A subset of patients with systemic lupus erythematosus fails to degrade DNA from multiple clinically relevant sources

Patients with systemic lupus erythematosus (SLE) have a decreased ability to clear cell remnants and multiple deficiencies in the ability to degrade cellular chromatin have been linked to the disease. Since the discovery of neutrophil extracellular traps (NETs), a renewed interest has been sparked in this field of research with multiple studies reporting a decreased ability of patients with SLE to degrade NETs. In this study we extend these findings by investigating the ability of patients with SLE to degrade chromatin from multiple clinically relevant sources

IRF7-Associated Immunophenotypes Have Dichotomous Responses to Virus/Allergen Coexposure and OM-85-Induced Reprogramming

High risk for virus-induced asthma exacerbations in children is associated with an IRF7lo immunophenotype, but the underlying mechanisms are unclear. Here, we applied a Systems Biology approach to an animal model comprising rat strains manifesting high (BN) versus low susceptibility (PVG) to experimental asthma, induced by virus/allergen coexposure, to elucidate the mechanism(s)-of-action of the high-risk asthma immunophenotype. We also investigated potential risk mitigation via pretreatment with the immune training agent OM-85. Virus/allergen coexposure in low-risk PVG rats resulted in rapid and transient airways inflammation alongside IRF7 gene network formation. In contrast, responses in high-risk BN rats were characterized by severe airways eosinophilia and exaggerated proinflammatory responses that failed to resolve, and complete absence of IRF7 gene networks. OM-85 had more profound effects in high-risk BN rats, inducing immune-related gene expression changes in lung at baseline and reducing exaggerated airway inflammatory responses to virus/allergen coexposure. In low-risk PVG rats, OM-85 boosted IRF7 gene networks in the lung but did not alter baseline gene expression or cellular influx. Distinct IRF7-associated asthma risk immunophenotypes have dichotomous responses to virus/allergen coexposure and respond differentially to OM-85 pretreatment. Extrapolating to humans, our findings suggest that the beneficial effects OM-85 pretreatment may preferentially target those in high-risk subgroups

Progressive increase of FcεRI expression across several PBMC subsets is associated with atopy and atopic asthma within school-aged children

Background: Antigen-specific IgE binds the Fcε receptor I (FcεRI) expressed on several types of immune cells, including dendritic cells (DCs). Activation of FcεRI on DCs in atopics has been shown to modulate immune responses that potentially contribute to asthma development. However, the extent to which DC subsets differ in FcεRI expression between atopic children with or without asthma is currently not clear. This study aimed to analyse the expression of FcεRI on peripheral blood mononuclear cells (PBMCs) from atopic children with and without asthma, and non-atopic/non-asthmatic age-matched healthy controls. Methods: We performed multiparameter flow cytometry on PBMC from 391 children across three community cohorts and one clinical cohort based in Western Australia. Results: We confirmed expression of FcεRI on basophils, monocytes, plasmacytoid and conventional DCs, with higher proportions of all cell populations expressing FcεRI in atopic compared to non-atopic children. Further, we observed that levels of FcεRI expression were elevated across plasmacytoid and conventional DC as well as basophils in atopic asthmatic compared to atopic non-asthmatic children also after adjusting for serum IgE levels. Conclusion: Our data suggest that the expression pattern of FcεRI on DC and basophils differentiates asthmatic from non-asthmatic atopic children. Given the significant immune modulatory effects observed as a consequence of FcεRI expression, this altered expression pattern is likely to contribute to asthma pathology in children

Basophil levels in PBMC population during childhood acute wheeze/asthma are associated with future exacerbations

Our data suggest that a basophil level above 0.18% of the PBMC population during an acute respiratory exacerbation is associated with an increased risk for future exacerbations in children with asthma and/or wheeze

Complement in Autoimmunity - the importance of clearing waste

Systemic lupus erythematosus (SLE) is an autoimmune disease where improperly cleared apoptotic cells and neutrophil extracellular traps (NETs) induce an autoimmune response. Complement is crucial to prevent SLE by tailoring immune responses and opsonizing dead cells but may also induce inflammation and tissue damage once the disease is initiated. Complement C1q binds to apoptotic cells and ensures rapid and tolerogenic clearance by phagocytes. C1q can also activate complement. To avoid excessive activation, binding of the complement inhibitor factor H to the apoptotic cells is crucial. In this thesis we have discovered that factor H as well as C1q bind to the phospholipid binding proteins annexin A2 and that C1q also binds A5. These proteins are expressed on apoptotic cells. Further, we have observed that both C1q and factor H bind to the chromatin constituents, DNA and histones. Binding of C1q to these ligands led to complement activation indicating the need for factor H on the apoptotic cells. NETs constitute one mechanism of how neutrophils can protect the body from pathogens. By releasing chromatin covered with antimicrobial enzymes the neutrophil can catch and kill pathogens. In this thesis we confirm that NETs are not degraded properly in 30% of patients with SLE. Further, C1q binds to NETs, prevents degradation and also activates complement. Consequently, the patients with decreased ability to degrade NETs more often suffer from complement consumption and glomerulonephritis, manifestations of severe SLE. This initial study was followed-up by a longitudinal study where temporal associations such as glomerulonephritis, pleuritis and elevated levels of histone antibodies could then be linked to a decreased ability to degrade NETs. NET degradation was also affected in some patients with antiphospholipid syndrome and systemic sclerosis. However the effect was not as pronounced as in SLE and was more evident the more SLE-like the APS was. In conclusion, complement may both prevent and contribute to the pathogenesis in SLE. In this thesis, ligands for complement C1q and factor H have been revealed on the apoptotic cells and further, the interactions of complement with NETs have been elucidated. Additionally, the ability to degrade NETs has been analyzed in SLE and SLE like diseases, which may be used to better diagnose or treat these patients in the future

The complement system in systemic lupus erythematosus: an update.

The complement system plays a major role in the autoimmune disease, systemic lupus erythematosus (SLE). However, the role of complement in SLE is complex since it may both prevent and exacerbate the disease. In this review, we explore the latest findings in complement-focused research in SLE. C1q deficiency is the strongest genetic risk factor for SLE, although such deficiency is very rare. Various recently discovered genetic associations include mutations in the complement receptors 2 and 3 as well as complement inhibitors, the latter related to earlier onset of nephritis. Further, autoantibodies are a distinct feature of SLE that are produced as the result of an adaptive immune response and how complement can affect that response is also being reviewed. SLE generates numerous disease manifestations involving contributions from complement such as glomerulonephritis and the increased risk of thrombosis. Furthermore, since most of the complement system is present in plasma, complement is very accessible and may be suitable as biomarker for diagnosis or monitoring of disease activity. This review highlights the many roles of complement for SLE pathogenesis and how research has progressed during recent years

Degradation of neutrophil extracellular traps is decreased in patients with antiphospholipid syndrome.

A decreased ability to degrade neutrophil extracellular traps (NETs) is seen in a subgroup of patients with systemic lupus erythematosus (SLE) and correlates with the presence of autoantibodies. Antiphospholipid syndrome (APS) can develop secondary to SLE or as a primary disease. In the current study we investigated the ability of sera from patients with APS to degrade NETs. The presence of antibodies against NETs and neutrophil remnants were also determined in the same patients