Complete complement deficiency in a large cohort of familial systemic lupus erythematosus.

Genetic complete deficiency of the early complement components such as C1, C2 and C4 commonly results in a monogenetic form of systemic lupus erythematosus (SLE). However, previous studies have examined groups of complete complement deficient subjects for SLE, while a familial SLE cohort has not been studied for deficiencies of complement. Thus, we undertook the present study to determine the frequency of hereditary complete complement deficiencies among families with two or more SLE patients. All SLE patients from 544 such families had CH50 determined. Medical records were examined for past CH50 values. There were 66 individuals in whom all available CH50 values were zero. All but four of these had a SLE-affected relative with a non-zero CH50; thus, these families did not have monogenetic complement deficient related SLE. The four remaining SLE-affected subjects were in fact two sets of siblings in which three of the four SLE patients had onset of disease at <18 years of age. Both patients in one of these families had been determined to have C4 deficiency, while the other family had no clinical diagnosis of complement deficiency. In this second family, one of the SLE patients had had normal C4 and C3 values, indicating that either C1q or C2 deficiency was possible. Thus, only 2 of 544 SLE families had definite or possible complement deficiency; however, 1 of 7 families in which all SLE patients had pediatric onset and 2 of 85 families with at least 1 pediatric-onset SLE patent had complete complement deficiency. SLE is found commonly among families with hereditary complement deficiency but the reverse is not true. Complete complement deficiency is rare among families with two or more SLE patients, but is concentrated among families with onset of SLE prior to age 18.

Evaluation of C1q genomic region in minority racial groups of lupus.

Complement cascade plasma proteins play a complex role in the etiopathogenesis of systemic lupus erythematosus (SLE). Hereditary C1q deficiency has been strongly related to SLE; however, there are very few published SLE studies that evaluate the polymorphisms of genes encoding for C1q (A, B and C). In this study, we evaluated 17 single nucleotide polymorphisms (SNPs) across 37 kb of C1QA, C1QB and C1QC in a lupus cohort of individuals of the African-American and Hispanic origin. In a case-only analysis, a significant association at multiple SNPs in the C1QA gene was detected in African Americans with kidney nephritis (best P=4.91 x 10(-6)). In addition, C1QA was associated with SLE in African Americans with a lack of nephritis and accompanying photosensitivity when compared with that in normal controls (P=6.80 x 10(-6)). A similar trend was observed in the Hispanic subjects (P=0.003). Quantitative analysis showed that some SNPs in C1q genes might be correlated with C3 complement levels in an additive model among African Americans (best P=0.0001). The C1QA gene is associated with subphenotypes of lupus in the African-American and Hispanic subjects. Further studies with higher SNP densities in this region and other complement components are necessary to elucidate the complex genetics and phenotypic interactions between complement components and SLE.

Lupus/Sjögren's autoantibody specificities in sera with paraproteins.

Antinuclear antibody and anti-RNA-protein autoantibodies were determined in 143 sera containing paraproteins and 39 control sera. Antinuclear antibodies were commonly present in the paraprotein sera by indirect immunofluorescence. 19 of 143 sera (13%) had elevated anti-Ro/SSA activity in a solid phase Ro/SSA binding assay, and 5 (3.5%) had Ro/SSA precipitating autoantibody. Eighteen sera had La/SSB binding autoantibodies (12%) but only one had an anti-La/SSB precipitin. Anti-nRNP(Sm) was not detected in any of these sera. The solid phase anti-RNA protein assays were repeated using anti-lambda and anti-kappa conjugates. Both lambda and kappa light chain autoantibodies were found in all positive sera consistent with polyclonal anti-Ro/SSA and anti-La/SSB responses. Paraprotein sera containing Ro/SSA precipitins were analyzed by isoelectric focusing followed by exposure to 125I-labeled Ro/SSA and autoradiography. All sera with anti-Ro/SSA binding paraproteins also contained polyclonal anti-Ro/SSA. Our data are consistent with the hypothesis that anti-Ro/SSA paraproteins are common and arise from a previously present polyclonal anti-Ro/SSA response.

Analysis of the protein products encoded by variant glucokinase transcripts via expression in bacteria.

Five variant transcripts of the single rat glucokinase gene have been described that are naturally expressed in islets of Langerhans, liver and anterior pituitary. Four of these were prepared as cDNA and expressed in bacteria in order to begin to address their physiological roles. Expression of constructs pGKB1 (normal islet/pituitary glucokinase) and pGKL1 (normal liver glucokinase) resulted in a glucose-dependent, glucokinase-like activity, 7-fold and 45-fold, respectively, above background. Expression of pGKB3 (variant islet/pituitary glucokinase) and pGKL2 (variant liver glucokinase) in contrast, did not result in any glucokinase-like activity.

Patients with familial and sporadic onset SLE have similar clinical profiles but vary profoundly by race.

