Is immunogenetic susceptibility to neuropsychiatric systemic lupus erythematosus (SLE) different from non-neuropsychiatric SLE?

OBJECTIVES: To analyse frequency of HLA class II antigens (DR and DQ) and lymphocytotoxic autoantibodies in patients with systemic lupus erythematosus (SLE) and subsets with or without neuropsychiatric involvement. METHODS: Ninety three patients with SLE (42 with neuropsychiatric features) were typed for HLA class II antigens and investigated for the presence of lymphocytotoxic autoantibodies by a complement dependent microlymphocytotoxicity assay. A total of 191 controls of similar ethnic background were also typed for HLA antigens. RESULTS: HLA-DR3 antigen was increased in the total group of patients with SLE (p = 0.003) and in the neuropsychiatric group (p = 0.002). HLA-DR4 antigen frequency was increased in non-neuropsychiatric patients (p = 0.001) and decreased in patients with neuropsychiatric SLE (p = 0.0005). Comparisons of HLA frequencies between subgroups of patients showed decreased HLA-DR4 (p < 0.0001) and increased HLA-DR9 and HLA-DQ2 antigens (p = 0.0008 and 0.005 respectively) in the neuropsychiatric group. The frequency of lymphocytotoxic autoantibodies was increased in neuropsychiatric patients with SLE having HLA-DR9 specificity (p = 0.04). CONCLUSION: HLA-DR4 may have a protective specificity for the development of neuropsychiatric features of SLE and HLA-DR9, in addition to HLA-DR3, and the presence of lymphocytotoxic auto-antibodies may predispose to neuropsychiatric abnormalities.     

Antiendothelial cell antibodies (AECA) in systemic lupus erythematosus (SLE)

Mitogenic activity toward MCF-7 cells of two immunoreactive (high-molecular-weight form bFGF, HMW-bFGF; and 16-K bFGF, having the same molecular weight as recombinant bFGF) purified from pooled sera of breast cancer patients by heparin-affinity chromatography and gel filtration was investigated. The mitogenic activity of 16-K bFGF toward the cells was equal to that of recombinant bFGF, whereas the mitogenic effect of HMW-bFGF was weak. Most of the mitogenic activity of these two bFGFs was neutralized by anti-bFGF antibody. Also, the mitogenic activity of both HMW-bFGF and 16-K bFGF was markedly enhanced by aspartyl protease (cathepsin D), which is secreted in excess by breast cancer cells and is responsible for the enzymatic degradation of the extracellular matrix (ECM). By an enzyme immunoassay, we detected cathepsin D-mediated release of recombinant bFGF previously bound to the ECM of MCF-7 cells into the conditioned medium, and also observed cathepsin D-mediated proteolysis of HMW-bFGF to release free 16-K bFGF. These results suggest that 16-K bFGF is the bFGF molecule itself in the blood and that HMW-bFGF is a circulating form of bFGF in blood whose mitogenic activity is regulated by cathepsin D.     

Cardiac tamponade as a clinical symptom of systemic lupus erythematosus

Upper lid closure in facial nerve paresis induced lagophthalmos is often improved by implantation of gold weights. However, the tolerability of gold implants has not always met expectations. We therefore investigated whether results could be improved by implantation of well-tolerated platinum implants. PATIENTS AND METHODS: Three patients with lagophthalmos received pretarsal platinum-iridium implants in the upper lid. The implants were primary in two patients and secondary in one. In this patient, the previous gold implant had led to marked swelling and redness of the upper lid 6 weeks after surgery. The platinum implants were prefabricated with a radius of 20 mm and weighed between 1.3 and 1.4 g. During implantation, they were individually contoured to fit lidcurvature and attached pretarsally with nonresorbable thread. RESULTS: Postoperatively, the upper lid of all three patients could be closed completely. The implants healed without irritation. No lid swelling occurred during 2-to 6-month follow-up. Because platinum-iridium alloys have a higher specific gravity (Ptlr 90/10 = 21.65 g/cm3) than gold (18.43 g/cm3), they can attain equal weight at smaller size. CONCLUSIONS: Our first results show that platinum implants are a feasible alternative to gold implants in treating lagophthalmos due to better biocompatibility and higher specific gravity.     

