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Macrophages are a dynamic cell type of the immune system implicated in the pathophysiology of vascular diseases and are a major contributor to pathological inflammation. Excessive macrophage accumulation, activation, and polarization is observed in aortic aneurysm (AA), atherosclerosis, and pulmonary arterial hypertension. In general, macrophages become activated and polarized to a pro-inflammatory phenotype, which dramatically changes cell behavior to become pro-inflammatory and infiltrative. These cell types become cumbersome and fail to be cleared by normal mechanisms such as autophagy. The result is a hyper-inflammatory environment causing the recruitment of adjacent cells and circulating immune cells to further augment the inflammatory response. In AA, this leads to excessive ECM degradation and chemokine secretion, ultimately causing macrophages to dominate the immune cell landscape in the aortic wall. In atherosclerosis, monocytes are recruited to the vascular wall, where they polarize to the pro-inflammatory phenotype and induce inflammatory pathway activation. This leads to the development of foam cells, which significantly contribute to neointima and necrotic core formation in atherosclerotic plaques. Pro-inflammatory macrophages, which affect other vascular diseases, present with fragmented mitochondria and corresponding metabolic dysfunction. Targeting macrophage mitochondrial dynamics has proved to be an exciting potential therapeutic approach to combat vascular disease. This review will summarize mitochondrial and metabolic mechanisms of macrophage activation, polarization, and accumulation in vascular diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The vascular endothelium dynamically responds to environmental cues and plays a pivotal role in maintaining vascular homeostasis by regulating vasomotor tone, blood cell trafficking, permeability and immune responses. However, endothelial dysfunction results in various pathological conditions. Inflammasomes are large intracellular multimeric complexes activated by pathogens or cellular damage. Inflammasomes in vascular endothelial cells (ECs) initiate innate immune responses, which have emerged as significant mediators in endothelial dysfunction, contributing to the pathophysiology of an array of diseases. This review summarizes the mechanisms and ramifications of inflammasomes in ECs and related vascular diseases such as atherosclerosis, abdominal aortic aneurysm, stroke, and lung and kidney diseases. We also discuss potential drugs targeting EC inflammasomes and their applications in treating vascular diseases., (© 2024 British Pharmacological Society.)

Porto-sinusoidal vascular disorder (PSVD) encompasses a group of vascular disorders characterized by lesions of the portal venules and sinusoids with clinical manifestations ranging from non-specific abnormalities in serum liver enzymes to clinically overt portal hypertension and related complications. Several reports have documented cases of PSVD in patients with systemic autoimmune conditions, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. It is of note that these diseases share specific pathophysiological features with PSVD, including endothelial dysfunction, vascular inflammation, and molecular signatures. This narrative review aims to summarize the current knowledge on the association between PSVD and systemic autoimmune diseases, emphasizing the importance of promptly recognizing this condition in the rheumatological practice, and highlighting the key aspects where further research is necessary from both pathogenic and clinical perspectives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Cardiac allograft vasculopathy (CAV) causes late graft failure and mortality after heart transplantation. Donor-specific antibodies (DSAs) lead to chronic endothelial cell injury, inflammation, and arterial intimal thickening. In this study, GeoMx digital spatial profiling was used to analyze arterial areas of interest (AOIs) from CAV+DSA+ rejected cardiac allografts (N = 3; 22 AOIs total). AOIs were categorized based on CAV neointimal thickening and underwent whole transcriptome and protein profiling. By comparing our transcriptomic data with that of healthy control vessels of rapid autopsy myocardial tissue, we pinpointed specific pathways and transcripts indicative of heightened inflammatory profiles in CAV lesions. Moreover, we identified protein and transcriptomic signatures distinguishing CAV lesions exhibiting low and high neointimal lesions. AOIs with low neointima showed increased markers for activated inflammatory infiltrates, endothelial cell activation transcripts, and gene modules involved in metalloproteinase