ASE-1: an autoantigen in systemic lupus erythematosus

ASE-1 is a 55 kDa nucleolar autoantigen. We show that autoantibodies to this antigen occur at a higher frequency in the sera of patients with SLE than in other systemic rheumatic diseases and that the specificity of ASE-1 as a serum marker of SLE increases as the number of epitopes recognized by the sera increases. Autoantibodies to ASE-1 were temporally associated with autoantibodies to HsEg5 but were not found in conjunction with other known serum markers of SLE. The frequency of antibodies to ASE-1 epitopes in a SLE cohort was approximately the same as anti-dsDNA. However, anti-dsDNA is associated with renal involvement, whereas ASE-1 reactivity shows an association with a history of serositis. We conclude that ASE-1 is correlated with serositis and that ASE-1 should be added to a list of autoantigens that are considered important serological features of SLE.     

The centromere kinesin-like protein,CENP-E. An autoantigen in systemic sclerosis

Objective. Autoantibodies directed against centromere proteins (CENPs) are a serologic feature in some patients with systemic sclerosis (SSc). Previous studies have focused on autoantibodies to CENPs A, B, and C. CENP-E is a recently described 312-kd protein that also localizes to the centromere. Therefore, we studied the presence of autoantibodies to recombinant CENP-E in patients with SSc. Methods. Sixty sera from patients with the SSc spectrum of diseases were screened for the presence of autoantibodies against CENP-E, by indirect immunofluorescence and immunoblotting using recombinant CENPE protein. HLA class II alleles were determined by DNA oligotyping. Results. Among the SSc sera, 15 of 60 (25%) demonstrated antibody reactivity with recombinant CENP-E, and 14 of these 15 sera (93%) had antibodies directed against another CENP. Anti–CENP-E was seen in 13 of 30 sera with anti-CENP (43%). All patients with anti–CENP-E had a limited form of SSc, known as the CREST variant (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias). When patients with anti-CENPs A, B, or C were compared with patients with anti–CENP-E, no unique clinical features in the anti–CENP-E positive group were identified. Ninety-three percent of the patients with anti–CENP-E had HLA–DQB1 alleles that had polar amino acids at position 26 (primarily DQB1*05), similar to patients with other CENP autoantibodies. Conclusion. Antibodies to CENP-E are common in patients with SSc, and are seen in higher frequency in sera from patients with a limited form, or CREST variant, of the disease.     

Mannose-binding protein gene polymorphism in systemic lupus erythematosus

Objective. To determine whether an allelic form of mannose-binding protein (MBP) incapable of activating complement is associated with susceptibility to systemic lupus erythematosus (SLE). Methods. MBP allele frequencies were determined by amplification refractory mutation system–polymerase chain reaction in 102 white SLE patients and 136 controls. Results. The MBP allele that is unable to activate complement was present in 42 SLE patients (41%) and in 41 controls (30%) (P = 0.08, odds ratio [OR] = 1.6, 95% confidence interval [95% CI] 1.0–2.8). The gene frequency of this allele was 0.25 in SLE patients and 0.19 in controls (P = 0.08, OR = 1.5, 95% CI 1.0–2.3). Conclusion. Our results suggest that this allele of the MBP gene represents a minor risk factor for SLE.     

系统性红斑狼疮抗活化的蛋白C研究

目的　了解抗活化的蛋白C(APCR)在系统性红斑狼疮 (SLE)患者中的发生情况 ,并进一步探讨SLE患者发生血栓的机制。方法　采用APC KPTT法 ,ELISA法和PTT LA法分别对5 0例SLE患者及 2 0例正常对照 (NC)进行APCR、抗心磷脂抗体 (ACA)和狼疮抗凝物 (LA)检测。结果　SLE患者APCR阳性率 ( 5 8% )明显高于NC组 ( 5 % ) (P <0 0 0 5 ) ,APCR阳性患者中血栓发生率( 2 7 6% )明显高于APCR阴性患者 ( 4 8% ) (P <0 0 1) ,患者LA阳性率 ( 2 2 % )明显高于对照组 ( 0 /10 ) (P <0 0 5 ) ,患者ACA IgG及IgM明显高于对照组 (P <0 0 5 ) ,而IgA与对照组差异不显著 (P >0 0 5 ) ,LA阳性组中的APCR阳性率 ( 90 9% )明显高于LA阴性组 ( 5 3 8% ) (P <0 0 5 ) ,ACA阳性组中的APCR阳性率 ( 64 7% )与ACA阴性组 ( 60 6% )未发现明显相关性 (P >0 0 5 )。结论　APCR在国人SLE患者中有较高的发生率且与LA有明显相关性 ,APCR可能是SLE患者诱发血栓的主要原因之一。     

