Confirmation of genetic linkage between human systemic lupus erythematosus and chromosome 1q41.

OBJECTIVE: Genetic susceptibility to systemic lupus erythematosus (SLE) is undoubtedly complex and, presumably, involves multiple loci. Linkage of SLE to D1S229 at chromosome 1q41 has been previously reported in a cohort of 52 affected sibpairs. The present study sought to confirm this reported linkage in an independent cohort of 127 extended multiplex SLE pedigrees containing 107 affected sibpairs. METHODS: Genotype data were collected for D1S229 and 18 flanking microsatellite markers spanning chromosome 1q32-1q42. Analyses of genotype data included a model-based logarithm of odds (LOD) score approach, affected sibpair analyses, and transmission disequilibrium tests. RESULTS: A maximum LOD score of 1.46 was found with D1S229 in a subgroup of 78 European American pedigrees, with additional support from multiple markers clustered around D1S229. Increased allele sharing in affected siblings was most significant at D1S2616, particularly in European Americans (P = 0.0005), followed by D1S229 (P = 0.002), D1S490 (P = 0.028), and D1S1605 (P = 0.037). Although linkage in a subgroup of 40 African American pedigrees was not suggested by the analyses of any marker tested in the chromosomal region surrounding D1S229, a maximum LOD score of 3.03 was found with D1S3462, mapped 15 centimorgans distal to D1S229. CONCLUSION: Our linkage analysis results in European Americans at D1S229 are remarkably similar to those previously reported. That at least 1 genetic effect near this locus is important for susceptibility to lupus should now be generally accepted, and efforts to identify the gene are thereby justified.     

Genome-wide scan of Graves' disease: evidence for linkage on chromosome 5q31 in Chinese Han pedigrees

Graves' disease (GD), which is a common organ-specific autoimmune disorder, is multifactorial and develops in genetically susceptible individuals. Despite many studies of candidate genes, only associations with human leukocyte antigen and cytotoxic T lymphocyte antigen 4 have been generally detected, and the number of susceptibility genes remains unknown. To identify chromosomal regions contributing to GD, we conducted a genome-wide scan on 322 individuals from 54 Chinese Han multiplex GD pedigrees. Parametric linkage analysis revealed the strongest evidence for linkage at D5S436 on chromosome 5q31, with a maximum two-point LOD score of 2.8 and a maximum multipoint LOD score of 2.3. To further assess the significance of this suggestive finding, we typed four additional markers around D5S436 in this chromosome region, and a maximum two-point LOD score of 4.31 and a maximum multipoint LOD score of 4.12 were obtained for marker D5S2090 (with heterogeneity, = 0.38). Nonparametric multipoint analysis also showed significant excess allele sharing, with a P value as low as 0.001, at the same locus. Our findings provide evidence for a susceptibility locus for GD on chromosome 5q31 and support the existence of genetic heterogeneity in GD.     

Genetic linkage and association of Fcgamma receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus

OBJECTIVE: Although low-affinity alleles of human Fcgamma receptor types IIA and IIIA (FcgammaRIIA and FcgammaRIIIA, respectively) polymorphisms have been associated with systemic lupus erythematosus (SLE) in case-control studies, the relative contribution of these genes to SLE susceptibility has not been resolved. METHODS: We analyzed the distribution of alleles of FcgammaRIIA, FcgammaRIIIA, and FcgammaRIIIB in 126 multiplex-SLE pedigrees and FcgammaRIIA and FcgammaRIIIA in a case-control replication study, using allele-specific polymerase chain reaction and direct sequencing of genomic DNA. Statistical tests of association were performed to detect evidence of linkage between the single nucleotide polymorphisms and SLE. RESULTS: We found evidence for linkage at both the FcgammaRIIIA (single-point nonparametric linkage [NPL] 1.8, P = 0.038; multipoint NPL 2.7, P = 0.004) and the FcgammaRIIA (single-point NPL 2.0, P = 0.021; multipoint NPL 2.6, P = 0.006) loci, but not the FcgammaRIIIB locus. Family-based tests of association demonstrated increased transmission of the low-affinity F176 allele at the FcgammaRIIIA locus (odds ratio [OR] 2.18, P = 0.0005 by transmission disequilibrium test and P = 0.002, by pedigree disequilibrium test [PDT]), but little evidence of preferential transmission of alleles at FcgammaRIIA (P = 0.089 by PDT). Stratification by ethnicity showed preferential transmission of the associated FcgammaRIIIA allele both in families of African American ancestry and in those of European American ancestry. Despite significant linkage disequilibrium between these genes, 2- and 3-locus haplotype analysis of the extended Fcgamma receptor cluster did not reveal any significant association beyond that observed with FcgammaRIIIA alone. In a large case-control replication study of 438 patients with SLE and 219 controls, FcgammaRIIIA provided the strongest evidence of an FcgammaR-SLE association (additive model: V/V 176 versus V/F 176 OR 1.51, V/V 176 versus F/F 176 OR 1.98, P = 0.007). CONCLUSION: To our knowledge, these data are the first to demonstrate linkage and both family-based and case-control-based association of FcgammaRIIIA with SLE. These data provide genetic evidence supporting a role for the physiologically relevant single nucleotide polymorphism of the FcgammaRIIIA gene in the pathophysiology of this complex genetic disease.     

Genetic linkage and association of Fcγ receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus

Objective

Although low‐affinity alleles of human Fcγ receptor types IIA and IIIA (FcγRIIA and FcγRIIIA, respectively) polymorphisms have been associated with systemic lupus erythematosus (SLE) in case–control studies, the relative contribution of these genes to SLE susceptibility has not been resolved.

Methods

We analyzed the distribution of alleles of FcγRIIA, FcγRIIIA, and FcγRIIIB in 126 multiplex‐SLE pedigrees and FcγRIIA and FcγRIIIA in a case–control replication study, using allele‐specific polymerase chain reaction and direct sequencing of genomic DNA. Statistical tests of association were performed to detect evidence of linkage between the single nucleotide polymorphisms and SLE.

Results

We found evidence for linkage at both the FcγRIIIA (single‐point nonparametric linkage [NPL] 1.8, P = 0.038; multipoint NPL 2.7, P = 0.004) and the FcγRIIA (single‐point NPL 2.0, P = 0.021; multipoint NPL 2.6, P = 0.006) loci, but not the FcγRIIIB locus. Family‐based tests of association demonstrated increased transmission of the low‐affinity F176 allele at the FcγRIIIA locus (odds ratio [OR] 2.18, P = 0.0005 by transmission disequilibrium test and P = 0.002, by pedigree disequilibrium test [PDT]), but little evidence of preferential transmission of alleles at FcγRIIA (P = 0.089 by PDT). Stratification by ethnicity showed preferential transmission of the associated FcγRIIIA allele both in families of African American ancestry and in those of European American ancestry. Despite significant linkage disequilibrium between these genes, 2‐ and 3‐locus haplotype analysis of the extended Fcγ receptor cluster did not reveal any significant association beyond that observed with FcγRIIIA alone. In a large case–control replication study of 438 patients with SLE and 219 controls, FcγRIIIA provided the strongest evidence of an FcγR–SLE association (additive model: V/V 176 versus V/F 176 OR 1.51, V/V 176 versus F/F 176 OR 1.98, P = 0.007).

Conclusion

To our knowledge, these data are the first to demonstrate linkage and both family‐based and case–control–based association of FcγRIIIA with SLE. These data provide genetic evidence supporting a role for the physiologically relevant single nucleotide polymorphism of the FcγRIIIA gene in the pathophysiology of this complex genetic disease.

