Phoenix from the flames: Rediscovering the role of the CD40–CD40L pathway in systemic lupus erythematosus and lupus nephritis

Lupus nephritis (LN) is a significant complication of systemic lupus erythematosus (SLE), increasing its morbidity and mortality. Although the current standard of care helps suppress disease activity, it is associated with toxicity and ultimately does not cure SLE. At present, there are no therapies specifically indicated for the treatment of LN and there is an unmet need in this disease where treatment remains a challenge.The CD40–CD40L pathway is central to SLE pathogenesis and the generation of autoantibodies and their deposition in the kidneys, resulting in renal injury in patients with LN. CD40 is expressed on immune cells (including B cells, monocytes and dendritic cells) and also non-haematopoietic cells. Interactions between CD40L on T cells and CD40 on B cells in the renal interstitium are critical for the local expansion of naive B cells and autoantibody-producing B cells in LN. CD40L-mediated activation of myeloid cells and resident kidney cells, including endothelial cells, proximal tubular epithelial cells, podocytes and mesangial cells, further amplifies the inflammatory milieu in the interstitium and the glomeruli. Several studies have highlighted the upregulated expression of CD40 in LN kidney biopsies, and preclinical data have demonstrated the importance of the CD40–CD40L pathway in murine SLE and LN. Blocking this pathway is expected to ameliorate inflammation driven by infiltrating immune cells and resident kidney cells.Initial experimental therapeutic interventions targeting the CD40–CD40L pathway, based on CD40L antibodies, were associated with an increased incidence of thrombosis. However, this safety issue has not been observed with second-generation CD40/CD40L antibodies that have been engineered to prevent platelet activation.With these advancements, together with recent preclinical and clinical findings, it is anticipated that selective blockade of the CD40–CD40L pathway may address the unmet treatment needs in SLE, LN and other autoimmune diseases.     

Does the BAFF dysregulation play a major role in the pathogenesis of systemic lupus erythematosus?

Given the prominent role currently assigned to B lymphocytes in systemic lupus erythematosus, it is not surprising that the B cell activity factor belonging to the tumor necrosis factor family (BAFF) is involved in its pathogenesis. This cytokine is produced in excess, and inserted into its receptors on the surface of circulating B cells. Up-regulation of BAFF is most likely to lead to breach of tolerance by aberrant survival of B cells directed to the self. Trials aimed at blocking BAFF have thus been set out. Yet the results are awaited.     

ICOS gene polymorphisms in systemic lupus erythematosus: A case–control study

The inducible T-cell costimulator (ICOS) may play an important role in adaptive immunity by regulating the interaction between T cells and antigen-presenting cells. Disruption of this molecule can lead to autoimmune diseases, in particular systemic lupus erythematosus (SLE). In this study, we aimed to explore the possible association between ICOS gene polymorphisms and SLE as well as their influence on disease susceptibility and clinical outcomes. A further objective was to assess the potential impact of these polymorphisms on RNA expression. A case–control study, including 151 patients with SLE, and 291 unrelated healthy controls (HC) matched in gender, and geographical origin, was performed to genotype two polymorphisms located in the ICOS gene: rs11889031 (−693 G/A) and rs10932029 (IVS1 + 173 T/C); using the polymerase chain reaction (PCR)-restriction fragment length polymorphism method. The different genotypes were validated by direct sequencing. The expression level of ICOS mRNA was assessed by quantitative PCR in peripheral blood mononuclear cells of SLE patients and HC. The results were analysed using Shesis and spss .20. Our results revealed a significant association between ICOS gene rs11889031 > CC genotype and SLE disease (codominant genetic model 1, (C/C vs. C/T), p = .001, odds ratio [OR] = 2.18 IC [1.36–3.49]); codominant genetic model 2, (C/C vs. T/T) p = .007, OR = 15.29 IC [1.97–118.5]); dominant genetic model, (C/C vs. C/T + T/T) p = .0001, OR = 2.44 IC [1.53–3.9]). Besides, there was a marginal association between rs11889031 > TT genotype and T allele with a protective role from SLE (recessive genetic model, p = .016, OR = 0.08 IC [0.01–0.63] and p = 7.6904E − 05, OR = 0.43 IC = [0.28–0.66], respectively). Moreover, statistical analysis indicated that the rs11889031 > CC genotype was linked with clinical and serological manifestations of SLE, including blood pressure, and anti-SSA antibodies production in SLE patients. However, the ICOS gene rs10932029 polymorphism was not associated with susceptibility to SLE. On the other side, we did not note any effect of the two selected polymorphisms on the level of ICOS mRNA gene expression. The study showed a significant predisposing association of the ICOS rs11889031 > CC genotype with SLE, in contrast to a protective effect of rs11889031 > TT genotype in Tunisian patients. Our results suggest that ICOS rs11889031 may act as a risk factor for SLE and could be used as a genetic susceptibility biomarker.     