Studies of serum C-reactive protein in systemic lupus erythematosus

OBJECTIVE: To examine the relationship of serum C-reactive protein (CRP) levels to other indicators of disease activity during the course of systemic lupus erythematosus (SLE). METHODS: In 124 patients serum CRP was measured retrospectively by ELISA and in some instances by radial immunodiffusion. Serum CRP levels were compared to laboratory, clinical, and radiographic assessments of disease activity. In many patients, serial CRP levels were measured over months or years to determine whether elevations of serum CRP reflected apparent changes in other disease activity variables. CRP was also measured in lyophilized aliquots of 24 h urine samples from SLE patients and controls with other renal disorders. Parallel determinations of interleukin 6 (IL-6) were made by ELISA in healthy controls and SLE patients. RESULTS: Of the 124 SLE patients studied, most showed elevations in serum CRP levels in the course of their disease. No inverse or direct correlation was noted between serum CRP and levels of nucleosome antigen or serum IgM or IgG anti-DNA antibody. In patients with renal involvement and proteinuria, CRP was often detected in 24-h urine samples. A strong correlation (p < 0.001) was noted between CRP and IL-6 levels in healthy subjects, but no correlation was recorded between serum CRP and IL-6 in SLE. CONCLUSION: Contrary to previous reports, most patients with SLE in our study showed elevations of serum CRP during the course of their illness, and extremely high serum CRP was recorded in some patients. CRP was also found in concentrated urine samples from patients with renal involvement and often paralleled elevated serum levels. In patients, no correlation was seen between CRP serum levels and serum IL-6, whereas a strong correlation between CRP level and IL-6 was recorded in healthy subjects.     

Serum interleukin-15 is elevated in systemic lupus erythematosus

OBJECTIVE: To investigate if interleukin-15 (IL-15) (rather than IL-2) is increased in systemic lupus erythematosus (SLE) and might be responsible for immunological abnormalities of SLE such as the increased lymphocytic expression of Bcl-2 and CD25. METHODS: Serum IL-15, IL-2 and tumour necrosis factor (TNF) levels of 65 SLE patients, 20 healthy persons and 10 rheumatoid arthritis (RA) patients were measured by enzyme-linked immunosorbent assay (ELISA). For 25 SLE patients, the percentage of CD25 + lymphocytes and the lymphocytic Bcl-2 levels were simultaneously determined by fluorocytometry. Peripheral blood mononuclear cells (PBMC) of 15 SLE patients were incubated with or without recombinant IL-15 and the influence on Bcl-2 and CD25 was determined. RESULTS: IL-15 was found to be elevated in 25 SLE sera (38%), but in none of the 20 healthy sera (P = 0.0005) and none of the 10 RA sera. Both lymphocyte CD25 and Bcl-2 expression significantly correlated with serum IL-15 and were increased by recombinant IL-15. CONCLUSION: Serum IL-15 may in part be responsible for the immunological abnormalities seen in active SLE.     

Chylomicron metabolism is markedly altered in systemic lupus erythematosus

OBJECTIVE: To verify the in vivo status of chylomicron metabolism in systemic lupus erythematosus (SLE) since there is a high incidence of atherosclerosis in this disease and chylomicrons may have an important role in atherogenesis. METHODS: A chylomicron-like emulsion labeled with 14C-cholesteryl esters and 3H-triglycerides was injected intravenously into 10 female patients with inactive SLE and 10 healthy age- and sex-matched control subjects to determine the plasma kinetics of the emulsion lipids from consecutive plasma samples taken at regular intervals for 1 hour. Lipolytic activity was determined in vitro after incubation of the labeled emulsion with postheparin plasma. RESULTS: The decay curves for the emulsion were markedly slowed in SLE. Chylomicron lipolysis, indicated by the fractional clearance rate (FCR) of emulsion 3H-triglyceride, was 2-fold smaller in SLE patients than in controls (mean +/- SD 0.023 +/- 0.011 versus 0.047 +/-0.015 minute(-1); P = 0.010). Chylomicron removal, indicated by emulsion 14C-cholesteryl ester FCR, was 3-fold smaller in SLE patients than in controls (0.007 +/-0.007 versus 0.023 +/- 0.011 minute(-1); P = 0.009). In vitro lipolysis in SLE patients was nearly half that of the controls (mean +/- SD 10,199 +/- 2,959 versus 6,598 +/-2,215; P = 0.014). Higher levels of very-low-density lipoprotein cholesterol and triglycerides and lower levels of high-density lipoprotein cholesterol and apolipoprotein A-I were also observed in the SLE patients. CONCLUSION: SLE patients have disturbances in chylomicron metabolism that are characterized by decreased lipolysis and chylomicron remnant removal from the plasma. This finding, together with other alterations in lipid profiles that were confirmed in the present study, is largely accountable for the accelerated atherosclerotic process of the disease.     

