed to react with native U1RNP in ELISA or in RNA immunoprecipitation experiments. These newly recognized cross reactions of anti-nDNA may amplify the immune response to DNA and be part of the original immunogenic drive.

Anti-PM/Scl autoantibodies in patients without clinical polymyositis or scleroderma.

OBJECTIVE: To characterize patients with anti-PM/Scl but no definite myositis-scleroderma (PM/SSc) overlap or either polymyositis/dermatomyositis (PM/DM) or systemic sclerosis (SSc) alone. METHODS: Review of all patients with anti-PM/Scl identified at a reference serologic clinical laboratory. RESULTS: We identified 5 patients with anti-PM/Scl not considered to have either PM, SSc, or PM/SSc. One had primary Sjögren's syndrome but the other 4 had some feature(s) of illness consistent with PM/DM or SSc, such as hypertensive crisis or interstitial lung disease. These 5 patients represented 10% of the total number of patients with anti-PM/Scl identified in our clinical laboratory. CONCLUSION: Anti-PM/Scl may be a marker for atypical or subclinical presentations of the usually associated disease, or this autoantibody may precede expression of the underlying disease. The antibody may also be present in patients who never express PM, SSc, or PM/SSc. Anti-PM/Scl without the usually described illnesses is not uncommon in our series of 55 patients with anti-PM/Scl.

The presence of masked antiribosomal P autoantibodies in healthy children.

OBJECTIVE: To determine if antiribosomal P (anti-P) autoantibodies are present in healthy children. METHODS: Sera from healthy children were screened for anti-P by conventional enzyme-linked immunosorbent assay and immunoblot techniques. Sera were also treated with immobilized ribosomal P antigens on nitrocellulose strips; affinity-purified fractions were tested for anti-P by high-sensitivity immunoblot. The relative binding affinities were compared for affinity-purified anti-P antibodies from healthy children and adults, and patients with systemic lupus erythematosus. IgG fractions of anti-P-depleted sera from healthy children were assessed for inhibition of autologous anti-P activity. RESULTS: Conventional serologic screening showed no IgG nor IgM anti-P in 88 untreated sera. IgG anti-P were unmasked in all 79 sera treated by the membrane batch affinity technique. IgM anti-P were identified in 27 of the treated sera; the percentage of positive sera decreased with increasing age (chi(2) for linear trend P = 0.00081). Affinity-purified anti-P from children had relative binding affinities similar to those of anti-P from other groups. Sera from healthy children contained inhibitory IgG antibodies to anti-P. CONCLUSION: These results show that anti-P autoantibodies are present in all healthy children. The majority of these autoantibodies are masked by IgG antibodies, suggesting concordant development of a regulatory network.

Prevalence of autoantibodies to ribosomal P proteins in juvenile-onset systemic lupus erythematosus compared with the adult disease.

OBJECTIVE: To determine the prevalence of anti-ribosomal P (anti-P) proteins in several groups of patients with juvenile-onset systemic lupus erythematosus (SLE) in comparison with the prevalence in adult SLE. METHODS: Serum samples were pooled together from 3 cohorts of patients with juvenile-onset SLE in 3 different medical centers and from a miscellaneous group of juvenile-onset SLE patients whose samples were sent by regional physicians. Sera were studied for the presence of anti-P using 2 assays: Western blot with ribosomes as antigen, and an enzyme-linked immunosorbent assay with the COOH-terminal 22 amino acids of the ribosomal P protein in a multiantigenic peptide format as antigen. Sera found positive by both tests were considered positive for anti-P antibodies. Findings from similar studies involving a large cohort of patients with adult-onset SLE from Oklahoma City were used for comparison. RESULTS: The prevalence of anti-P antibodies in the pooled sample of juvenile-onset SLE sera was 45 of 108, or 42%, while in the adult cohort from Oklahoma City, 20 of 260, or 7.7%, were positive for anti-P (odds ratio [OR] 9.6, P < 10(-8) by Fisher's exact test). In addition, it was shown that 12 of 13 patients with both anti-P and anti-double-stranded DNA (anti-dsDNA) in the juvenile SLE cohort had nephritis, while only 8 of 22 patients without both antibodies were nephritic (OR 21.0, P < 10(-8)). It was also shown that in 9 illustrative cases, the levels of anti-P and anti-dsDNA antibodies usually varied together and in concordance with the clinical activity as measured by the SLE Disease Activity Index (SLEDAI). Finally, anti-P-positive and anti-P-negative patients had a similar prevalence of anti-dsDNA, anti-Ro/SSA, and anti-La/SSB antibodies, but patients with anti-P had a higher prevalence of anti-U1 RNP and anti-Sm (P = 0.041 and P = 0.0385, respectively, by Fisher's exact test). CONCLUSION: Antibodies to ribosomal P protein are more prevalent in juvenile-onset SLE than in adult-onset SLE. Levels of antibodies to ribosomal P protein vary with the clinical disease activity as measured by the SLEDAI, often in concordance with the levels of anti-dsDNA. The presence of both anti-P and anti-dsDNA antibodies was powerfully associated with nephritis in the cohort of patients for whom comprehensive clinical and serologic data were available.