High α-defensin levels in patients with systemic lupus erythematosus

Innate immunity plays a role in systemic lupus erythematosus (SLE). Our objective was to determine the levels of defensins, which are antimicrobial and immunomodulatory polypeptides, in SLE. Sera from SLE patients and healthy controls were tested for pro-inflammatory human β-defensin 2 (hBD-2) and for α-defensin human neutrophil peptide 1 (HNP-1). hBD-2 could not be detected by enzyme-linked immunosorbent assay (ELISA) and its mRNA levels were low in SLE patients and similar to those found in controls. In contrast, the mean α-defensin level in the sera of all SLE patients (11·07 ± 13·92 ng/μl) was significantly higher than that of controls (0·12 ± 0·07 ng/μl). Moreover, 60% of patients demonstrated very high serum levels (18·5 ± 13·36 ng/μl) and 50% showed elevated gene expression in polymorphonuclear cells. High α-defensin levels correlated with disease activity, but not with neutrophil count. Thus, activation and degranulation of neutrophils led to α-defensin secretion in SLE patients. Given the immunomodulatory role of α-defensins, it is possible that their secretion may activate the adaptive immune system leading to a systemic response.     

Restoring regulation – IL-2 therapy in systemic lupus erythematosus

Introduction: The pathogenesis of systemic lupus erythematosus (SLE) involves an acquired deficiency of the cytokine IL-2, an essential growth and survival factor for regulatory T cells (Treg), which play an important role in the control of autoimmunity in SLE. In contrast to currently available therapies that broadly suppress the immune system, low-dose IL-2 therapy in SLE aims to compensate the pre-existing IL-2 deficiency and thus to restore a physiological state, where Treg can regain their ability to efficiently counteract autoimmunity.

Areas covered: Here we summarize key findings that led to the development of this novel therapeutic concept and will highlight the key rationales for the clinical translation of low-dose IL-2 therapy in SLE.

Expert commentary: The concept of low-dose IL-2 therapy in SLE has evolved from pathophysiological findings and thus can be considered a selective biological treatment strategy in SLE. Preliminary results from phase I/II studies are promising by proving selective Treg expansion and by providing first evidence for the clinical efficacy of low-dose IL-2 therapy in SLE.     

Genome–environment interactions in the molecular pathogenesis of dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by impaired contractility and dilation of the ventricles. In a subset of DCM patients, classical inheritance patterns occur (familial DCM), which have led to the identification of specific genomic loci and gene defects causing monogenic DCM subtypes. In the majority of DCM patients, however, there is no evidence for a monogenic etiology of the disorder (sporadic DCM), and in the absence of other recognizable etiological factors, these cases were classified as idiopathic. Recent research suggests that cardiotropic viruses are important environmental factors in the pathogenesis of idiopathic cases and that DCM commonly results from interactions between genetic and environmental factors, whereas pure genetic forms are rather rare. Regarding genetics, the clinical cardiomyopathic phenotype associated with single gene defects may be highly variable for unknown reasons. Furthermore, a novel class of genetic defects was identified recently which provide a molecular basis for abnormal reactions of cardiomyocytes to environmental stress. These defects are paradigms of specific molecular links between genome and environment during the pathogenesis of DCM. Regarding environmental factors, a recent molecular virological study based on myocardial biopsies in a large series of sporadic DCM patients has detected cardiac viral infections in the majority of patients, with a broad spectrum of virus species being involved. Apparently, DCM does not only occur as a late sequela of acute viral myocarditis, but also in patients without clinical history of cardiac viral disease. Cardiotropic viruses thus emerge as prevalent environmental factors which may cause or influence the course of DCM in a large fraction of cases. Synopsis of current data suggests that a comprehensive picture of DCM pathogenesis can only be drawn if both genetic and environmental pathogenetic factors are considered. The course of cardiac viral infections depends strongly on genetic host factors and may range from rapid and complete virus elimination or silencing without clinical symptoms, to rapidly progressive or fatal disease. Viruses interact not only with genetically heterogenous host systems of virus uptake, migration, and antiviral immunity, but, due to their prevalence in DCM hearts, are also likely to encounter multiple structural proteins of cardiac cells known to be defective in familial DCM. The combined knowledge on DCM-associated gene defects and viruses therefore suggests in-depth studies on genome–environment interactions in DCM pathogenesis which may underlie the high clinical variability observed both in monogenic and virus-associated DCM and have implications for the clinical management of DCM patients.     