activation and TP53 regulation of caspases. Inflammatory and apoptotic proteins correlated with inflammatory modules in low neointima AOIs. High neointima AOIs exhibited elevated TGFβ-regulated transcripts and modules enriched for platelet activation/aggregation. Proteins associated with growth factors/survival correlated with modules enriched for proliferation/repair in high neointima AOIs. Our findings reveal novel insight into immunological mechanisms mediating CAV pathogenesis., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cardio-cerebrovascular diseases encompass pathological changes in the heart, brain and vascular system, which pose a great threat to health and well-being worldwide. Moreover, metabolic diseases contribute to and exacerbate the impact of vascular diseases. Inflammation is a complex process that protects against noxious stimuli but is also dysregulated in numerous so-called inflammatory diseases, one of which is atherosclerosis. Inflammation involves multiple organ systems and a complex cascade of molecular and cellular events. Numerous studies have shown that inflammation plays a vital role in cardio-cerebrovascular diseases and metabolic diseases. The absent in melanoma 2 (AIM2) inflammasome detects and is subsequently activated by double-stranded DNA in damaged cells and pathogens. With the assistance of the mature effector molecule caspase-1, the AIM2 inflammasome performs crucial biological functions that underpin its involvement in cardio-cerebrovascular diseases and related metabolic diseases: The production of interleukin-1 beta (IL-1β), interleukin-18 (IL-18) and N-terminal pore-forming Gasdermin D fragment (GSDMD-N) mediates a series of inflammatory responses and programmed cell death (pyroptosis and PANoptosis). Currently, several agents have been reported to inhibit the activity of the AIM2 inflammasome and have the potential to be evaluated for use in clinical settings. In this review, we systemically elucidate the assembly, biological functions, regulation and mechanisms of the AIM2 inflammasome in cardio-cerebrovascular diseases and related metabolic diseases and outline the inhibitory agents of the AIM2 inflammasome as potential therapeutic drugs., (© 2024 British Pharmacological Society.)

Background: This study evaluated the efficacy and safety of baricitinib (Janus kinase-1/2 inhibitor), in adult and pediatric Japanese patients with Nakajo-Nishimura syndrome/chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (NNS/CANDLE), stimulator of interferon genes-associated vasculopathy with onset during infancy (SAVI), or Aicardi-Goutières syndrome (AGS)., Methods: A Phase 2/3, multicenter, open-label study (NCT04517253) was conducted across 52 weeks. Primary efficacy endpoint assessed the change in mean daily diary score (DDS) from baseline to the end of primary treatment period. Other efficacy endpoints included change in mean DDS to the end of maintenance period, daily corticosteroid use, Physician's Global Assessment of Disease Activity (PGA) scores, and daily symptom-specific score (DSSS) from baseline to primary and maintenance treatment periods. All treatment-emergent adverse events (TEAEs) that occurred postdosing were recorded., Results: Overall, 9 patients (5 with NNS, 3 with SAVI, and 1 with AGS) were enrolled; 55.6% were females, mean age was 26 years, and mean corticosteroid use/weight was 0.2 mg/kg. At the end of primary treatment period, mean DDS decreased from baseline in patients with NNS/CANDLE (0.22) and SAVI (0.21) and increased in the patient with AGS (0.07). At the end of maintenance treatment period, mean DDS decreased from baseline in patients with NNS/CANDLE (0.18) and SAVI (0.27) and increased in the patient with AGS (0.04). Mean percent corticosteroid use decreased by 18.4% in 3 out of 5 patients with NNS/CANDLE and 62.9% in 1 out of 3 patients with SAVI. Mean PGA score decreased from baseline in patients with NNS/CANDLE (1.60), SAVI (1.33), and AGS (1.0), and mean DSSS improved from baseline. All patients reported ≥ 1 TEAE. Frequently reported AEs included BK polyomavirus detection (3; 33.3%), increased blood creatine phosphokinase (2; 22.2%), anemia (2; 22.2%), and upper respiratory tract infection (2; 22.2%). Three (33.3%) patients reported serious adverse events, 1 of which was related to study drug. One patient with SAVI died due to intracranial hemorrhage, which was not related to study drug., Conclusion: Baricitinib may offer a potential therapeutic option for patients with NNS/CANDLE, SAVI, and AGS, with a positive benefit/risk profile in a vulnerable patient population with multiple comorbidities., Trial Registration: NLM clinicaltrials.gov, NCT04517253 . Registered 18 August 2020., (© 2023. The Author(s).)

