Antibodies to M-type phospholipase A2 receptor (PLA2R) in membranous lupus nephritis.

BACKGROUND: Antibodies to M-type phospholipase A2 receptor (a-PLA2R) have been identified in most patients with idiopathic membranous nephropathy, but the prevalence in membranous lupus nephritis (MLN) is still unclear. The objective of this study was to assess the prevalence of a-PLA2R antibodies in a large cohort of patients with lupus nephritis. METHODS: a-PLA2R antibodies were measured by ELISA in serum from patients with systemic lupus erythematosus ( n = 190), of whom 37 had a biopsy-proven MLN. Positive samples were confirmed by commercial ELISA kit, Western blot and immunohistochemistry in renal tissue. RESULTS: A total of 10 from 190 patients (5.3%) with systemic lupus erythematosus had circulating a-PLA2R measured by in-house ELISA assay. The antibodies were detected in 7 patients with MLN (18.9%) and 3 patients with non-renal lupus disease (3.2%). PLA2R staining was detected in the kidney biopsy of 5 of the 7 (71.4%) patients with MLN. a-PLA2R levels were associated with active disease but not proteinuria levels. Presence of a-PLA2R antibodies at baseline was associated with worse remission rates and longer time to remission compared to those patients serologically negative. CONCLUSIONS: a-PLA2R antibodies can be detected with low prevalence in MLN patients, but their detection is associated with a worse renal prognosis.

DUSP23 is over-expressed and linked to the expression of DNMTs in CD4+ T cells from systemic lupus erythematosus patients.

We evaluated the transcriptional expression of dual-specificity protein phosphatase 23 (DUSP23) in CD4+ T cells from 30 systemic lupus erythematosus (SLE) patients and 30 healthy controls. DUSP23 mRNA levels were considerably higher in the patient group: 1490 ± 1713 versus 294·1 ± 204·2. No association was found between DUSP23 mRNA expression and the presence of typical serological and clinical parameters associated with SLE. Meaningful statistical values were obtained in the patient group between the levels of DUSP23 and integrin subunit alpha L (ITGAL), perforin 1 (PRF1) and CD40L. Similarly, transcript levels of different DNA methylation-related enzymes [DNA methylation-related enzymes (DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4)] were also correlated positively with the expression of DUSP23. In an attempt to counteract the hypomethylation status of the promoters of certain genes known to be over-expressed in SLE, it is possible that DUSP23 acts as a negative regulatory mechanism which ultimately silences the transcription of these epigenetically regulated genes by triggering an increase in the expression of different DNMTs.

Microarray study reveals a transforming growth factor-ß-dependent mechanism of fibrosis in discoid lupus erythematosus.

BACKGROUND: Discoid lupus erythematosus (DLE) is characterized by scarring lesions that develop and perpetuate fibrotic lesions. These are not observed in subacute cutaneous lupus erythematosus (SCLE). The pathophysiological basis of this is currently unknown. OBJECTIVES: To identify contradistinctive signalling pathways and cellular signatures between the two type of lupus, with a focus on the molecular mechanisms leading to fibrosis. METHODS: We conducted a gene expression microarray analysis in lesional and nonlesional skin biopsy specimens of patients with DLE (n = 10) and SCLE (n = 10). Confirmatory reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry were performed on selected transcripts in a new cohort of paraffin-embedded skin biopsies (n = 20). Changes over time of a group of selected inflammatory and fibrotic genes were also evaluated in a second biopsy taken 12 weeks later. In vitro functional studies were performed in primary isolated fibroblasts. RESULTS: Compared with nonlesional skin, DLE samples expressed a distinctive T-cell gene signature. DLE samples displayed a significant CD4 T-cell enrichment with an imbalance towards T helper 1 cytokine predominance and a relative increased forkhead box (FOX)P3 response. RT-qPCR and immunochemical analysis over time showed a progressive increment of fibrotic markers and persistent FOXP3 recruitment. Ex vivo upregulation of SERPINE1, MMP9, TGFBR1, phosphorylated SMAD3 and TGFB1 suggested a transforming growth factor (TGF)-ß-dependent mechanism of fibrosis in DLE, also confirmed by the results observed following in vitro stimulation with TGF-ß. CONCLUSIONS: These results highlight major pathogenic pathways in DLE and provide novel molecular targets for the development of new therapies. The data suggest the existence of a TGF-ß-dependent pathway inducing fibrosis in DLE.