"Tree-barking" of the ascending aorta. Syphilis or systemic lupus erythematosus?

A case of unsuspected classical aortitis with "tree-barking" of the ascending aorta in a young woman with systemic lupus erythematosus and inconclusive syphilitic serologic results is presented. At autopsy, no definite diagnostic clues as to syphilitic or lupic aortitis could be obtained. Although infrequent today, the possibility of complicated cardiovascular syphilis still should be considered. Involvement of the ascending aorta by other systemic diseases is well known and can imitate syphilitic aortitis. Although the possibility of two concomitant diseases cannot be ruled out, the young age of the patient, the weak syphilitic serologic result, and active systemic lupus erythematosus demonstrated in other organs favor a diagnosis of lupic aortitis of the ascending aorta.     

Are anti-ribosomal P protein antibodies relevant in systemic lupus erythematosus?

Systemic lupus erythematosus (SLE) is a prototypal auto-immune disorder characterized with multiple organ involvement resulting in disability and increased mortality. Immune regulatory disturbances cumulate in activation of B cells and consequent auto-antibody production. Antigens for these auto-antibodies can be nuclear components and cytoplasmic elements. Anti-P antibodies react against acidic phosphorylated ribosomal proteins P0, P1, and P2 (with molecular mass of 38, 19, and 17 kDa, respectively) and are located on the S60 subunit of ribosomes. Ribosomal P proteins share a common 22-amino acid sequence that is present in the carboxyl-terminal. Anti-P antibodies can be detected in approx 15 to 20% of patients with lupus by several immunoassays, most frequently by enzyme-linked immunosorbent assay (ELISA) and/or Western blotting. However, no standardized assay is available. Auto-antibodies against eukaryotic P proteins appear highly specific for SLE; therefore, they can be used as diagnostic marker for the disease. Furthermore, association has been described with particular manifestations of lupus, especially with neuropsychiatric, renal, and hepatic involvements. Anti-P positivity and the titer of anti-P antibodies also fluctuate with clinical disease activity. Despite several lines of evidence, results are conflicting regarding the existence of such associations. Discrepancies can be explained by different study set-up or study population; it also can be attributed to the different sensitivity of tests used for the detection of anti-P antibody.     

Does parvovirus infection have a role in systemic lupus erythematosus?

We sought to evaluate a possible link between parvovirus B19 infection and the clinical and laboratory expression of systemic lupus erythematosus (SLE). SLE patients were examined to evaluate their clinical status and disease activity. A complete Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was obtained for each patient. In addition, we determined the level of systemic involvement throughout the course of the disease. Blood levels of IgM and IgG antibodies to parvovirus B19, levels of anti-dsDNA, C3, and C4 were measured. A PCR real-time assay was used to determine the presence of parvovirus B19 genetic material. The viral genome was found in sera of 2 of 51(3.9%) patients with SLE. There was no correlation between viral serology and the clinical and serological parameters of the disease. More SLE patients with secondary antiphospholipid syndrome (APS) had IgG and IgM antibodies to the virus (p < 0.029 and p < 0.018, respectively). These patients also had a higher titer of IgG antibodies to parvovirus B19 compared to SLE patients without APS. In this group of SLE patients, no association was found between parvovirus infection and the presence or activity of SLE. The results of the study suggest an association between parvovirus infection and antibody production directed against phospholipids.

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Influenza vaccination in systemic lupus erythematosus: safe and protective?

Patients with systemic lupus erythematosus (SLE) show decreased immune responsiveness and are vulnerable for infectious diseases, due to the underlying disease and the frequent use of immunosuppressive drugs. Influenza has a high incidence in the population and is associated with increased morbidity and mortality in immunocompromised patients. Therefore, routine influenza vaccination of SLE patients seems indicated. However, there have been concerns about the safety of influenza vaccination in SLE as vaccination was thought to activate the autoimmune response. Safety of influenza vaccination has been studied, and, as far as SLE patients with quiescent disease are concerned, it is now generally accepted that influenza vaccination is safe. Another point of concern is vaccine efficacy. In immunocompromised patients, the immunogenicity of vaccines may be reduced. In the immune response to influenza (vaccination) both humoral and cell-mediated responses are involved. In SLE, research on the immune response to influenza vaccination has focused on humoral immune responses, demonstrating a blunted humoral response. Future research should focus on cell-mediated immune responses as well, as these are important for clearing of influenza infection and are expected to be impaired in SLE. Because of the decreased immunogenicity of the current influenza vaccine in SLE, new influenza vaccination strategies should be explored to improve vaccination efficacy.     