Antibodies to protein P in systemic lupus erythematosus.

A synthetic peptide was used to develop an enzyme linked immunosorbent assay (ELISA) to detect antibodies to the ribosomal proteins P0, P1, and P2. Significantly increased levels of IgG antibodies to protein P were found in 16% (18/116) of patients with systemic lupus erythematosus but slightly increased levels were detected in 2% (2/98) of patients with rheumatoid arthritis and one normal control subject. No association was observed between the presence of IgG antibodies to protein P and either lupus psychosis or depression. Sequential studies in individual patients failed to show an association between antibody levels and the development of psychosis.     

C-Reactive protein and its implications in systemic lupus erythematosus

C-reactive protein CRP is an acute-phase protein known as a biomarker for inflammation. As such CRP levels have been traditionally used to detect and predict the outcome of infections inflammatory and necrotic processes and to monitor the efficacy of treatment in these conditions. With the development of high sensitivity assays CRP has resurfaced as a very strong predictor in cardiovascular disease and as a mediator of atherosclerosis. The Centers for Disease Control and American Heart Association have elaborated guidelines for the use of CRP in the primary prevention setting and in patients with stable coronary disease or acute coronary syndromes. CRP has been used for differentiation between Systemic Lupus Erythematosus activity and infection in individuals without serositis. More recently CRP has also elicited interest as a therapeutic option in lupus. Murine lupus models treated with CRP have been reported to present delayed Lupus onset decreased antibody levels enhanced survival and reversal of ongoing proteinuria. In this paper we reviewed the multiple roles of CRP particularly in lupus.     

Silica-associated systemic lupus erythematosus in an elderly man

The predominantly young woman-orientated systemic lupus erythematosus (SLE) is a disease that involves an extremely complicated and multifactorial interaction of various genetic and environmental factors. Crystalline silica (Si) may act as an immunoadjuvant to increase secretions of inflammatory endogenous substances and antibody production. In addition, previous studies have suggested that exposure to Si may induce SLE. Although the biologic mechanism of Si in SLE is unclear, defective apoptosis leading to the prolonged survival of pathogenic lymphocytes was thought to be one of mechanisms of Si-associated SLE (sSLE). In the present study, a rare case of an elderly man suffering from sSLE responded well to glucocorticoid therapy. The present findings were reviewed with reference to previous literature.     

Psychiatric symptoms before systemic lupus erythematosus is diagnosed

Psychiatric symptoms are rarely reported as an initial feature of systemic lupus erythematosus (SLE). Nevertheless, many patients have the feeling that psychiatric symptoms occurred before they were diagnosed as having SLE. This feeling was confirmed by an enquiry among members of the Dutch Lupus Patients Society: half of them had experienced psychiatric complaints before SLE was diagnosed. Two-thirds of these patients searched for professional help for these complaints. This motivated us to study whether SLE patients were admitted into psychiatric hospitals without being diagnosed as having SLE. Sera from 2121 patients admitted to a psychiatric hospital and from 500 controls matched for sex and age were tested for the presence of antinuclear antibodies (ANA) and antibodies to DNA. ANA were found in 3% of patients, as well as controls. Anti-DNA antibodies were found in 1% of both patients and controls. Two out of 114 patients psychiatric patients with ANA and/or anti-DNA antibodies had SLE and/or Sjögren's syndrome. We concluded that SLE is not an important cause of admission to psychiatric hospitals. Routine tests for the determination of antinuclear and anti-DNA antibodies on admissions in these hospitals thus would not seem useful. To study whether patients with another chronic disease also had psychiatric complaints before being diagnosed, we performed the same enquiry among members of the Dutch Sarcoidosis Patients Society. The results were almost equal to those of the enquiry of the members of the Dutch Lupus Patients Society. Why members of both societies so often report psychiatric symptoms before their disease is diagnosed should be a subject of further studies.     

The complement system in systemic lupus erythematosus

The etiology of SLE is multifactorial with an important genetic impact. Several genes involved in control of autoimmunity and inflammation appear to be important. Hereditary complement deficiency states are associated with increased risk of SLE, but contribute only marginally to the incidence of SLE in the population. However, these conditions have contributed considerably to the knowledge of pathogenetic mechanisms in this disease. Furthermore, acquired complement deficiency is a common finding in SLE. Complement has important protective functions but also contributes to tissue damage. Measurement of classical pathway complement components is important in the diagnosis of SLE and for monitoring of immune complex mediated manifestations, especially proliferative glomerulonephritis. New complement activation tests, although promising in studies of selected patient groups, have not yet been proven to be of clinical value.     