A case of systemic lupus erythematosus (SLE) successfully treated with mizoribine (Bredinin)

Mizoribine, a novel immunosuppressive agent developed in Japan, was administered as a monotherapy to a systemic lupus erythematosus (SLE) patient with the clinical symptoms and immunological abnormalities accompanying SLE showing marked improvement. The result of prolonged administration over 22 months in this case showed neither relapse nor side-effects. Reports have been made about mizoribine used concomitantly with steroids in the treatment of SLE; however, there have not been any reports of mizoribine as a monotherapy for SLE being effective. In this case, mizoribine (150 mg/day) was administered without steroids as a monotherapy on a outpatient basis since the patient's condition overall was relatively good and the serious complications of the heart, kidneys, and lungs that accompany SLE were not observed. The results of this treatment showed improvements in alopecia, arthritis, and systemic malaise from about the 4th week after the start of administration, and the clinical symptoms that accompany SLE had completely disappeared in the 8th week. Also, the immunological tests markedly improved. Four months after the start of administration the immunological abnormalities in the anti-DNA antibody, rheumatoid factor, and immune complex were completely corrected. This case showed dramatic improvement in the SLE clinical symptoms and immunological abnormalities with the mizoribine monotherapy as well as the potential for mizoribine monotherapy to maintain a state of remission over the long term.     

C4AQ0 superimposed on a primary defect increases the susceptibility to systemic lupus erythematosus (SLE) in a family with association between C4AQ0 and SLE

OBJECTIVE: To investigate the association of C4AQ0 with increased incidence of systemic lupus erythematosus (SLE) or positive serology (28%) in an extended Icelandic family, and whether this can be explained by impaired complement function in handling immune complexes (IC). METHODS: The ability of the classical pathway to opsonize nascent IC [alkaline phosphatase (AP)-anti-AP] and bind them to human erythrocytes was evaluated by the new ICRB assay. The capacity of erythrocytes from family members to bind nascent IC was also measured by a modification of the ICRB assay. IC levels were measured by complement consumption assay, C3d by a sandwich ELISA, factor B by immunoelectrophoresis, and the alternative pathway function by a hemolytic assay. RESULTS: Family members with homozygous or heterozygous C4AQ0 (47%) showed no impaired complement dependent opsonization of IC and binding to erythrocytes. Their factor B and alternative pathway function was normal. Fifty-six percent of the family members (n=18) had abnormally high IC levels, seemingly independent of C4AQ0. However, 6 of the 7 individuals with high IC levels and SLE symptoms had C4AQ0 compared to 2 of 11 symptom-free individuals with high IC levels. CONCLUSION: Our results suggest that the susceptibility for SLE in this family may result from 2 different defects, one leading to elevated IC levels, and another associated with C4AQ0 without detectable impairment in the complement dependent IC transport mechanism. Individuals with both abnormalities have increased susceptibility to SLE.     

Anti-C1q receptor/calreticulin autoantibodies in patients with systemic lupus erythematosus (SLE)

We report a case of acute glomerulonephritis associated with acute Q fever. An abattoir worker with a nonspecific febrile illness and pneumonia and abnormal liver function test results developed hematuria, proteinuria, and acute renal failure that resolved with appropriate antimicrobial therapy. Renal biopsy demonstrated diffuse proliferative and exudative glomerulonephritis. Serological tests confirmed recent infection with Coxiella burnetii, with a fourfold rise in the titer of phase II antibody, positive phase II IgM antibody, and negative phase I antibody. Other known causes of glomerulonephritis were excluded. Most reports of renal complications of C. burnetii infection describe glomerulonephritis associated with endocarditis due to chronic Q fever. Renal involvement in patients with acute C. burnetii infection has been rarely described. Glomerulonephritis should be recognized as a complication of acute C. burnetii infection and endocarditis due to chronic Q fever.     