Few large, multi-ethnic studies have examined the clinical and serologic differences between familial and sporadic SLE patients. Understanding these similarities and differences is critical for interpreting genetic studies and developing therapeutic strategies. We compiled information on 1915 patients with SLE in a large multi-racial cohort, including general demographics, pedigree structure and the specific American College of Rheumatology (ACR) criteria met. One patient was randomly selected from each multiplex family for analysis, yielding 554 European-Americans (EA), 373 African-Americans (AA), 193 Hispanics (HI) and 237 patients of other of mixed races. When comparing familial and sporadic patients stratified by race, lupus erythematosus (LE) cells and arthritis were increased in white familial cases (P = 5.5 x 10(-6) and P = 0.028, respectively), but no other significant differences between familial and sporadic patients were found. We found that there were profound differences in clinical profiles between races. For example, photosensitivity and malar rash were decreased in AA (P = 1.3 x 10(-13) and 1.4 x 10(-7), respectively), whereas discoid rash was increased in AA (P = 5.5x10(-6)). EA had significantly less renal disease (P = 5.4x10(-13)), proteinuria (P = 4 x 10(-12)) and anti-Sm (P = 1.7 x 10(-12)) than AA or HI. We, therefore, conclude that familial and sporadic onset patients may be treated similarly with respect to clinical and genetic studies.

Familial aggregation of lupus and autoimmunity in an unusual multiplex pedigree.

OBJECTIVE: To evaluate an unusual pedigree with 8 members diagnosed with systemic lupus erythematosus (SLE) METHODS: Pedigree members were evaluated through questionnaires, interviews, and medical records. Sixty members contributed serum samples for autoantibody analysis. RESULTS: The 8 affected females shared several disease features, including arthritis (8/8), antinuclear antibodies (ANA) (8/8), pleuritis (6/8), malar rash (6/8), photosensitivity (5/8), and nephritis (4/8). A total of 15 of 51 (29%) blood relatives had autoantibodies; 9 had autoimmune disease, including 7 with SLE, one with psoriasis, and one with Sjögren's syndrome. Five of 11 (45%) nonconsanguineous spouses also had autoantibodies; one spouse had SLE, and 2 others had thyroid disease. Among 68 spouses of patients with SLE in other pedigrees, only 9 (13%) had autoantibodies, and none were symptomatic (p = 0.02). CONCLUSION: The high rate of autoimmunity among both blood relatives and nonconsanguineous mates in this unusual pedigree suggests a complex interaction of genetic and environmental factors contributing to disease.

A model for disease heterogeneity in systemic lupus erythematosus. Relationships between histocompatibility antigens, autoantibodies, and lymphopenia or renal disease.

We composed a model from autoimmune serologic findings, HLA antigens, and clinical findings that explains, at least partially, the clinical heterogeneity of 40 patients with systemic lupus erythematosus (SLE). In these patients, anti-RO (SS-A) was related to the HLA-DQ1/DQ2 heterozygotes, anti-La (SS-B) was related to HLA-B8 and HLA-DR3, and anti-nuclear RNP (Sm) was related to HLA-DR4. Lymphopenia was associated with anti-Ro (SS-A) and, secondarily, with anti-single-stranded DNA. Renal disease in these SLE patients was inversely associated with anti-La (SS-B) and was positively associated with anti-double-stranded DNA. There were no associations between the HLA antigens and these clinical manifestations. The results support a model of disease expression in which individuals are nonspecifically potentiated for SLE. Their HLA antigen composition influences the production of particular autoantibodies that are related in complex ways to the different particular clinical findings of SLE manifested in individual patients.

Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure.

OBJECTIVE: The possible molecular mimicry of the Epstein-Barr virus (EBV) peptide PPPGRRP by the peptide PPPGMRPP from Sm B'/B of the human spliceosome is consistent with the possibility that EBV infection is related to the origin of systemic lupus erythematosus (SLE) in some patients. Association of EBV exposure with SLE was therefore tested for and subsequently found in children and adolescents (odds ratio [OR] 49.9, 95% confidence interval [95% CI] 9.3-1,025, P < 10(-11)). These results were confirmed at the level of EBV DNA (OR > 10, 95% CI 2.53-infinity, P < 0.002). Much smaller seroconversion rate differences were found against 4 other herpes viruses. Herein, we extend these studies to adults and test the hypothesis that EBV infection is associated with adult SLE. METHODS: We selected 196 antinuclear antibody-positive adult SLE patients (age > or =20 years) and 2 age-, race-, and sex-matched controls per patient. SLE patients and matched controls were tested for evidence of previous infection with EBV, cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), or varicella-zoster virus (VZV) by standardized enzyme-linked immunosorbent assays. RESULTS: Of the 196 lupus patients tested, all but 1 had been exposed to EBV, while 22 of the 392 controls did not have antibodies consistent with previous EBV exposure (OR 9.35, 95% CI 1.45-infinity, P = 0.014). No differences were observed between SLE patients and controls in the seroconversion rate against CMV, HSV-2, or VZV. CONCLUSION: These new data from adults, along with the many suggestive features of EBV infection, are consistent with the contribution of this infection to the etiology of SLE.