The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus.

The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus.

Vascular damage in systemic lupus erythematosus.

Vascular disease is a major cause of morbidity and mortality in patients with systemic autoimmune diseases, particularly systemic lupus erythematosus (SLE). Although comorbid cardiovascular risk factors are frequently present in patients with SLE, they do not explain the high burden of premature vascular disease. Profound innate and adaptive immune dysregulation seems to be the primary driver of accelerated vascular damage in SLE. In particular, evidence suggests that dysregulation of type 1 interferon (IFN-I) and aberrant neutrophils have key roles in the pathogenesis of vascular damage. IFN-I promotes endothelial dysfunction directly via effects on endothelial cells and indirectly via priming of immune cells that contribute to vascular damage. SLE neutrophils are vasculopathic in part because of their increased ability to form immunostimulatory neutrophil extracellular traps. Despite improvements in clinical care, cardiovascular disease remains the leading cause of mortality among patients with SLE, and treatments that improve vascular outcomes are urgently needed. Improved understanding of the mechanisms of vascular injury in inflammatory conditions such as SLE could also have implications for common cardiovascular diseases, such as atherosclerosis and hypertension, and may ultimately lead to personalized therapeutic approaches to the prevention and treatment of this potentially fatal complication.

Impact of fragility fractures on activities of daily living and productivity in community-dwelling women: a multi-national study.

We estimated the short-term impact of fragility fractures on community-dwelling women in five countries. Women with fragility fractures reported significantly more difficulties performing activities of daily living and significantly higher levels of lost productivity and caregiver support than those without fractures; results highlight the multi-country indirect burden of fragility fractures. INTRODUCTION: To estimate the impact of fragility fractures on activities of daily living (ADL), productivity loss and caregiver support in women with a recent fragility fracture. METHODS: This multi-centre cross-sectional study enrolled community-dwelling women aged ≥ 50 years in South Korea, Spain, Germany, Australia and the United States. The fragility fracture cohort consisted of women with an index fragility fracture in the past 12 months; the fracture free cohort consisted of women with no fracture in the 18 months prior to study enrolment. Study participants completed three validated questionnaires: Lawton Instrumental ADL (IADL), Physical Self-Maintenance Scale (PSMS) and iMTA Productivity Cost Questionnaire (iPCQ). RESULTS: In total, 1,253 participants from 41 sites across the five countries were included. Compared with the fracture free cohorts, fragility fracture cohorts had significantly lower function and were more dependent on support (p < 0.05 in all countries for Lawton IADL, and in South Korea, Spain, Australia and the United States for PSMS), significantly higher hours of paid absenteeism (p < 0.05, Spain, Germany, Australia), significantly higher unpaid lost productivity (p < 0.05, South Korea, Spain, Germany), significantly more days of paid help received in the home (p < 0.05 South Korea, Spain and the United States), and significantly more days of unpaid help from family members or friends (p < 0.05, all countries). CONCLUSION: In this multi-national study, fragility fractures in community-dwelling ≥ 50 years women were associated with several outcomes indicating higher indirect burden and lower quality of life, including more difficulties performing ADL and higher levels of lost productivity and caregiver support.

Refractory systemic onset juvenile idiopathic arthritis: current challenges and future perspectives.

Systemic juvenile idiopathic arthritis (SJIA) is a rare disease with distinct features not seen in other categories of juvenile idiopathic arthritis. In recent years, advances in the understanding of disease immunopathogenesis have led to improved targeted therapies with significant improvement in patient outcomes. Despite these advances, there remain subsets of SJIA with refractory disease and severe disease-associated complications. This review highlights existing options for treatment of refractory SJIA and explores potential future therapeutics for refractory disease.Key Points:Despite targeted Interleukin IL-1 and IL-6 inhibitors a subset of SJIA remains refractory to therapy. About 1 in 7 SJIA patients will be refractory to targeted IL-1 or IL-6 therapy.There is no current agreed upon definition for refractory SJIA and we propose in this review that refractory SJIA is presence of active systemic or arthritic features despite treatment with anti-IL-1 or anti-IL-6 therapy or disease requiring glucocorticoids for control beyond 6 months.SJIA disease associated complications include presence of associated macrophage activation syndrome (MAS), interstitial lung disease (ILD) or amyloidosis and management of each differs.Refractory SJIA treatment options currently include additional conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS), biologic (bDMARDS), combination biologic therapy, targeted synthetic (tsDMARDS) or other immunomodulatory therapies.