Dissection of the effects of tumor necrosis factor-alpha and class II gene polymorphisms within the MHC on murine systemic lupus erythematosus (SLE)

Gene(s) in the MHC of the NZW strain (H-2z) up-regulate(s) systemic lupus erythematosus (SLE) in (NZB x NZW) F1 mice. So far, two plausible mechanisms have been implicated: (i) unique mixed haplotype class II molecules formed in the F1 mice act as a restriction element for self-reactive T cells and (ii) a unique polymorphism in the H-2-linked NZW tumor necrosis factor (TNF)-alpha allele which down-regulates TNF-alpha is contributory. Because of the difficulty in dissecting these alleles within the H-2 complex, it has not been determined which is indeed the case. We addressed this issue by establishing three different H-2-congenic (NZB x NZW) F1 mice bearing distinct haplotypes at class II and TNF-alpha regions, i.e. (NZB x NZW) F1 (H-2d/z:A(d/u)E(d/u)TNF(d/z)), (NZB x NZW.PL) F1 (H-2(d/u):A(d/u)E(d/u)TNF(d/d)) and (NZB x NZW.H-2d) F1 (H-2(d/d):A(d/d)E(d/d)TNF(d/d)). Among these, only (NZB x NZW) F1 produced a markedly lower level of TNF-alpha, due to the unique NZW TNF-alpha allele (TNF(z)). Studies of anti-DNA antibodies and lupus nephritis revealed that, compared to (NZB x NZW) F1, the disease of (NZB x NZW.H-2d) F1 was markedly reduced. In (NZB x NZW.PL) F1, the onset of renal disease was significantly delayed, while the extent of proteinuria and renal histopathology in individuals that had developed the disease was comparable to that seen in (NZB x NZW) F1. It seems likely that both class II and TNF-alpha gene polymorphisms are functioning as H-2-linked predisposing genetic elements, and that the TNF-alpha polymorphism acts to modulate an initial process of the renal disease.     

Subarachnoid hemorrhage as a form of onset of systemic lupus erythematosus

INTRODUCTION: The most frequent cause of spontaneous subarachnoid hemorrhage (SAH) is rupture of intracranial arterial aneurysms (> 70%). The remainder are due to many different aetiologies. Although SAH is a relatively common neuropathological finding in systemic lupus erythematosus (SLE), it is normally due to the extent of the intercerebral hemorrhage and not to its isolated presentation. CLINICAL CASE: We report the case of a 34 year old woman who presented with non-traumatic SAH at the onset of her lupus disorder. The patient was attended for SAH and at the same time a multisystemic disorder and severe thrombocytopenia were found, leading to a diagnosis of SLE. The neuroimaging techniques, selective cerebral arteriography, cerebral and spinal magnetic resonance, and magnetic resonance angiography did not show any vascular malformations. The patient was treated with immunosuppressive therapy, nimodipine, and following angiographic tests, with antiaggregants and anticoagulants. CONCLUSIONS: The greater frequency of SAH in patients with lupus, as compared to the general population, has been attributed to the presence of intracranial vasculitis. However, neuropathological studies have shown that true vasculitis is very infrequent in the central nervous system of SLE patients. In the case we describe, the first in which SAH appeared at the onset of the disease, we consider that the origin of the hemorrhage was her high arterial blood pressure and thrombopenia.     