Prevalence of HHV-8 in systemic autoimmune diseases.

BACKGROUND: Epidemiological data suggest that some viruses may be linked to the development of autoimmunity. OBJECTIVES: The objective of this work was to determine the presence of HHV-8 viral DNA in whole blood from patients suffering from different systemic autoimmune diseases (SAD). We also aimed at testing the prevalence of patients showing antibodies against an HHV-8 orfK8.1 peptide. STUDY DESIGN: Two hundred and eighty SAD patients and 50 healthy blood donor controls were included. Molecular analyses were performed by nested PCR from DNA obtained from whole blood and an enzyme immunoassay was developed in order to test for the presence of antibodies directed against a synthetic peptide derived from the HHV-8 orfK8.1 protein. RESULTS: Only 2 out of the 280 samples analyzed yielded the specific HHV-8 PCR product. Antibodies against orfK8.1 were detected in 2 SLE patients, 1 patient suffering from Sjögren's syndrome and 2 patients with vasculitis. CONCLUSIONS: We conclude that HHV-8 is usually not present in blood neither from autoimmune patients nor from healthy controls. Furthermore, HHV-8 antibodies against the HHV-8 orfK8.1 peptide were rarely detected. It leads us to infer that HHV-8 is not involved on the development of these disorders. It does not rule out the possibility that other environmental and microbiological triggers may account for their etiopathogenesis.

Activation of the signal transducer and activator of transcription-1 in diffuse proliferative lupus nephritis.

Difuse proliferative lupus nephritis (DPLN) is the most common and severe form of lupus nephritis. A predominance of IFN-gamma-producing T cells in both peripheral and renal tissues of patients with DPLN has been identified which suggests an important role for cell-mediated immunity in the pathogenesis of this complication in SLE. The biological effects of IFN-gamma rely mainly on the activity of the transcription factor called signal transducer and activator of transcription (STAT)-1. To assess the IFN-gamma/STAT-1 pathway in DPLN, we examined the expression of STAT-1 in renal biopsies from 15 DPLN patients by immunohistochemical staining with an anti-STAT-1 antibody. The expression of STAT-1 in renal tissues was correlated with several clinical and laboratory findings in these DNPN patients.STAT-1 was activated in the tubular cells in all DPLN patients. Seven of 15 DPLN biopsies (46.7%) showed positive cells in glomeruli. Five of these seven DPLN biopsies (71.4%) with positive glomerular cells showed a serum creatinine >1.5 mg/mL at the time the biopsy was carried out whereas only one of eight DPLN biopsy specimens (12.5%) without positive glomerular cells, showed a serum creatinine >1.5 mg/mL (P = 0.041). Moreover, the percentage of DPLN patients with a worse renal outcome in those who showed expression of STAT-1 in glomerulari were higher in comparison to those without STAT-1 expression (P = 0.041). Our results show that STAT-1 is activated in DPLN suggesting that biological effects of IFN-gamma in renal tissues depend, at least in part, on the activation of STAT-1.

Antinuclear antibody testing in pleural fluid for the diagnosis of lupus pleuritis.

We sought to determine whether measuring antinuclear antibodies (ANA) and their specificities [dsDNA, extractable nuclear antigens (ENA)] on pleural fluid may contribute to the differential diagnosis of pleural effusions. ANA were tested by indirect immunofluorescence on Hep-2 cells in the pleural fluid of 266 patients with effusions of different etiologies, including 15 lupus pleuritis. The cutoff value for diagnostic use was set at 1:160. Pleural fluid analysis of specific autoantibodies, such as anti-dsDNA and anti-ENA, was also performed if a positive ANA test was obtained. All patients with lupus pleurisy and 16 of 251 (6.4%) patients with pleural effusions secondary to other causes were ANA positive. Fifty-six percent of the positive ANAs in non-lupus pleural fluids were due to neoplasms. The pleural fluid ANA titers were low (< or = 1:80) or absent in two patients with systemic lupus erythematosus (SLE) and effusions due to other factors. Whereas ANA staining patterns in pleural fluid did not help to discriminate lupus pleuritis from non-lupus etiologies, the absence of pleural fluid anti-dsDNA or anti-ENA favored the latter. ANAs in pleural fluid provided no additional diagnostic information beyond that obtained by the measurement in serum and, therefore, these tests need not be routinely performed on pleural fluid samples. However, in patients with SLE and a pleural effusion of uncertain etiology, lack of ANAs or specific autoantibodies in pleural fluid argues against the diagnosis of lupus pleuritis.