We have successfully created induced pluripotent stem cells (iPSC) from patients carrying a heterozygous mutation in the gene encoding STING. The gain-of-function mutation leads to constitutive activation of STING which leads to the development of the disease STING-associated vasculopathy with onset in infancy (SAVI). The iPSC lines derived from the SAVI patitents are shown to be morphologically and phenotypically normal and have the potential to self renew and differentiate into the three germ layers. These iPSC provide a powerful tools to investigate the role of STING in the regulation of immune responses and vascular renegeration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Pediatric patients with constitutively active mutations in the cytosolic double-stranded-DNA-sensing adaptor STING develop an autoinflammatory syndrome known as STING-associated vasculopathy with onset in infancy (SAVI). SAVI patients have elevated interferon-stimulated gene expression and suffer from interstitial lung disease (ILD) with lymphocyte predominate bronchus-associated lymphoid tissue (BALT). Mice harboring SAVI mutations (STING V154M [VM]) that recapitulate human disease also develop lymphocyte-rich BALT. Ablation of either T or B lymphocytes prolongs the survival of SAVI mice, but lung immune aggregates persist, indicating that T cells and B cells can independently be recruited as BALT. VM T cells produced IFNγ, and IFNγR deficiency prolonged the survival of SAVI mice; however, T-cell-dependent recruitment of infiltrating myeloid cells to the lung was IFNγ independent. Lethally irradiated VM recipients fully reconstituted with wild type bone-marrow-derived cells still developed ILD, pointing to a critical role for VM-expressing radioresistant parenchymal and/or stromal cells in the recruitment and activation of pathogenic lymphocytes. We identified lung endothelial cells as radioresistant cells that express STING. Transcriptional analysis of VM endothelial cells revealed up-regulation of chemokines, proinflammatory cytokines, and genes associated with antigen presentation. Together, our data show that VM-expressing radioresistant cells play a key role in the initiation of lung disease in VM mice and provide insights for the treatment of SAVI patients, with implications for ILD associated with other connective tissue disorders.

Vascular endothelial cells are major participants in and regulators of immune responses and inflammation. Vascular endotheliitis is regarded as a host immune-inflammatory response of the endothelium forming the inner surface of blood vessels in association with a direct consequence of infectious pathogen invasion. Vascular endotheliitis and consequent endothelial dysfunction can be a principle determinant of microvascular failure, which would favor impaired perfusion, tissue hypoxia, and subsequent organ failure. Emerging evidence suggests the role of vascular endotheliitis in the pathogenesis of coronavirus disease 2019 (COVID-19) and its related complications. Thus, once initiated, vascular endotheliitis and resultant cytokine storm cause systemic hyperinflammation and a thrombotic phenomenon in COVID-19, leading to acute respiratory distress syndrome and widespread organ damage. Vascular endotheliitis also appears to be a contributory factor to vasculopathy and coagulopathy in sepsis that is defined as life-threatening organ dysfunction due to a dysregulated response of the host to infection. Therefore, protecting endothelial cells and reversing vascular endotheliitis may be a leading therapeutic goal for these diseases associated with vascular endotheliitis. In this review, we outline the etiological and pathogenic importance of vascular endotheliitis in infection-related inflammatory diseases, including COVID-19, and possible mechanisms leading to vascular endotheliitis. We also discuss pharmacological agents which may be now considered as potential endotheliitis-based treatment modalities for those diseases., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Sterile chronic inflammation causes cardiometabolic disorders; however, the mechanisms are not fully understood. Previous studies have demonstrated the degradation of cells/tissues in the vasculature and metabolic organs in lifestyle-associated diseases, such as diabetes and hyperlipidemia, suggesting the release and/or accumulation of nucleic acids from damaged cells. DNA is indispensable for life; however, DNA fragments, especially those from pathogens, strongly induce inflammation by the activation of DNA sensors. Growing evidence suggests that DNA-sensing mechanisms, which are normally involved in self-defense against pathogens as the innate immune system, are associated with the progression of inflammatory diseases in response to endogenous DNA fragments. There are several types of DNA sensors in our bodies. Toll-like receptor 9 (TLR9)-one of the most studied DNA sensors-recognizes DNA fragments in endosome. In addition, stimulator of interferon genes (STING), which has recently been extensively investigated, recognizes cyclic GMP-AMP (cGAMP) generated from DNA fragments in the cytosol. Both TLR9 and STING are known to play pivotal roles in host defense as the innate immune system. However, recent studies have indicated that the activation of these DNA sensors in immune cells, such as macrophages, promotes inflammation leading to the development of vascular and metabolic diseases associated with lifestyle. In this review, we discuss recent advances in determining the roles of DNA sensors in these disease contexts. Revealing a novel mechanism of sterile chronic inflammation regulated by DNA sensors might facilitate clinical interventions for these health conditions.