Antibodies to beta 2-glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus

OBJECTIVE: To investigate whether anticardiolipin antibodies (aCL) in patients with systemic lupus erythematosus (SLE) bind to beta 2-glycoprotein I (beta 2GPI), and to search for a relationship between the presence of IgG and/or IgM anti-beta 2GPI antibody and clinical manifestations in SLE patients. METHODS: IgG and IgM anti-beta 2GPI in 308 Japanese SLE patients were measured using phospholipid-independent enzyme immunoassays. Relationships to clinical histories and to various laboratory data were examined. RESULTS: The values of anti-beta 2GPI and aCL, as measured by conventional enzyme immunoassay, showed a strong correlation, but the anti-beta 2GPI assay was more useful in distinguishing beta 2GPI-dependent aCL from beta 2GPI-independent aCL. The presence of IgG anti-beta 2GPI was associated with an increased frequency of a history of thrombosis. Comparisons of various laboratory data suggested that the titer of anti-beta 2GPI may fluctuate with disease activity. CONCLUSION: The results suggest that pathogenic aCL is directed against structurally altered beta 2GPI and that enzyme immunoassay for anti-beta 2GPI may prove useful in evaluating the risk of thrombosis and monitoring the clinical course in patients with SLE.     

Development of a clinical chart to compute different disease activity indices for systemic lupus erythematosus

Between 1990 and 1995 a European Consensus Group carried out a multicenter study to reach agreement of the definition of disease activity in systemic lupus erythematosus (SLE). A new index, the European Consensus Lupus Activity Measurement (ECLAM) index, was developed. In a second phase of the study, a prospective survey aimed at validating ECLAM and 4 other scales as steady-state and transition indices for disease activity in SLE was completed. We present the results of this survey. A standardized clinical chart was developed, together with a computer program that could automatically calculate the ECLAM score, as well as the scores for some of the disease activity scales most widely used at present, i.e., the British Isles Lupus Assessment Group, Systemic Lupus Activity Measure, SLE Disease Activity Index, and the SLE Index Score (SIS). With the participation of 28 centers in 15 different European countries, data from 121 prospectively selected new lupus patients were collected. The validity of the 5 activity scales was assessed by comparing the computed scores for each patient to a gold standard, i.e., the physician's subjective judgment on disease activity measured using a semiquantitative scale. All the indices were found to be valid instruments for measuring disease activity in SLE in both the steady-state and transition phases. The results for the various indices closely correlated with one another. Thus, the computerized chart developed by the European Consensus Group offers a simple and reliable instrument to assess disease activity and could be used to monitor lupus patients both in clinical practice and in clinical trials.     

Anti-dsDNA production coincides with concurrent B and T cell activation during development of active disease in systemic lupus erythematosus (SLE)

The objective was to serially analyse T and B cell activation in relation to autoantibody production during the development of relapses in SLE. In a prospective study we serially analysed, by flow cytometry, T cell activation in relation to B cell activation and anti-dsDNA production in quiescent SLE and during the development of a clinical relapse. In addition, we related changes in T and B cell activation to changes in levels of anti-dsDNA and total IgG. During periods with clinically quiescent disease, the expression of activation markers on T cells (IL-2R and HLA-DR) and B cells (CD38) was persistently higher in SLE than in healthy controls (P < 0.001). Percentages of CD20+ CD38+ B cells were related to levels of total IgG (P < 0.02), but not to levels of anti-dsDNA. Development of disease activity was paralleled by an increase in the percentages of CD4+ T cells (P < 0.005) and CD20+ CD38+ B cells (P < 0.001), which were interrelated. Increases in B cell activation were related to increases in levels of anti-dsDNA (P < 0.005), but not to changes in total IgG levels. B cells expressing high levels of CD38 spontaneously produced IgG class anti-dsDNA in vitro. Persistence of activated B cells during periods with clinically quiescent disease in SLE seems to underly hypergammaglobulinaemia but not anti-dsDNA production. Prior to clinical disease activity, further activation of T and B cells occurs, which is paralleled by rises of anti-dsDNA but not of total IgG. This suggests that the production of anti-dsDNA is a T cell-dependent antigen-driven process, which is independent of the polyclonal activation of the immune system inherent to the disease.     