     

The C1q binding assay in systemic lupus erythematosus

To investigate the relationship of C1q binding assay (C1qBA) to disease activity in systemic lupus erythematosus (SLE), a retrospective study was carried out on 232 C1qBA performed in 33 patients with SLE. When initial values only were assessed (33 tests in 33 patients), there was no relationship between positive and negative C1qBA and abnormal renal function (P = 0.482, Fisher exact test). Of 87 tests performed during active renal disease, 34 (39%) were positive; of 48 tests during active non-renal disease, 25(52%) were positive; of 83 tests when the disease was inactive, 45(54%) were positive; and of 14 tests during episodes of infection, 10 (71%) were positive. Corresponding means for the C1qBA were as follows: renal 65.66, non-renal 78.02, in-active 56.04, infection 135.79 (no significant differences by Student's t-test). There was no significant relationship with the C1qBA when comparing active disease (renal and non-renal) with inactive disease (X² Yates = 1.875, P = 0.171). When renal function abnormalities were analyzed separately, the C1qBA values were independent of azotemia or proteinuria (X² Yates = 1.399, P = 0.237). Patients were seen with progressive renal disease who had consistently negative C1qBA, as well as patients with benign clinical courses despite elevated C1qBA. The discordance of the C1qBA results with disease activity in SLE highlights the limitations of immune complex (IC) determinations by a single technique, and stresses the importance of evaluating such tests in terms of both their specificity and sensitivity. These data further suggest that the relationship of IC to the disease process in SLE may be a complex one.     

Evidence for the presence of autoantibodies to the collagen-like portion of C1q in systemic lupus erythematosus

We investigated the connection between the C1q solid-phase binding assay (C1q SPBA) and double-stranded DNA antibodies, and analyzed the immune complex material in systemic lupus erythematosus (SLE) sera. Comparison with a new monoclonal assay for C1q-bearing immune complexes (the 242G3 assay) revealed that the immune complexes in SLE bind specifically to solid-phase C1q, and not to fluid-phase C1q. The C1q solid-phase binding activity sedimented as 7S IgG, was insensitive to DNase treatment, and could be selectively absorbed by C1q-coupled beads and by bovine serum albumin-anti-bovine serum albumin C1q beads, but not by DNA. Thus, antibodies to double-stranded DNA do not interfere in the C1q SPBA. Isolated IgG from SLE serum precipitated the collagen-like portions, and not the globular, Fc-recognizing portions, of C1q. F(ab')2 fragments of IgG from SLE patient serum were able to bind C1q. These data show that in SLE sera, especially in those with low levels of CH50 and C1q, autoantibodies that react with the collagen-like part of C1q are detectable. Since in the C1q SPBA, the C1q molecule is randomly fixed to the solid phase, we can detect not only immune complexes, but also antibodies that react with the collagen part of C1q; this may explain the high percentage of positive results for SLE sera in the C1q SPBA, in contrast to results of other immune complex assays.     

Evidence for a susceptibility gene (SLEH1) on chromosome 11q14 for systemic lupus erythematosus (SLE) families with hemolytic anemia

Hemolytic anemia is a forme fruste of systemic lupus erythematosus (SLE), being observed months or even years before the onset of other clinical manifestations in some patients. We hypothesized that hemolytic anemia in those SLE-affected patients would identify a group of SLE pedigrees that share a high degree of genetic homogeneity. From 160 multiplex SLE pedigrees, we sought evidence for linkage in 35 (16 African-American, 17 European-American, and 2 Hispanic) who had at least one SLE-affected patient with hemolytic anemia. Significant linkage was present at 11q14 in the 16 African-American pedigrees, yielding a maximum two-point logarithm of odds (LOD) score of 4.5 at D11S2002. The segregation pattern of SLE in these African-American pedigrees suggested a dominant mode of inheritance and, when maximized across penetrance and disease allele frequencies, produced a multipoint LOD of 4.7. Multipoint analysis yielded a multipoint heterogeneity LOD score of 3.6 (alpha = 0.63), again with maximum LOD at D11S2002. Finally, markers typed 7 centimorgans to either side of D11S2002 achieved LOD scores of 3 or better by using the maximized model, supporting linkage to 11q14. Clearly, pedigree ascertainment based on select clinical manifestations is an important tool, capable of revealing otherwise cryptic genetic linkages in complex genetic diseases. Thus, we show strong evidence for an SLE susceptibility gene, SLEH1, near D11S2002 in African-American pedigrees multiplex for SLE that have at least one SLE-affected patient with hemolytic anemia.     

