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.     

Evaluation of the BCL-2 gene locus as a susceptibility locus linked to the clinical expression of systemic lupus erythematosus (SLE)

Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by the production of a large number of autoantibodies. It has been postulated that this may be the result of prolonged longevity of auto-reactive B cells due to defective regulation of programmed cell death (apoptosis). The proto-oncogene bcl-2 is involved in the control of apoptosis in immunocompetent cells, and its over-expression is noted in T and B cells from SLE patients. This study examined the genetic linkage between the bcl-2 gene locus and SLE susceptibility using the affected sib-pair method in SLE families. Seventeen caucasian multiplex families were evaluated. A polymorphic microsatellite marker closely linked to the bcl-2 gene on 18q21.3 was used to determine the bcl-2 genotype. We demonstrated that haplotype sharing among the affected sibling pairs was not statistically different from random (P > 0.5). This suggests that the bcl-2 gene locus does not confer a genetic susceptibility to SLE expression.     

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.     

IgM anti-dsDNA antibodies in systemic lupus erythematosus: negative association with nephritis. SLE Study Group

Antibodies against dsDNA of the IgM class were measured in sera of 352 patients with systemic lupus erythematosus, 81 blood donors and 189 patients with rheumatoid arthritis using a new ELISA based on human recombinant dsDNA as antigen. IgM anti-dsDNA antibodies were found in 52.3% of the sera from patients with systemic lupus erythematosus, but in none of the sera from 81 normal controls and 189 patients with rheumatoid arthritis. The association of these autoantibodies with 31 clinical and 37 laboratory parameters was calculated. There was a highly significant negative correlation between IgM anti-dsDNA antibodies and nephritis as well as all the laboratory parameters indicating renal disease (elevated serum creatinine concentration, proteinuria, erythrocyte casts in the urine). IgM anti-dsDNA antibodies indicate protection of lupus patients against the development of lupus nephritis. Further experiments will show whether application of IgM anti-dsDNA antibodies is effective in treating lupus nephritis.     

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.     

Different manifestations of the antiphospholipid antibody syndrome in a family with systemic lupus erythematosus

OBJECTIVE: Familial associations of the antiphospholipid antibody syndrome (APS) offer the opportunity to study genetic mechanisms of autoantibody production and disease, but are unusual. We identified a family, including identical twins and their mother, in which all members had systemic lupus erythematosus (SLE) and presented with different manifestations of the APS. METHODS: Review of case histories and clinical laboratory results, antiphospholipid antibody (aPL) studies, complement C4 protein and gene analysis, and HLA typing of family members were performed. RESULTS: Each of the 3 family members presented with a different clinical association of the APS. These various clinical presentations were closely temporally related. No particular aPL activity could be separated out that would account for the different manifestations, although the twin with thrombocytopenia and livedo reticularis had a strikingly high IgM anticardiolipin antibody level. C4A or C4B deficiencies could not be implicated in the autoimmune process. However, the mother and the twins shared the HLA haplotype that included the class II antigens DR4, DRw53, and DQw7, which has previously been associated with aPL production. CONCLUSION: This family study emphasizes the different clinical associations of aPL production in SLE. In addition to genetic influences that appear to include HLA class II antigens, the clinical presentations also suggest an environmental trigger.     

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.     

Renal microscopic polyarteritis replaced by pericarditis with episodic increases in MPO-ANCA in a patient with systemic lupus erythematosus

BACKGROUND: An abnormally increased presence of type VI collagen has been shown in the lamina cribrosa of patients with primary and secondary glaucoma. This study was undertaken to investigate the pattern of type VI collagen within the aqueous outflow structures of glaucoma patients. METHODS: Trabecular meshwork samples of eight normal donor eyes and trabeculectomy specimens of 21 patients with different types of glaucoma were processed for either cryo-sectioning or for paraffin embedding. Immunohistochemical staining was conducted by use of polyclonal rabbit antibodies against human collagen type VI. RESULTS: Immunoreactivity for type VI collagen was evident in the cores of all trabecular beams. The strongest staining was detected in the uveal region of the human trabecular meshwork. Immunohistochemical labelling for type VI collagen was not more pronounced in the aqueous outflow structures of glaucoma patients than in normal eyes. CONCLUSION: Collagen type VI is a ubiquitous structural component of the extracellular matrix in the human trabecular meshwork. However, type VI collagen does not appear to be of greater importance for the increased trabecular outflow resistance in glaucoma patients than in normal eyes.     

Autoantibodies to DEK oncoprotein in a patient with systemic lupus erythematosus and sarcoidosis

A patient was identified with an unusual autoimmune syndrome consisting of systemic lupus erythematosus and sarcoidosis. Her serum contained extremely high levels of autoantibodies to the DEK protooncogene product. The patient's serum was used to clone a dek complementary DNA, which was expressed as a histidine-tagged fusion protein in Escherichia coli. Using affinity-purified recombinant DEK protein, anti-DEK autoantibodies were found in the patient's serum at a titer of 1:10(6) by enzyme-linked immunosorbent assay (ELISA). Longitudinal studies revealed marked variations in anti-DEK autoantibody levels over time. Although it has been suggested that anti-DEK autoantibodies are a marker for pauciarticular juvenile rheumatoid arthritis with iridocyclitis, the present data suggest that they may be associated with other disease subsets as well. The quantitative ELISA technique will be useful for defining these subsets further and for examining the relationship between anti-DEK titers and disease activity.     