Prevalence of the type I complement C2 deficiency gene in Swedish systemic lupus erythematosus patients

The prevalence of type I complement C2 deficiency in Swedish systemic lupus erythematosus (SLE) patients was investigated by DNA analysis. The characteristic 28 base pair deletion was determined by polymerase chain reaction analysis followed by gel electrophoresis. Five of the 86 patients (5.8%) retrieved from a defined population of 160,000 individuals were heterozygous for the C2Q0 gene compared with one heterozygote of 100 local blood donors (1%), the difference in prevalence not being significant. Among 26 other SLE patients, two patients who are siblings were C2Q0 homozygous. No distinctive clinical features among the patients with C2Q0 genes were obvious, although none had renal involvement.     

Association of systemic lupus erythematosus with promoter polymorphisms of the mannose-binding lectin gene

OBJECTIVE: To investigate the distribution of promoter variants of the mannose-binding lectin (MBL) gene and correlations between the promoter variants and serum MBL concentrations in Chinese patients with systemic lupus erythematosus (SLE) and in healthy Chinese controls. METHODS: We studied the serum MBL levels and codon 54 mutation in 112 Chinese patients with SLE and 110 healthy controls. Genotyping of promoter variants of the MBL gene were done by polymerase chain reaction and allele-specific oligonucleotide hybridization. RESULTS: We found significant differences in the distribution of the 2 pairs of promoter polymorphisms, H/L and Y/X, between SLE patients and controls (P=0.018 and P=0.019, respectively). Analysis of the correlation between promoter haplotypes and serum MBL levels revealed HY as the highest-producing, LY as the intermediate-producing, and LX as the lowest-producing haplotypes. The LX haplotype was present at a frequency of 0.259 in SLE patients and 0.154 in controls and was significantly associated with SLE (P=0.019, odds ratio 1.79, 95% confidence interval 1.12-2.85). CONCLUSION: The low-producing promoter polymorphism of the MBL gene is associated with SLE, and a low serum MBL level is a risk factor for SLE. Even allowing for promoter polymorphisms and structural mutations of the MBL gene, serum MBL levels in SLE patients are still lower than those in controls, suggesting a trans-factor in regulating serum MBL levels.     

系统性红斑狼疮患者血清增殖诱导配体水平的检测及其临床意义

目的:检测系统性红斑狼疮(SLE)和类风湿性关节炎(RA)患者血清中增殖诱导配体(APRIL)的水平,探讨APRIL水平与SLE患者临床指标的相关性及APRIL在SLE发病中的作用.方法:采用ELISA法检测SLE患者组(48例)、RA患者组(16例)和正常对照组(16例)血清APRIL水平,并与SLE活动指数(SLEDAI)及实验室指标进行对比分析.结果:SLE组和RA组血清APRIL水平高于正常对照组(P<0.01),SLE组高于RA组(P<0.01).SLE组中抗Sm抗体阳性患者APRIL水平高于阴性患者( P<0.05).抗U1-RNP抗体阳性患者APRIL水平高于阴性患者( P<0.05),抗SSA /SSB抗体、抗ACL抗体、抗ds-DNA抗体阳性和阴性患者APRIL水平差异无统计学意义.SLE患者血清APRIL水平与其补体C3、C4呈负相关关系(r1=-0.819,P<0.01;r2=-0.549,P<0.01),与SLEDAI评分、免疫球蛋白、抗核抗体谱等免疫学指标无相关性.结论:APRIL在SLE患者中特异性升高,可能在狼疮发病中起重要作用;血清APRIL水平可能与SLE患者疾病活动程度有关联,但尚不能确定是否可作为疾病活动性指标.     