Anti-C1q antibodies in pregnant patients with systemic lupus erythematosus

OBJECTIVE: To study anti-C1q antibodies in pregnant patients with systemic lupus erythematosus (SLE) and to evaluate their prognostic significance for the occurrence of disease flares or pregnancy complications. METHODS: Twenty-one pregnancies in 19 SLE patients prospectively followed were analyzed. Disease activity was evaluated on the basis of the physician's intention to treat and a modified version of the ECLAM index. Anti-C1q and anti-dsDNA antibodies were detected in the sera by an ELISA assay. Antinuclear antibodies, anti-ENA antibodies, anticardiolipin antibodies and lupus anticoagulant were also performed. RESULTS: In all the patients the disease was inactive at the beginning of the pregnancy. Four flares of disease activity were observed in 4 pregnancies (19%) and obstetric complications were encountered in 7 pregnancies (43%). Anti-C1q antibodies were positive in 4 (19%) pregnancies and anti-dsDNA antibodies in 8 (38%). The presence of anti-phospholipid antibodies at the first assessment was correlated with the occurrence of obstetric complications (p<0.05). The presence of anti-C1q and anti-dsDNA antibodies at the first assessment had no prognostic significance for the occurrence of flares or obstetric complications during the course of pregnancy. Although the small number of patients studied did not allow for statistically significant analysis, flares appeared to be more likely to occur in patients presenting with anti-dsDNA or anti-C1q antibodies during pregnancy compared to patients with no changes in these antibody titers (43% vs 8% respectively). CONCLUSIONS: The presence of anti-C1q and anti-dsDNA antibodies does not seem to be prognostic for the occurrence of flares during pregnancy. Further studies are warranted to explore this possibility.     

Linkage at 5q14.3-15 in multiplex systemic lupus erythematosus pedigrees stratified by autoimmune thyroid disease

OBJECTIVE: To identify genetic effects potentially shared between systemic lupus erythematosus (SLE) and autoimmune thyroiditis (AITD). METHODS: Families from the Lupus Multiplex Registry and Repository were studied in which there was at least 1 member who had both SLE and AITD (Graves' disease or Hashimoto thyroiditis). Genome scan genotyping findings in these pedigrees were evaluated for evidence of genetic linkage, by the maximum-likelihood parametric method. Nineteen pedigrees were used in the initial genome scan. Subsequently, an independent sample of 16 pedigrees was used to replicate findings. RESULTS: Studies of the first set of 19 pedigrees yielded a 2-point parametric logarithm of odds (LOD) of 4.97, which was independently confirmed in the replication sample of 16 pedigrees (LOD 2.89). For all 35 pedigrees together, the 2-point LOD was 7.86, under a dominant model used for screening with 90% penetrance and a disease allele frequency of 10%. The multipoint locus homogeneity LOD in the 35 pedigrees was 6.90 (alpha = 1.0) at 5q14.3-15 between D5S1725 and D5S1453, a 12-cM interval, with the peak at D5S1462 at 96.64 cM (nonparametric linkage P = 0.00002). Fine mapping further confirmed the genetic linkage effect and narrowed the region likely to contain the gene to approximately 5 Mb. CONCLUSION: These results suggest that stratifying SLE pedigrees by the presence of other autoimmune disorders may facilitate the discovery of genes related to SLE and that 5q14.3-15 harbors a susceptibility gene shared by SLE and AITD.     