Chronic intestinal pseudo-obstruction associated with biliary tract dilatation in a patient with systemic lupus erythematosus.

We present the case of a 57-year old female patient diagnosed with systemic lupus erythematosus (SLE) along with glomerulonephritis and chronic intestinal pseudo-obstruction (CIPO). Dilatation of bile and pancreatic ducts not associated with malignant or litiasic obstruction is reported. The combination of bile duct associated with CIPO in a patient with lupus has not been previously reported in the literature and it probably suggests a smooth muscle dysmotility.

[Pulmonary hemorrhage and anti-phospholipid syndrome]. / Hemorragia pulmonar y síndrome antifosfolipídico.

The presence of anti-phospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant) associated to venous and/or arterial thrombotic phenomena and fetal losses define the anti-phospholipid syndrome. On rare occasions severe hypoprothrombinemia associated with this disease as a cause of hemorrhagic manifestations has been described. In addition very few cases of alveolar hemorrhage in anti-phospolipid syndrome (APS) have been described, being this complication usually related to microthrombosis and/or capillaritis of pulmonary vessels. We describe two patients without previous clinical manifestations of anti-phospholipid syndrome that showed pulmonary hemorrhage with anticardiolipin antibodies positivity. The first of them, a 33-year-old male, began his disease with low prothrombin time and the presence of antiprothrombin antibodies. In the biopsy by thoracoscopy the presence of pulmonary hemorrhage without capillaritis nor thrombotic phenomena was demonstrated, becoming evident certain clinical improvement and normalization of the prothrombin time after receiving immunosuppressive treatment but with persistence of the pulmonary hemorrhage 5 years later. The second case, a 89-year-old male, began his condition with bilateral lung infiltrates and hemoptysis, anticardiolipin antibodies positivity, and thrombopenia, with recurrence of the condition 1 year later. After other etiological possibilities were ruled out, and despite hemorrhagic trait in both patients, we consider that they should be in the clinical context of the anti-phospholipid syndrome, although at this time they did not meet the criteria recognized in order to diagnose this disease. Within the ampliable clinical spectrum of the anti-phospholipid syndrome we should take into account the pulmonary hemorrhage.

Complement C4B null allele status confers risk for systemic lupus erythematosus in a Spanish population.

Genetic susceptibility to systemic lupus erythematosus (SLE) may vary amongst different populations. In UK patients, genes encoded in the HLA class II (DQA*0501/DRB1*0301) and class III [C4A*Q0 and tumour necrosis factor (TNF) polymorphisms] subregions appear to contribute to disease susceptibility. We have examined HLA-DRB1, C4 and TNF microsatellites in 50 Spanish SLE patients and 48 matched controls. HLA-DRB1*0301 was increased in patients but did not achieve statistical significance (41% vs. 25.5%). C4A*Q0 was not increased in patients, but C4B*Q0 allele frequency was significantly increased compared with the controls (29% vs. 6%; OR: 6.0). TNF c2 microsatellite allele frequency was also increased in SLE patients. The C4B null allele (C4B*Q0) appears to play an important role in SLE susceptibility in the Spanish population.

Adult onset of nemaline myopathy presenting as respiratory insufficiency.

A 49-year-old woman was admitted to the hospital for hypercapnia. Pulmonary function testing showed small lung volumes without parenchymal lung disease. Muscle enzyme levels were normal and the EMG was nonspecific. Finally, muscle biopsy revealed abundant nemaline bodies characteristic of nemaline myopathy. Nasal intermittent pressure ventilation was started with a preset pressure ventilator during sleeping hours with a good response.