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic vasculitis syndrome caused by autosomal-recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1). Vasculitis, vasculopathy, and inflammation are dominant clinical features of this disease; the spectrum of manifestations includes immunodeficiency and lymphoproliferation as well as hematologic manifestations. ADA2 is primarily secreted by stimulated monocytes and macrophages. Aberrant monocyte differentiation to macrophages and neutrophils are important in the pathogenesis of DADA2, but little is known about T lymphocytes in this disease. We performed combined single-cell RNA sequencing and single-cell TCR sequencing in order to profile T cell repertoires in 10 patients with DADA2. Although there were no significant alterations of T cell subsets, we observed activation of both CD8 + and CD4 + T cells. There was no clonal expansion of T cells: most TCRs were expressed at basal levels in patients and healthy donors. TCR usage was private to individual patients and not disease specific, indicating as unlikely a common pathogenic background or predisposition to a common pathogen. We recognized activation of IFN pathways as a signature of T cells and STAT1 as a hub gene in the gene network of T cell activation and cytotoxicity. Overall, T cells in DADA2 patients showed distinct cell-cell interactions with monocytes, as compared with healthy donors, and many of these ligand-receptor interactions likely drove up-regulation of STAT1 in both T cells and other immune cells in patients. Our analysis reveals previously undercharacterized cell characteristics in DADA2., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) is an intracellular innate immune receptor that recognizes a diverse range of stimuli derived from pathogens, damaged or dead cells, and irritants. NLRP3 activation causes the assembly of a large multiprotein complex termed the NLRP3 inflammasome, and leads to the secretion of bioactive interleukin (IL)-1β and IL-18 as well as the induction of inflammatory cell death termed pyroptosis. Accumulating evidence indicates that NLRP3 inflammasome plays a key role in the pathogenesis of sterile inflammatory diseases, including atherosclerosis and other vascular diseases. Indeed, the results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study trial demonstrated that IL-1β-mediated inflammation plays an important role in atherothrombotic events and suggested that NLRP3 inflammasome is a key driver of atherosclerosis. In this review, we will summarize the current state of knowledge regarding the role of NLRP3 inflammasome in vascular diseases, in particular in atherosclerosis, vascular injury, aortic aneurysm, and Kawasaki disease vasculitis, and discuss NLRP3 inflammasome as a therapeutic target for these disorders., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Increased soluble endoglin (sENG) has been observed in human brain arteriovenous malformations (bAVMs). In addition, the overexpression of sENG in concurrence with vascular endothelial growth factor (VEGF)-A has been shown to induce dysplastic vessel formation in mouse brains. However, the underlying mechanism of sENG-induced vascular malformations is not clear. The evidence suggests the role of sENG as a pro-inflammatory modulator, and increased microglial accumulation and inflammation have been observed in bAVMs. Therefore, we hypothesized that microglia mediate sENG-induced inflammation and endothelial cell (EC) dysfunction in bAVMs. In this study, we confirmed that the presence of sENG along with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, we observed increased microglial activation around dysplastic vessels with the expression of NLRP3, an inflammasome marker. We found that sENG increased the gene expression of VEGF-A, pro-inflammatory cytokines/inflammasome mediators (TNF-α, IL-6, NLRP3, ASC, Caspase-1, and IL-1β), and proteolytic enzyme (MMP-9) in BV2 microglia. The conditioned media from sENG-treated BV2 (BV2-sENG-CM) significantly increased levels of angiogenic factors (Notch-1 and TGFβ) and pERK1/2 in ECs but it decreased the level of IL-17RD, an anti-angiogenic mediator. Finally, the BV2-sENG-CM significantly increased EC migration and tube formation. Together, our study demonstrates that sENG provokes microglia to express angiogenic/inflammatory molecules which may be involved in EC dysfunction. Our study corroborates the contribution of microglia to the pathology of sENG-associated vascular malformations.