Urinary loss of immunoglobulin G anti-F(ab)2 and anti-DNA antibody in systemic lupus erythematosus nephritis

The objective of this study was to determine whether the low levels of serum immunoglobulin G (IgG) anti-F(ab)2 seen in some patients with active systemic lupus erythematosus (SLE) were directly related to the deposition of antibody with this specificity in the kidney or alternatively to the urinary loss of IgG anti-F(ab)2. Serum Levels of IgG anti-F(ab)2, anti-tetanus toxoid, and anti-ds DNA antibody were measured in parallel with urinary excretion of these same 3 antibodies in 28 patients with SLE nephritis and in 28 control patients with other forms of chronic kidney disease. Low levels of both serum IgG anti-F(ab)2 or anti-tetanus antibody appeared to correlate with increased levels of urinary loss of these same antibodies in some patients with SLE and in control subjects with kidney disease. However, urinary loss could not account for low serum levels of either IgG antibody in many subjects. Quantitative 24-hour urinary losses of IgG anti-F(ab)2 and anti-DNA were much higher in patients with SLE than in control subjects with kidney disease (P < .05), whereas amounts of IgG urinary loss of anti-tetanus were similar in patients with SLE and in control subjects. In nearly 1 third of SLE nephritis patients, 13% to 53% of total excreted urinary IgG showed anti-DNA enzyme-linked-immunosorbent assay reactivity. Urinary IgG in many patients with SLE showed both anti-DNA and anti-F(ab)2 reactivity, but dual anti-DNA/F(ab)2 specificity was more pronounced in affinity-isolated serum IgG anti-DNA or anti-F(ab)2 than in excreted urinary IgG molecules. The affinity of urinary IgG for either DNA or F(ab)2 was much lower than the same antibody activities measured either in serum or in kidney biopsy eluates. When the relative affinity of anti-DNA antibody in serum, urine, and kidney biopsy eluate was measured in parallel, the highest affinity antibody was found in kidney biopsy eluates, followed by serum antibody with urine antibody affinity showing the lowest values. These findings suggest a relative concentration of the highest affinity, doubly reactive IgG anti-DNA/F(ab)2 in SLE kidney tissues during SLE nephritis and implicate this process as an important factor in ongoing tissue damage.     

Neuropsychiatric systemic lupus erythematosus and the syndrome of inappropriate secretion of antidiuretic hormone: a case report with very late onset systemic lupus erythematosus

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with neuropsychiatric lupus (NP-SLE) is rare. We report a case of SIADH associated with the new onset of SLE in an 88-yr-old female. The unique features of this case include the extreme age of onset of SLE presenting with neuropsychiatric manifestations and positive antiribosomal P antibody titres. Both the NP manifestations of SLE and SIADH were highly correlated with the SLE disease activity. This case illustrates a novel presentation of NP-SLE with SIADH which may develop due to antibody-mediated hypothalamic dysfunction.     

Antibodies to beta2-glycoprotein I: a potential marker for clinical features of antiphospholipid antibody syndrome in patients with systemic lupus erythematosus

OBJECTIVE: To clarify risk factors for the development of clinical features of antiphospholipid syndrome (APS) in patients with anticardiolipin antibodies (aCL) in systemic lupus erythematosus (SLE). METHODS: We studied 65 SLE patients, all with positive IgG and/or IgM aCL. Patients were divided into 2 groups; I: 29 SLE patients with features of APS (SLE/APS) and II: 36 aCL positive SLE patients without any feature of APS (SLE/aCL). Serum samples were collected from our serum bank. Anti-beta2-glycoprotein I (anti-beta2-GPI) were tested by ELISA using irradiated plates in the absence of cardiolipin. Anti-dsDNA antibodies were tested by standard Farr assay. RESULTS: There were no major differences between SLE clinical manifestations in both groups. However, the frequency of IgG anti-beta2-GPI was markedly increased in SLE/APS (18/29, 62%) than in SLE/aCL (4/36, 11%) (chi-squared 18.6, p=0.0001). The levels of anti-dsDNA antibodies in the same samples were slightly lower in SLE/APS. CONCLUSION: Our data suggest that increased levels of IgG anti-beta2-GPI may be a specific feature of SLE/APS patients rather than reflecting a polyclonal B cell activation.