Stratification of pedigrees multiplex for systemic lupus erythematosus and for self-reported rheumatoid arthritis detects a systemic lupus erythematosus susceptibility gene (SLER1) at 5p15.3

OBJECTIVE: Arthritis is a common manifestation in systemic lupus erythematosus (SLE), appearing in approximately 85% of patients. Often, the polyarthritis at presentation of SLE cannot be distinguished from rheumatoid arthritis (RA) by physical examination or history. Indeed, physicians initially tell many SLE patients that they have RA (one source of "self-reported RA"), only to have SLE established later. In addition, RA aggregates in families with an SLE proband. We predicted that pedigrees multiplex for both SLE and for self-reported RA would better isolate particular genetic effects. If this proved to be true, we would then use the increased genetic homogeneity to more easily reveal genetic linkage. METHODS: From a collection of 160 pedigrees multiplex for SLE, we selected 36 pedigrees that also contained >or=2 members with self-reported RA (19 pedigrees were African American, 14 were European American, and 3 were of other ethnic origin). Data from a genome scan of 307 microsatellite markers were evaluated for SLE linkage by contemporary genetic epidemiologic techniques. RESULTS: The most significant evidence of linkage to SLE was obtained at 5p15.3 in the European American pedigrees by both parametric (logarithm of odds [LOD] score 6.2, P = 9.3 x 10(-8)) and nonparametric (LOD score 6.9, P = 1.7 x 10(-8)) methods. The best-fitting model for this putative SLE gene in this region was a recessive gene with a population frequency of 5% and with 50% penetrance in females and 15% penetrance in males at virtually 100% homogeneity. CONCLUSION: For a genetically complex disease phenotype, an unusually powerful linkage has been found with SLE at 5p15.3 in European American pedigrees multiplex for SLE and for self-reported RA. This result predicts the presence of a gene at the top of chromosome 5 in this subset of patients that is important for the pathogenesis of SLE.     

Significance of low molecular weight C1q in systemic lupus erythematosus.

The significance of high serum concentrations of low molecular weight C1q (LMW-C1q) in patients with systemic lupus erythematosus (SLE) was studied. Concentrations of LMW-C1q were increased in SLE, but not in rheumatoid arthritis or acute poststreptococcal glomerulonephritis. Concentrations of LMW-C1q in SLE serum samples correlated with titres of anti-dsDNA and were inversely related to concentrations of normal C1q and C3. Serial studies in six patients, who had rising anti-dsDNA titres and who developed a major exacerbation requiring admission to hospital, showed that LMW-C1q increased in parallel with anti-dsDNA, reaching peak values of more than 2000% of normal just before or at the time of clinical relapse and decreasing during convalescence. Most marked increases in LMW-C1q were noted in the three patients in whom C1q concentrations remained normal, whereas increases were less in the three patients who had strongly depressed concentrations of normal C1q. A study of C1q biosynthesis by macrophages cultured from patients with SLE and high serum concentrations of LMW-C1q did not show impaired secretion of normal C1q in favour of LMW-C1q, but indicated that serum concentrations of LMW-C1q may reflect the synthetic rate of C1q in vivo. The results show that increased serum concentrations of LMW-C1q may be helpful in diagnosing SLE and suggest that serial determination of LMW-C1q in serum may have predictive value in monitoring patients with SLE.     