Background: Cigarette smoke (CS) is associated with vascular injury and dysfunction, which may be mediated by iNOS and NLRP3. However, the exact mechanism is unknown., Methods: iNOS-knockout and NLRP3-knockout C57BL/6 mice were exposed to air or CS. The vascular structure was examined by hematoxylin-eosin staining. The vascular tension was measured by a vascular reactivity assay. The expression of iNOS, NLRP3, caspase-1p20, IL-1β and eNOS were measured by western blotting. Human aortic endothelial cells (HAECs) were exposed to L-NIL (iNOS inhibitor), MCC950 (NLRP3 inhibitor), ODQ (sGC inhibitor), KT5823 (PKG inhibitor) or TAPI-1 (TACE/ADAM17 inhibitor) for 1 h prior to cigarette smoke extract (CSE) treatment. The cell viability and lactate dehydrogenase activity were assessed and pyroptosis was determined by scanning electron microscopy. The mRNA expression of TNF-α, and protein expression of iNOS, active-TACE, NLRP3, caspase-1p20, IL-1β, and eNOS were measured., Results: CS resulted in shrinkage of endothelial cells, impaired aorta relaxation, reduced eNOS expression, and induced expression of iNOS, NLRP3, caspase-1p20 and IL-1β, which could be prevented by knockdown of iNOS and NLRP3. CSE reduced cell viability, induced LDH release and pyroptosis, and promoted iNOS, NLRP3, caspase-1p20, and IL-1β expression and reduced eNOS reduction, which could be reversed by inhibition of iNOS or NLRP3 in HAECs. Altogether, activation of the NLRP3 inflammasome by iNOS in CS-exposed HAECs may be mediated by the sGC/cGMP/PKG/TACE/TNF- α pathway., Conclusion: These results link iNOS to NLRP3 in CSE-stimulated HAECs through the sGC/cGMP/PKG/TACE/TNF-α pathway. The findings identify a mechanism through which iNOS and NLRP3 contribute to the pathogenesis of CS-induced pyroptosis and impaired aorta relaxation in HAECs., (Copyright © 2021. Published by Elsevier B.V.)

In patients with SSc, the coexistence of ANCA-associated vasculitis (SSc-AAV) has been reported to be associated with a severe disease course, including significant pulmonary and renal involvement. The presence of ANCA is not uncommon in patients with SSc, and therefore clinicians must maintain a high index of clinical suspicion about SSc-AAV. p-ANCA and anti-myeloperoxidase antibodies are the most common antibodies observed. Patients typically present with clinical features of microscopic polyangiitis or renal-limited vasculitis. There are multiple areas of potential interaction in the pathogenesis of SSc and AAV, which can exacerbate/compound vascular disease. In addition, similar patterns of major internal organ involvement (e.g. lung and kidneys) are seen in both conditions. We highlight a diagnostic approach to SSc-AAV and the paucity of data to inform management. As such, SSc-AAV is typically treated as per isolated AAV, which can potentially be hazardous in patients with SSc (e.g. due to the association between high-dose steroid and scleroderma renal crisis). We propose that this rare clinical entity warrants rigorous investigation, including definition of a therapeutic strategy to ameliorate the potentially devastating combination of pathologies in SSc-AAV., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Direct immunofluorescence (DIF) findings in patients with livedoid vasculopathy (LV) may have benefits for disease differentiation when clinical presentations and/or histopathological findings are inconclusive., Aim: To investigate DIF findings in patients with a clinical and histopathological diagnosis of LV., Methods: DIF findings of 62 patients with LV were analysed, and the published literature in the PubMed database was also reviewed and summarized., Results: This study demonstrated deposition of immunoreactants in blood vessels (BVs) in 59 of the 62 patients (95.2%), and almost all cases were positive for a combination of multiple immunoreactants. Complement C3 and IgM formed the most common combination. The most common pattern was deposition in BVs and at the dermoepidermal junction (DEJ) (59.3%), followed by deposition in BVs alone (40.7%). Immunoreactant deposition in BVs involved superficial BVs with or without deep BVs. The median age of patients with positive DIF findings was significantly higher than that of patients with negative DIF findings for LV (P < 0.03). More recent lesions (present for < 6 months) had a significantly higher percentage of positive results than older lesions (present for ≥ 6 months) (85.2% vs. 14.8%, respectively; P < 0.001)., Conclusion: In both the present study and in the published literature, DIF study in patients with LV showed positive immunoreactants ranging from 42.9% to 100%. C3 and IgM were the most common immunoreactants deposited in BVs, while the most common pattern was immunoreactant deposition in BVs and at the DEJ. Older patients and those with more recent lesions (< 6 months) had a significantly higher percentage of positive DIF results for LV than did younger patients and those with older lesions (≥ 6 months)., (© 2020 British Association of Dermatologists.)

