Deleting the BAFF receptor TACI protects against systemic lupus erythematosus without extensive reduction of B cell numbers

B cell-activating factor of the TNF family (BAFF) is an essential B cell survival factor. However, high levels of BAFF promote systemic lupus erythematosus (SLE) in mice and humans. Belimumab (anti-human BAFF) limits B cell survival and is approved for use in patients with SLE. Surprisingly, the efficacy of rituximab (anti-human CD20) in SLE remains controversial, despite depleting B cells more potently than belimumab. This raises the question of whether B cell depletion is really the mechanism of action of belimumab. In BAFF transgenic mice, SLE development is T cell-independent but relies on innate activation of B cells via TLRs, and TLR expression is modulated by the BAFF receptor TACI. Here, we show that loss of TACI on B cells protected against BAFF-mediated autoimmune manifestations while preserving B cells, suggesting that loss of BAFF signaling through TACI rather than loss of B cells may underpin the effect of belimumab in the clinic. Therefore, B cell-sparing blockade of TACI may offer a more specific and safer therapeutic alternative to broad B cell depletion in SLE.     

Tumor necrosis factor-alpha and neuropsychiatric lupus erythematosus: relation to single photon emission computed tomography findings

This study was designed to highlight the relation of tumor necrosis factor- (TNF-) to neuropsychiatric lupus (NPLE) manifestations. The relation of TNF- to the type of single photon emission computed tomography (SPECT) findings in this context was also studied. Twenty-one systemic lupus erythematosus (SLE) females, mean age 27.57 ± 9.89 years, and twenty age-matched normal females (controls), were subjected to TNF- assessment. Different clinical and neuropsychiatric manifestations were evaluated. SPECT was carried out for all patients. The results showed that the mean TNF- level (pg/ml) was significantly raised in patients compared with controls (167.8 ± 102.5 versus 64 ± 50.2, respectively, P 0.005). Thirteen patients (69.1%) had NPLE manifestations. NPLE patients had a significantly higher mean TNF- than patients without NPLE (203 ± 102.8 versus 109 ± 47.3, respectively, P 0.03). Positive SPECT findings were found in 18 lupus patients (85.7%), including all 13 patients with NPLE (100% sensitivity), with a multiple focal pattern of hypoperfusion being the most frequent type (9/13), followed by diffuse (3/13), and then single focal pattern (1/13). The mean TNF- was significantly higher in patients with multiple focal pattern (P 0.001). In conclusion, results of this work support the hypothesis that TNF- could be involved in the pathogenesis of NPLE, and hence, it could be speculated that the evolving anti-TNF therapy can play a potential role in the management of this disease.     

Visceral Leishmaniasis mimicking a flare of systemic lupus erythematosus

Summary Fever in systemic lupus erythematosus (SLE) may be caused by exacerbation of the disease itself or by infection. We report on a patient with a long standing history of SLE that was complicated by fever and pancytopenia with no splenomegaly. SLE disease activity was suspected because of an elevated DNA-antibody titer. The early positive response to corticoid therapy may have masked the underlying infection. Visceral leishmaniasis was diagnosed by a repeated bone marrow biopsy and serological testing.     

Relationship of Interleukin-12 and Interleukin-13 imbalance with class-specific rheumatoid factors and anticardiolipin antibodies in systemic lupus erythematosus

 The aim of the study was to evaluate whether the imbalance between IL-12 and IL-13 serum levels, reflecting Th1/Th2 activity, is related to class-specific circulating rheumatoid factors (RF) and anticardiolipin (aCL) antibodies in SLE. Using ELISA we measured serum IL-12, IL-13, RF and aCL antibodies in 73 SLE patients and 20 healthy controls. The determination of IL-12/IL-13 ratio showed that IL-12 levels were above (group A), equal to (group B) or below (group C) IL-13 levels in 71.2%, 15.1% and 13.7% of SLE patients, respectively. IgM-RF levels were significantly higher in group C than in groups A (P < 0.002) and B (P < 0.019). Group C had also higher IgM-aCL levels than group A (P < 0.04). No relationship between IL-12/IL-13 ratio and clinical or other laboratory parameters was found. It was concluded that the increased levels of both IgM-RF and IgM-aCL in patients with prevalent Th2 activity suggest that the predominance of Th2 over Th1 could drive autoantibody production in SLE patients. Received: 15 July 2002 / Accepted: 23 September 2002     

Treatment with DNAse I fosters binding to nec PBMC of CRP

CRP is an important inflammatory marker, however, CRP levels are relatively low in patients with SLE. In addition patients with SLE often display low activities and serum levels for DNase I and complement, respectively. Here we show that DNase I treatment of nec PBMC increased their binding of CRP. Consequently, reduced DNase I activity in patients with SLE may contribute to the impaired opsonisation by CRP of dead cells, exacerbating the clearance defect in SLE of apo and nec cells.     