Update on human systemic lupus erythematosus genetics

PURPOSE OF REVIEW: Susceptibility to systemic lupus erythematosus (SLE) has a genetic component. In recent years, nine complete genome scans using family collections that differ greatly in ethnic compositions and geographic locations have identified several strong, confirmed SLE susceptibility loci. Evidence implicating individual gene polymorphisms (or haplotypes) within some of the linked intervals has been reported. This review highlights recent findings that may lead to the identification of putative genes and new insights in the pathogenesis of SLE. RECENT FINDINGS: Eight of the best-supported SLE susceptibility loci are 1q23, 1q25-31, 1q41-42, 2q35-37, 4p16-15.2, 6p11-21, 12p24, and 16q12. These are chromosomal regions exhibiting genome-wide significance for linkage in single studies and suggestive evidence for linkage in other samples. Linkage analyses conditioning on pedigrees in which one affected member manifesting a particular clinical condition have also yielded many chromosomal regions linked to SLE. The linked interval on chromosome 6p has been narrowed to 0.5 approximately 1.0 Mb (million basepairs) of 3 MHC class II containing risk haplotypes in white subjects. Cumulative results have shown that hereditary deficiencies of complement component C4A (a MHC class III gene) confer risk for SLE in almost all ethnic groups studied. The FcgammaR genes (located at 1q23) have been convincingly demonstrated to play an important role in susceptibility to SLE (and/or lupus nephritis). The evidence for the intronic single nucleotide polymorphism of program cell death gene 1 (PDCD1 at 2q37) to confer susceptibility is promising but not yet compelling. Within several established susceptibility loci, evidence for association of positional candidate genes is emerging. SUMMARY: Further replications of linkage and association are the immediate task. The respective contribution of each susceptibility gene, relationships between genotypes and phenotypes, and potential interactions between susceptibility gene products need to be elucidated. This line of investigation is now well poised to provide novel insights into how genetic variants can affect functional pathways leading to the development of SLE.     

Y chromosome microchimerism in patients with systemic lupus erythematosus

Aim of the workTo identify the association of Y chromosome microchimerism with systemic lupus erythematosus (SLE) and investigate its relation to pregnancy history, clinical and laboratory variables.Patients and methodsThe presence of Y chromosome microchimerism was screened in 90 females including 35 women with renal lupus, 25 patients with cutaneous lupus and 30 healthy control females using real time polymerase chain reaction. Demographic parameters, reproductive history, clinical and laboratory data were recorded.ResultsThe percentage of Y chromosome microchimerism was significantly higher in SLE patients compared to healthy women and in females with renal lupus versus those with cutaneous lupus. Among patients with renal lupus, Y chromosome microchimerism was strongly associated with disease activity and damage indices as well as with number of pregnancies, while this association was absent regarding number of pregnancies in cutaneous lupus females. A significant increase in disease activity and severity scores was detected in microchimeric renal lupus females when compared to microchimeric cutaneous lupus patients. Healthy control and cutaneous lupus women with microchimerism experienced significant decrease in number of pregnancies and abortions against microchimeric renal lupus group.ConclusionsThese results may provide a preliminary suggestion that Y chromosome microchimerism could have a pathogenic role in SLE and it may be related to inflammation, the extent of disease damage and reproductive history. Further studies are needed among SLE patients with different clinical presentations, as fetal microchimerism is a promising field of investigation which may lead to novel strategies in treatment.     

Genome scan of systemic biomarkers of vascular inflammation in the Framingham Heart Study: evidence for susceptibility loci on 1q

Vascular inflammation plays a central role in atherosclerosis and inflammatory biomarkers predict risk of cardiovascular disease (CVD). Thus, finding genes that influence systemic levels of inflammatory biomarkers may provide insights into genetic determinants of vascular inflammation and CVD. We conducted variance-component linkage analyses of blood levels of four biomarkers of vascular inflammation [C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1)] in 304 extended families from the Framingham Heart Study, using data from a 10cM genome scan. We computed p-values by a permutation approach. Heritability estimates ranged from 14% (IL-6) to 44% (MCP-1) after log transforming and adjusting for covariates. Significant linkage to MCP-1 was found on chromosome 1 (LOD=4.27 at 186cM; genome-wide p=0.005), in a region containing inflammatory candidate genes such as SELE, SELP (E- and P-selectin) and CRP. Other linkage peaks with LOD scores >2 were found for MCP-1 on chromosome 1 (LOD=2.04 at 16cM; LOD=2.34 at 70cM) and chromosome 17 (LOD=2.44 at 22cM) and for sICAM-1 on chromosome 1 at 229cM (LOD=2.09) less than 5cM from the interleukin-10 (IL10) gene. Multiple genes on chromosome 1 may influence inflammatory biomarker levels and may have a potential role in development of CVD.     