Immunoglobulin A nephropathy (IgAN) is considered as mesangiopathy since it initiates in the mesangium; however, other glomerular components are involved and the glomerular capillary wall offers the first contact to circulating macromolecular IgA1. Acute and active forms of IgAN are associated with endocapillary hypercellularity and vascular damage of various degrees, in severe cases with microangiopathy (MA) without or with thrombosis [thrombotic microangiopathy (TMA)]. Vascular damage activates complement and coagulation cascades. A defective complement regulation has recently been detected in active and progressive cases of IgAN. C4d deposits in renal biopsies have been found to be an early risk factor. These observations have raised interest in manifestation of MA and TMA in progressive cases of IgAN. MA-TMA lesions have been found in various percentages (2-53%) of patients with IgAN according to patients' selection and pathology definition of TMA. The association with hypertension (HTN) was so strong that it led to the hypothesis that MA/TMA in IgAN was a mere consequence of severe HTN. Old and new clinical and experimental data indicate that in IgAN the interaction of the glomerular capillary wall with immune reactants and complement uncontrolled activation leading to C4b deposits favours the development of MA-TMA, which plays a role in progression and renal function decline. The central role of complement activation is relevant also for the new therapeutic interventions offered by the pharma., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Sickle Cell Anemia (SCA) is the most common genetic disorder around the world. The mutation in the β-globin gene is responsible for a higher hemolysis rate, with further involvement of immunological molecules, especially cytokines, chemokines, growth factors, and anaphylatoxins. These molecules are responsible for inducing and attracting immune cells into circulation, thus contributing to increases in leukocytes and other pro-inflammatory mediators, and can culminate in a vaso-occlusive crisis (VOC). This study aimed to characterize the levels of these molecules in SCA patients in different clinical conditions in order to identify potential hallmarks of inflammation in these patients. An analytical prospective study was conducted using the serum of SCA patients in steady-state (StSt; n = 27) and VOC ( n = 22), along with 53 healthy donors (HD). Samples from the VOC group were obtained on admission and on discharge, in the convalescent phase (CV). Levels of chemokines (CXCL8, CXCL10, CL2, CLL3, CCL4, CL5, and CCL11), cytokines (IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12p70, IL-13, IL-17A, TNF-α, and IFN-γ) and growth factors (VEGF, FGFb, PDGF-BB, GM-CSF, and G-CSF) were measured using a Luminex assay, and anaphylatoxins (C3a, C4a, and C5a) were measured using Cytometric Bead Array. SCA patients in StSt showed a pro-inflammatory profile, and were indicated as being higher producers of CCL2, IL-1β, IL-12p70, IFN-γ, IL-17A, and GM-CSF, while VOC is highlighted by molecules IL-4 and IL-5, but also IL-2, IL-7, PDGF-BB, and G-CSF. PDGF-BB and IL-1ra seemed to be two important hallmarks for the acute-to-chronic stage, due to their significant decrease after crisis inflammation and statistical difference in VOC and CV groups. These molecules show higher levels and a strong correlation with other molecules in VOC. Furthermore, they remain at higher levels even after crisis recovery, which suggest their importance in the role of inflammation during crisis and participation in immune cell adhesion and activation. These results support a relevant role of cytokines, neutrophil and monocytes, since these may act as markers of VOC inflammation in SCA patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Silva-Junior, Garcia, Cardoso, Dias, Tarragô, Fraiji, Gomes, Amaral, Teixeira-Carvalho, Martins-Filho, De Paula, Costa and Malheiro.)