The epidemiology of systemic lupus erythematosus

The present review has focused on the methods and results of epidemiological studies of SLE for clues to its etiology based on reports of the occurrence of SLE in the general population and on the conditions under which it is likely to occur. The review covers the period from 1950 to 1972, and is limited to idiopathic SLE.Reports of population studies on SLE were published from four widely scattered regions, namely, New York City; Jefferson County, Alabama; Rochester, Minnesota; and Malmo, Sweden. Geographic variations in the prevalence of the disorder were observed, which were largely attributed to regional differences in completeness of case finding. The reported crude rates were highest in Rochester, lowest in Jefferson County, and at an intermediate level in Malmo and New York City where the findings were similar.In New York City, the annual incidence of newly occurring cases of idiopathic SLE from 1956 to 1965 appeared to be stabilized at a level of about 2.5/100,000 general population, while the prevalence of existing cases rose progressively from 4.1 to 15.5 per 100,000 during the same 10-yr period. The even level in incidence trend indicated that the occurrence of SLE was not appreciably influenced by changes in host or environmental conditions during the study period. The steady increase in prevalence was attributed to earlier recognition of the disease and to longer survival because of improved therapy. The annual mortality was roughly half the incidence in the decade 1956–1965.The specific incidence of the disease by age and sex was usually highest at 15–44 yr of age, while its prevalence was maximal at 45–64 yr. The respective incidence and prevalence rates at these ages were 14.0 and 90.9/100,000 for black females and 3.8 and 27.6 for white females in New York City. The rates among Puerto Ricans appeared to be intermediate between those for blacks and whites. However, some of the evidence on age and SLE pointed to an earlier age-distribution of cases among Puerto Ricans than among blacks or whites.The risk of SLE was higher for black females than whites in both New York City and Jefferson County, Alabama, according to cooperative studies there. In males, however, the comparative results on ethnic differences in the occurrence of SLE were conflicting and inconclusive because of the small number of cases in each area.The higher rates of SLE for blacks and Puerto Ricans could not be related to more complete case finding or to unfavorable environmental conditions in low socioeconomic groups. On the other hand, the results appeared to be related to underlying ethnic differences in immune mechanism, according to studies on serum gamma globulin level and Mantoux reaction to BCG in normal subjects.Familial studies revealed some evidence of an increase in serum gamma globulin, and possibly in antinuclear factor and other SLE-related immunological and clinical abnormalities among first-degree relatives of SLE cases. The findings were indicative of a demonstrable familial or a genetic influence in the occurrence of the disorder. The abnormalities were mainly concentrated in selected families, and environmental factors could not be excluded. However, the occurrence of the disease was found to be independent of birth order, an indication that it represents a random event consistent with genetic factors and unrelated to change with time in parity, parental age, and related environmental influences.More direct evidence for genetically determined host factors in the predisposition to SLE has been sought in studies on the relationship of the disorder to the histocompatibility (HL-A) antigens which may be closely linked to the activity of the immune mechanism. Thus far, different specific HL-A antigens, viz., A5, A7, A8, A13, W5, W15, and an X type, were observed by various investigators in association with SLE and the risk of developing the disease. Whether these diverse findings have biological significance or are artifacts attributable to chance and other factors unrelated to SLE is still not known.In the predisposed subject, each of the three broad groups of environmental agents, namely, physical, chemical, and biologic, has been associated with SLE. The relationship of the disorder to physical agents such as ultraviolet radiation and trauma has been well documented in past clinical experiences. The association of SLE and chemical agents described in early clinical reports on inducing factors has been strengthened by many studies on procainamide, hydralazine, and other drugs responsible for an increased frequency of drug-induced SLE. Interest in the role of biological agents has been renewed by reports on increased antibody levels for paramyxovirus and other viral antigens in affected patients, and the detection of cellular inclusions resembling paramyxoviruses in cases of SLE and other disorders. Whether these widespread findings in man are coincidental manifestations of SLE or evidence of persistent virus infections that may be responsible for the disease has not yet been ascertained.In animals, however, support for the role of viral and genetic factors in the pathogenesis of SLE has been well documented in the susceptibility of inbred NZB/NZW mice to SLE-like disorders, and the identification of a virus-like agent in the affected NZB mice. In susceptible dogs, also, SLE-like manifestations appear to be due to genetic and nongenetic factors, presumably of viral origin.