Anti-chromatin and anti-C1q antibodies in systemic lupus erythematosus compared to other systemic autoimmune diseases

OBJECTIVE: To evaluate the prevalence, sensitivity, and specificity of anti-chromatin and anti-C1q antibodies in systemic lupus erythematosus (SLE) and lupus nephritis compared to small vessel vasculitis and other connective tissue diseases. To provide long-term follow-up data for anti-chromatin antibodies in lupus nephritis. METHODS: We determined the significance of anti-nuclear antibodies (ANA), anti- double-stranded DNA (anti-dsDNA), anti-chromatin, and anti-C1q antibodies, as well as complement factors C3 and C4, in relation to disease activity in SLE patients with (n = 47; long-term follow-up data for 33 patients) and without (n = 31) biopsy-confirmed lupus nephritis, microscopic polyangiitis (n = 37), Wegener's granulomatosis (n = 66), primary Sj?gren's syndrome (n = 17), limited scleroderma (CREST syndrome) (n = 6), and progressive systemic scleroderma (PSS) (n = 11). RESULTS: Anti-chromatin antibodies were more specific and sensitive than anti-C1q antibodies in distinguishing SLE patients from those with other systemic autoimmune diseases [anti-chromatin: sensitivity 64.1%, specificity 99.2%, odds ratio (OR) 219.6; anti-C1q: sensitivity 50%, specificity 72.6%, OR 2.65]. Anti-C1q antibodies were present in 75% of patients with Sj?gren's syndrome and 35.1% of patients with microscopic polyangiitis. Anti-chromatin antibodies could identify SLE in patients with positive ANA but negative anti-dsDNA antibodies. Persisting anti-chromatin antibodies indicated SLE disease activity, even if anti-dsDNA antibodies had become negative. In long-term follow-up, those SLE patients with negative anti-dsDNA antibodies but persisting ANA and anti-chromatin antibodies relapsed if immunosuppression had been tapered. Anti-chromatin antibodies correlated with the SLE disease activity index (SLEDAI) as a marker of disease activity. CONCLUSIONS: The measurement of anti-chromatin, but not anti-C1q, antibodies in patients with systemic autoimmune diseases increases diagnostic sensitivity and specificity for SLE and assists in treatment decisions in anti-dsDNA-negative patients.     

Predictive value of IgG autoantibodies against C1q for nephritis in systemic lupus erythematosus.

OBJECTIVES--Antibodies against C1q (C1qAb) have been demonstrated in the serum of patients with several immune complex diseases. Patients, particularly those with lupus nephritis, were found to have increased serum titres of IgG C1qAb in a cross-sectional analysis. In the present prospective study correlations were sought between serum titres of IgG C1qAb and clinical as well as laboratory parameters of disease activity in patients with systemic lupus erythematosus (SLE). METHODS--Titres of IgG C1qAb in the serum of 68 SLE patients were measured serially during a three year period. At the same time clinical and laboratory parameters of disease activity were assessed. RESULTS--Increased titres of IgG C1qAb were found in the serum of 56% of SLE patients during the study. Significant correlations were found between increased titres of IgG C1qAb and renal involvement. Clinical signs of renal involvement were found to be associated with significant increases of serum titres of IgG C1qAb in the six months preceding this appearance. Fifty per cent of the increases in serum titres of IgG C1qAb were followed by the development of renal involvement. Elevated serum titres of IgG C1qAb were especially related to proliferative forms of glomerulonephritis. Furthermore, significant correlations were found between serum titres of IgG C1qAb and serum levels of immune complexes, levels of complement components, and titres of antibodies to DNA. CONCLUSIONS--The results suggest that IgG C1qAb play a pathogenic role in the development of lupus nephritis and that serial measurement of serum titres of IgG C1qAb is useful in the management of SLE patients.     