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.     

Alteration of T-lymphocyte subpopulations in patients with primary renal diseases and systemic lupus erythematosus

Forty-eight patients with a variety of primary renal diseases and systemic lupus erythematosus (SLE) were examined for the proportion of circulating T lymphocytes bearing receptors for IgM (T mu cells) or IgG (T gamma cells). Although the control group showed strikingly similar mean values for both T mu and T gamma cells, the whole group of patients with primary renal diseases and SLE showed a wide scatter of values. Sixteen patients with primary renal diseases and SLE had higher proportions of T gamma cells than the control group, whereas seven patients with chronic glomerulonephritis (CGN), membranoproliferative glomerulonephritis (MPGN), lipoid nephrosis (LN), and SLE showed very marked decrease in the proportions of T gamma cells in the peripheral blood. On the other hand, six out of the total group of patients had low proportions of T mu cells in the peripheral blood. However, no consistent relationship between the proportion of T mu and T gamma cells was found in our study. These findings indicate that there exists a heterogeneity of T-lymphocyte subpopulation distribution in some patients with primary renal diseases and SLE. The possible significance of these phenomena in the pathophysiology of renal diseases is discussed.     

Depressive symptoms in patients with systemic lupus erythematosus: association with central nervous system lupus and Sj?gren's syndrome

OBJECTIVE: To determine if patients with systemic lupus erythematosus (SLE) with depressive symptoms differ in regard to organ involvement and serological activity from other patients with SLE. METHODS: Disease manifestations were compared between 71 patients with SLE with a history of depressive symptoms and 278 patients without a history of depressive symptoms by univariate analysis and multiple logistic regression. RESULTS: Both univariate and logistic regression analysis revealed an association of depressive symptoms with neuropsychiatric lupus and secondary Sj?gren's syndrome (SS). Patients with neuropsychiatric lupus had an adjusted odds ratio of 3.43 (95% CI 2.55, 4.63; p = 0.00005), and patients with secondary SS had an adjusted odds ratio of 2.97 (95% CI 2.08, 4.25; p = 0.0006) for depressive symptoms. No other organ involvement or serological abnormality was associated with depressed mood. CONCLUSION: These discrete associations of depressive symptoms with neuropsychiatric lupus and secondary SS suggest that depression does not occur purely as a response to social stresses, and may be a manifestation of autoimmune disease in some patients.     

Intravenous immunoglobulin administration to a patient with systemic lupus erythematosus and pneumococcal septicemia

A case history is presented of a woman with systemic lupus erythematosus, sepsis and pneumonia caused by Streptococcus pneumoniae. Conventional treatment was supplemented with intravenous human immunoglobulin with remarkable effect. The treatment is discussed.     

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.     

Favorable response to corticoid therapy in a patient with transverse myelitis in systemic lupus erythematosus

Transverse myelitis is one of the most unusual neurologic complications of systemic lupus erythematosus. Its pathogenetic mechanisms are controversial. Several therapeutic regimens have been attempted with contradictory results. Corticotherapy appears to improve prognosis, although some authors question its beneficial effects. The case of a patient with systemic lupus erythematosus and transverse myelitis, who presented a favourable clinical course following early treatment with high-dose corticoids, is reported.     

Relationship between endocrine, immune, and clinical variables in patients with systemic lupus erythematosus

OBJECTIVE: To assess the frequency of increased plasma prolactin (PRL) in patients with systemic lupus erythematosus (SLE) and to evaluate its relationship to other hormonal and immune variables. METHODS: Thirty-five patients with SLE with various levels of disease activity were studied. Plasma PRL, cortisol, growth hormone (GH) were determined by radioimmunoassay and interleukin 6 (IL-6) by ELISA: SLE activity was evaluated using the European Consensus Lupus Activity Measurement (ECLAM). RESULTS: Increased plasma PRL concentration (> 20 ng/ml) was recorded in 11 patients (31%). No correlation was found between plasma PRL and GH, IL-6, cortisol, or C-reactive protein, nor was any significant correlation observed between plasma PRL and the ECLAM score. Patients with hyperprolactinemia were, however, found to have been treated with higher doses of prednisone therapy than patients with normal plasma PRL. Further analysis of the relationship of plasma PRL and therapy showed that patients with SLE selected by the attending physician for prednisone therapy in doses > or = 10 mg/day were more frequently hyperprolactinemic. CONCLUSION: Our findings that patients with SLE with a more active form of the disease and who are less responsive to therapy had increased plasma PRL levels more frequently may be indicative of a potential relationship of hyperprolactinemia to severity of disease.