Management of immune cytopenias in patients with systemic lupus erythematosus — Old and new

There are various immune cytopenias associated with systemic lupus erythematosus (SLE). The most common one is anemia; however, there are different etiologies for the anemia caused by SLE. Anemia could be due to chronic disease, secondary to renal insufficiency, blood loss, drug induced or autoimmune hemolysis. There are other very rare causes of anemia secondary to SLE which include red cell aplasia, aplastic anemia, and microangiopathic hemolytic anemia. Treatment of the anemia would be according to the cause. Leukopenia, neutropenia, and lymphopenia are hematologic complications associated with SLE, and in majority of cases no treatment is required. Thrombocytopenia is one of the complications of SLE and is usually treated by steroids. However, there are significant numbers of patients which will either not respond to or relapse after treatment. This article summarizes immune cytopenias seen in patients with SLE, and it also discusses management of these cytopenias.     

Regulatory effect of IL-38 on NF-κB pathway in systemic lupus erythematosus

BackgroundIL-38 is a newly identified cytokine that exhibits immunosuppression effects. However, there are few studies focusing on the effects and mechanisms of IL-38 in the systemic lupus erythematosus (SLE).AimWe investigated the effects and mechanisms of IL-38 on NF-κB signaling pathway in SLE.MethodsLevels of IL-38, IL-36R, IL-1RAcP, IKKα/β, NF-κB, TNF-α and anti-dsDNA antibody levels in peripheral blood of SLE patients, and in peripheral blood and kidney tissues of MRL/lpr mice, were examined with real-time PCR, ELISA, Western blot and immunohistochemistry. Pathological changes of kidney were detected with PAS staining. Recombinant human IL-38 protein and IL-38 siRNA were used to intervene the PBMCs of SLE patients and MRL/lpr mice.ResultsThe mRNA and protein levels of IL-38 in peripheral blood of SLE patients decreased and were positively correlated. The mRNA and protein levels of IKKα/β, NF-κB, and TNF-α increased, especially in patients with active SLE. There was a negative correlation between IL-38 and the levels of IKKα/β, NF-κB and TNF-α in SLE patients. In vitro experiments showed that the levels of IKKα/β, NF-κB and TNF-α, and anti-dsDNA antibodies decreased in PBMCs of SLE patients after treatment with human recombinant IL-38 protein. These effects were reversed after IL-38 siRNA intervention. Consistent results were obtained on IL-38, IKKα/β, NF-κB, and TNF-α in MRL/lpr lupus mice after treatment with IL-38 protein or IL-38 shRNA. Additionally, kidney function (reflected by creatinine and blood urea nitrogen), anti-dsDNA antibody, complement C3, and urinary protein levels decreased after treatment with IL-38 protein but increased after IL-38 shRNA treatment. PAS staining showed IL-38 protein treatment induced mild hyperplasia of glomerular mesangial cells and a small amount of lymphocyte infiltration. However, these were aggravated after IL-38 shRNA treatment.ConclusionIL-38 may be involved in the occurrence and development of SLE by regulating the NF-κB signaling pathway. This study only discussed the relationship between IL-38 and NF-κB, and more biological functions of IL-38 need to be further studied.     

Role of Fcγ receptor IIb polymorphism in the genetic background of systemic lupus erythematosus: Insights from Asia

FCGR2B codes for an inhibitory receptor expressed in B cells and monocytes. Polymorphisms of Fcgr2b in mice have been shown to be associated with autoimmune diseases including systemic lupus erythematosus (SLE) and targeted disruption of Fcgr2b renders mice susceptible to induced or spontaneous autoimmunity, depending on the genetic background. Polymorphism screening of FCGR2B has been hampered by the complexity and extreme homology among FCGR family members. We established a specific genotyping system, detected a SNP that changes position 232 amino acid in the transmembrane region from Ile to Thr and found a significant association of 232Thr with SLE in the Japanese, Thai and Chinese populations. In contrast, promoter polymorphism of FCGR2B, but not Ile232Thr, was shown to be associated with SLE in Caucasians. Linkage disequilibrium was observed among FCGR2A, 2B, 3A and 3B genes with varying degrees, but in the Asian populations, each of FCGR2B, 3A and 3B genes was suggested to contribute to the susceptibility to SLE. These results indicate that FCGR2B is a susceptibility gene to SLE in the context of a genetic background, both in humans and mice.     

The expression of PD-1 and level of CXCL10 in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is known tobe a chronic and complicated rheumatic diseasewith an autoimmune etiology.SLEis also a proto-type of autoimmune disease due to a substantialoverlapinits clinical symptoms withother autoim-mune diseases . The immune systemof SLElosesbalance of auto-tolerance ,in which lymphocytesare activated excessively,contributingto SLE de-velopment .It has been well established that effi-cient T cell-mediated immune responses requirenot only the TCR-mediat…