Advances in understanding and examining lymphatic function: relevance for understanding autoimmunity.

PURPOSE OF REVIEW: The aim of this review is to give insights into how novel lymphatics functions may influence autoimmunity. RECENT FINDINGS: The lymphatic system connects peripheral tissues to draining lymph nodes to regulate adaptive immunity and directly interfaces with leukocytes in lymph vessels and in the lymph node. Here, we discuss recent findings showing evidence of dysfunctional lymphatics in autoimmune disease, new understanding of how afferent lymphatic regulation can modulate immunity, lymph node lymphatic heterogeneity and how these lymphatics can directly modulate lymphocyte function, how this understanding can be harnessed for new therapeutics, and new tools for the investigation of lymphatic and immune biology. SUMMARY: Lymphatics have an active role in the regulation of inflammation and the adaptive immune response. Here, we review recent findings in lymphatics biology in peripheral tissues and lymph nodes and emphasize the relevance for better understanding autoimmune diseases.

Immune Cell-Stromal Circuitry in Lupus Photosensitivity.

Photosensitivity is a sensitivity to UV radiation (UVR) commonly found in systemic lupus erythematosus (SLE) patients who have cutaneous disease. Upon even ambient UVR exposure, patients can develop inflammatory skin lesions that can reduce the quality of life. Additionally, UVR-exposed skin lesions can be associated with systemic disease flares marked by rising autoantibody titers and worsening kidney disease. Why SLE patients are photosensitive and how skin sensitivity leads to systemic disease flares are not well understood, and treatment options are limited. In recent years, the importance of immune cell-stromal interactions in tissue function and maintenance is being increasingly recognized. In this review, we discuss SLE as an anatomic circuit and review recent findings in the pathogenesis of photosensitivity with a focus on immune cell-stromal circuitry in tissue health and disease.

Enhancing the Hydrophilicity and Cell Attachment of 3D Printed PCL/Graphene Scaffolds for Bone Tissue Engineering.

Scaffolds are physical substrates for cell attachment, proliferation, and differentiation, ultimately leading to the regeneration of tissues. They must be designed according to specific biomechanical requirements, i.e., certain standards in terms of mechanical properties, surface characteristics, porosity, degradability, and biocompatibility. The optimal design of a scaffold for a specific tissue strongly depends on both materials and manufacturing processes, as well as surface treatment. Polymeric scaffolds reinforced with electro-active particles could play a key role in tissue engineering by modulating cell proliferation and differentiation. This paper investigates the use of an extrusion-based additive manufacturing system to produce poly(ε-caprolactone) (PCL)/pristine graphene scaffolds for bone tissue applications and the influence of chemical surface modification on their biological behaviour. Scaffolds with the same architecture but different concentrations of pristine graphene were evaluated from surface property and biological points of view. Results show that the addition of pristine graphene had a positive impact on cell viability and proliferation, and that surface modification leads to improved cell response.

α4 integrin is a regulator of leukocyte recruitment after experimental intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is swiftly followed by an inflammatory response. A key component of this response is the recruitment of leukocytes into the brain, which promotes neurological injury in rodent models. However, the mechanisms by which leukocytes transmigrate across the endothelium into the injured brain are unclear. The present study examines leukocyte adhesion molecules (α4 integrin, L-selectin, and αLß2 integrin) on 4 leukocyte subtypes to determine which are important for leukocyte recruitment after ICH. METHODS: We used the blood injection mouse model of ICH, whereby 25 µL of blood was injected into the striatum. Flow cytometry was used to quantify leukocyte populations and adhesion molecule expression in brain and blood. An α4 integrin-blocking antibody was administered to evaluate the contribution of α4 integrin in leukocyte migration and neurological injury. RESULTS: α4 integrin was elevated on all leukocyte populations in brain after ICH, whereas L-selectin was unchanged and αLß2 was increased only on T cells. Antagonism of α4 resulted in decreased leukocyte transmigration and lessened neurobehavioral disability. CONCLUSIONS: α4 integrin is an important cell adhesion molecule involved in neuroinflammation after ICH.