Infections and SLE

Viral and bacterial infections may serve as an environmental trigger for the development or exacerbation of systemic lupus erythematosus (SLE) in the genetically predetermined individual. In addition, SLE patients are more prone to develop common (pneumonia, urinary tract infection, cellulitis, sepsis), chronic (tuberculosis), and opportunistic infections possibly due to inherit genetic and immunologic defects (complement deficiencies, mannose-binding lectin [MBL] polymorphisms, elevated Fcgamma III and GM-CSF levels, osteopontion polymorphism), but also due to the broad spectrum immunosuppressive agents that are part of therapy for severe manifestations of the disease. Hence, SLE patients are considered a high-risk population, where identification and treatment of chronic infections such as tuberculosis, hepatitis B or human immunodeficiency virus, are important prior to the institution of immunosuppression so as to prevent reactivation or exacerbation of the infection. Infections in SLE patients remain a source of morbidity and mortality. A caveat often encountered is to distinguish between a lupus flare and an acute infection; in such cases parameters including elevated CRP (and adhesion molecules) may aid in the diagnosis of infection. Recent research has provided convincing evidence that EBV infection may play a major role not only in molecular mimicry but also in aberrations of B cells and apoptosis leading to a state of perpetual heightened immune response in SLE.     

Systems biology in systemic lupus erythematosus: Integrating genes,biology and immune function

Overactive B cells, abnormally activated T cells and inappropriate handling of cellular debris by the innate immune system are central in the pathogenesis of systemic lupus erythematosus (SLE). Genetic studies in SLE patients have unraveled allelic variations in genes encoding key molecules that control inter- and intra-cellular signaling and play a role in the abnormal handling of apoptotic material. Despite recent breakthroughs though, it is still unclear how exactly genes and environment interact to produce the characteristic immune dysregulation in SLE.     

Patients with unstable angina pectoris show an increased frequency of the Fc gamma RIIa R131 allele

Patients with Systemic Lupus Erythematosus (SLE) carry an increased risk for the development of coronary artery disease (CAD). The R131 allele of the Fc gamma receptor IIa (FcγRIIa) is associated with SLE incidence and disease severity but also with CAD. Compared to stable angina pectoris (SAP) the unstable angina (UAP), as a manifestation of destabilizing CAD, is associated with increased risk of persistent instability, myocardial infarction, and death. Identification of clinically relevant determinants for unstable angina promises reduction of UAP-associated mortality in patients with SLE. We conducted a clinical study among 553 consecutive patients with stable angina pectoris (n = 330) and unstable angina pectoris (n = 223). All patients were genotyped for a frequent functional variant at position 131 of the mature FcγRIIa. UAP, but not SAP was significantly associated with the R/R131 genotype (P < 0.001). In troponin-negative patients with angina carrying the R/R131 genotype the odds ratio for suffering from UAP was 4.02 (95% confidence interval, 2.52–6.41) compared to those with non-R/R131 genotypes. In a multivariable analysis, the R/R131 genotype independently predicted the risk for development of UAP in a model adjusted for classical atherogenic risk factors. Our data imply that risk stratification of SLE- and other high risk patients with troponin-negative angina could be significantly improved by FcγRIIa genotyping.     

Suppression of dsDNA-specific B lymphocytes reduces disease symptoms in SCID model of mouse lupus

Abstract

Self-specific B cells play a main role in the pathogenesis of lupus. This autoimmune disease is characterized by the generation of autoantibodies against self antigens, and the elimination of B and T cells involved in the pathological immune response is a logical approach for effective therapy. We have previously constructed a chimeric molecule by coupling a DNA-mimotope peptides to an anti-CD32 antibody. Using this protein molecule for the treatment of lupus-prone MRL/lpr mice, we suppressed selectively the autoreactive B-lymphocytes by cross-linking B cell receptors with the inhibitory FcγRIIb receptors. This approach was limited by the development of anti-chimeric antibodies in MRL mice. In order to avoid this problem, we established a murine severe combined immunodeficiency lupus model, allowing a long-term chimera therapy. Elimination of the double-stranded DNA-specific B cells by chimera therapy in MRL-transferred immunodeficient mice resulted in inhibition of T cell proliferation and prevented the appearance of IgG anti-DNA antibodies and of proteinuria.