Clinical and therapeutic aspects associated to phospholipid binding antibodies (lupus anticoagulant and anticardiolipin antibodies).

Antiphospholipid antibodies (APA) comprise a family of immunoglobulins characterized by their pattern of reactivity in a number of laboratory tests. Included in this family are lupus anticoagulant (LA) anticardiolipin antibodies (ACA) and antibodies causing biologic false positive serologic tests for syphilis (BFP-STS). LA and ACA occur in a variety of conditions, including other autoimmunes disorders, infectious diseases, neoplasic disorders, in association with certain drugs and in otherwise healthy individuals. Clinical interest in LA and ACA is increasing. Antiphospholipid antibody syndrome is characterized by a triad of clinical features which include fetal loss, thromboembolic disease and thrombocytopenia. Other clinical manifestations related with APA are livedo reticularis, cutaneous necrosis, hemolytic anemia, heart valve disease, chorea, migraine and obstetric problems as fetal growth retardation, pre-eclampsia, post-partum serositis or neonatal thrombosis or catastrophic antiphospholipid syndrome. Therapy is mainly directed against the widespread and diverse manifestations associated with the obstruction of small and large vessels. Long-term treatment with oral anticoagulation therapy is advised, even if the venous or arterial occlusion occurred many years previously. In patients with primary antiphospholipid syndrome there is no evidence that the prophylactic administration of steroids or immunosuppression will prevent thromboembolic events. Although the administration of more energetic immunosuppression with cyclophosphamide in pulse form is effective in reducing elevated antibody levels, there is usually a rapid rebound to pretreatment levels shortly after discontinuation of the therapy. A history of recurrent fetal loss requires mandatory treatment during pregnancy. Although the actual prospective risk of pregnancy loss in women with antiphospholipid syndrome and prior pregnancy loss is unknown, it may exceed 60%. Because of this many investigators have treated women with antiphospholipid syndrome with either antiplatelet agents, immunosuppressive agents, or anticoagulants in an attempt to improve pregnancy outcome. Unfortunately, there is no unequivocal proof that any of these therapies are fully efficacious. Despite varying treatment protocols, the live birth rate with treatment was 70%, similar to that reported in the recent randomized clinical trial. Thrombocytopenia and autoimmune hemolytic anemia in patients with APA are treated similarly as patients without APA. Treatment of asymptomatic patients isn't indicated, because only approximately 10-15% of patients with APA developed complications.

Transverse myelitis in systemic lupus erythematosus: two cases with magnetic resonance imaging.

Transverse myelitis is one of the most serious neurological complications occurring in the course of systemic lupus erythematosus. We describe two lupus patients, with transverse myelitis, one of whom had associated optic neuritis. In both, magnetic resonance imaging of the spinal cord showed an abnormal signal. In one case a good response to steroid and immunosuppressive therapy was observed; the other case failed to improve despite the therapy applied.

Raynaud's phenomenon and positive antinuclear antibodies in a malignancy.

Both Raynaud's phenomenon and the presence of antinuclear antibodies are uncommon features of malignant disease and the association of both with a malignancy extremely rare. The case is reported of a 78 year old woman who presented with Raynaud's phenomenon and positive antinuclear antibodies related to adenocarcinoma of unknown primary site.

[Perinephritic abscesses: a review of 50 cases (author's transl)]. / Abscesos perinefríticos: revisión de 50 casos.

Accumulation of pus in the perinephritic cavity often gives rise to doubtful clinical manifestations, which hinder and delay prompt diagnosis of this severe process. The clinical, biological, radiological and therapeutic characteristics of 50 cases are reviewed; all were confirmed by either surgery or necropsy. The most frequent clinical manifestations were fever, lumbar pain and signs of localized inflammation. Biological data showed ESR elevation and left shift of leukocytes as the most constant finding. Pyelograms were abnormal in 90% with blurring of the psoas and contour of the kidney the most frequent finding. Gram-negative organisms were frequently isolated, with staphylococci accounting for 10%. Only surgical treatment had a definite effect on evolution. The mortality rate was high, due to incorrect or delayed diagnosis.