系统性红斑狼疮患者C1q受体和C1q抗体的表达及其与发病相关性的研究

目的 检测系统性红斑狼疮（SEE）患者外周血单个核细胞C1qRp和gC1qR的表达及与C1q抗体、补体C1q水平的关系，并进一步探讨其在SLE发病中的意义。方法 用流式细胞计数法测定58例SLE和30名正常人外周血中性粒细胞、单核细胞、淋巴细胞的C1qRp和gc1qR的表达，同时测血清C1q抗体、C1q水平．并将其与C3、c4、抗核抗体（ANA）、抗dsDNA抗体、SLEDAI积分做相关性分析。结果 SLE患者外周血中性粒细胞、单核细胞的C1qRp表达为（7．2±2-3）％和（3．4±2．1）％，均较正常人[（10．6±2．1）％和（9．0±8．7）％]降低（P〈0．05），淋巴细胞不表达C1qRp，但可表达gC1qR。C1qRp在SLE活动期表达略低于稳定期，但差异无统计学意义。SLE患者的gC1qR表达略高于正常人．gC1qR在活动期高于稳定期，但差异无统计学意义。SLE患者血清C1q抗体水平（98±41）U／ml，明显高于正常，C1q为（0．13±0．08）dE，低于正常值。外周血单个核细胞的C1qRp表达与血清C1qAb水平（Pearsonr=-0．574，P〈0．05）、双链DNA（ds—DNA）抗体滴度呈负相关，与补体C1q（Pearsonr=0．673．P〈0．01）、C3、C4水平呈正相关。gc1qR与C1qAb和补体C1q无明显相关性。结论 SLE患者外周血中性粒细胞、单个核细胞C1qR的表达缺陷，导致SLE吞噬功能受损，凋亡细胞清除障碍，诱导产生自身抗体，在SLE的免疫发病机制中起重要的作用。     

Prolactin in human systemic lupus erythematosus.

In the last decade, evidence has accumulated to support the hypothesis that both mild and moderate elevations of serum prolactin (PRL) participate in the clinical expression and pathogenesis of systemic lupus erythematosus (SLE). Hyperprolactinemia (HPRL) has been found in 20-30% of patients with SLE. HPRL seems to be associated with clinical activity of SLE during pregnancy. Although the relationship between HPRL and active SLE in non-pregnant patients is controversial, recent clinical and experimental studies support the potential role of prolactin (PRL) as a promoter of clinical activity and severity of SLE. Mild elevations of serum PRL secondary to microadenoma could trigger the onset of SLE in a subset of patients. Elevated PRL and interleukin (IL)-6 have been found in the urine of patients with active lupus nephritis and in cerebrospinal fluid (CSF) of patients with active central nervous system (CNS) SLE. PRL may therefore participate in the pathogenesis of lupus nephritis and cerebritis, and the presence of PRL may reflect an abnormal communication between the immune system and the neuroendocrine system in active SLE. Lymphocytes from patients with active SLE produce increased amounts of PRL, and this extrapituitary PRL may participate in aberrant immune processes in SLE. There is exciting new evidence that HPRL in SLE may be explained by stimulation of pituitary PRL secretion by cytokines. In addition, defects in peptidergic modulators and dopamine metabolism have been described in patients with SLE. The interactions between PRL, cytoquines, autoantibodies and organ involvement suggest that PRL participates in local and generalized immune and inflammatory processes and acts as a bridge between the neuroendocrine and immune systems in SLE. Understanding the interactions between these systems in SLE will help us to understand and treat this important autoimmune disease.