We report the first case of intravascular large B-cell lymphoma (IVLBCL) presenting with vasculitis-like symptoms and elevated serum levels of anti-neutrophil cytoplasmic antibody (ANCA) diagnosed by renal biopsy. The patient exhibited low-grade fever, systemic inflammatory reactions, multiple lung lesions, and persistent proteinuria, which were closely correlated with changes in serum titers of proteinase-3- and myeloperoxidase-ANCA. Preemptive therapy with prednisolone alone partially attenuated these symptoms. Renal biopsy did not reveal histopathological findings suggestive of granulomatous or microscopic polyangiitis. Glomerular and peritubular capillaries were diffusely occluded by CD20-positive large atypical mononuclear cells, with focal foot process effacement of podocytes in the glomeruli. Based on the specific immunophenotype of infiltrated atypical cells, the patient was diagnosed with IVLBCL. Chemotherapy regimens for IVLBCL improved clinical symptoms and led to remission of proteinuria. The ANCA titers decreased in parallel with reductions in the serum levels of the soluble interleukin-2 receptor, suggestive of an association between changes in ANCA levels and IVLBCL-related vascular injuries.

STING-associated vasculopathy of infantile-onset (SAVI) is one of the newly identified types of interferonopathies. SAVI is caused by heterozygous gain-of-function mutations in the STING1 . We herein report for the first time a homozygous variant in the STING1 gene in two siblings that resulted in constitutive activation of STING gene and the SAVI phenotype. Exome sequencing revealed a novel homozygous NM&#95;198282.3: c.841C>T; p.(Arg281Trp) variant in exon 7 of the STING1 gene. The variant segregated in the family to be homozygous in all affected and either heterozygous or wild type in all healthy. Computational structural analysis of the mutants revealed changes in the STING protein structure/function. Elevated serum beta-interferon levels were observed in the patients compared to the control family members. Treatment with Janus kinase inhibitor (JAK-I) Ruxolitinib suppressed the inflammatory process, decreased beta-interferon levels, and stopped the progression of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alghamdi, Mulla, Saheb Sharif-Askari, Guzmán-Vega, Arold, Abd-Alwahed, Alharbi, Kashour and Halwani.)

Background: Hypercoagulability is a risk factor of thromboembolic events in COVID-19. Anti-phospholipid (aPL) antibodies have been hypothesized to be involved. Typical COVID-19 dermatological manifestations of livedo reticularis and digital ischemia may resemble cutaneous manifestations of anti-phospholipid syndrome (APS)., Objectives: To investigate the association between aPL antibodies and thromboembolic events, COVID-19 severity, mortality, and cutaneous manifestations in patients with COVID-19., Methods: aPL antibodies [anti-beta2-glycoprotein-1 (B2GP1) and anti-cardiolipin (aCL) antibodies] were titered in frozen serum samples from hospitalized COVID-19 patients and the patients' clinical records were retrospectively analyzed., Results: 173 patients were enrolled. aPL antibodies were detected in 34.7% of patients, anti-B2GP1 antibodies in 30.1%, and aCL antibodies in 10.4%. Double positivity was observed in 5.2% of patients. Thromboembolic events occurred in 9.8% of patients, including 11 pulmonary embolisms, 1 case of celiac tripod thrombosis, and six arterial ischemic events affecting the cerebral, celiac, splenic, or femoral-popliteal arteries or the aorta. aPL antibodies were found in 52.9% of patients with vascular events, but thromboembolic events were not correlated to aPL antibodies (adjusted OR = 1.69, p = 0.502). Ten patients (5.8%) had cutaneous signs of vasculopathy: nine livedo reticularis and one acrocyanosis. No significant association was observed between the presence of cutaneous vasculopathy and aPL antibodies ( p = 0.692)., Conclusions: Anti-phospholipid antibodies cannot be considered responsible for hypercoagulability and thrombotic events in COVID-19 patients. In COVID-19 patients, livedo reticularis and acrocyanosis do not appear to be cutaneous manifestations of APS.

Innate immune sensing of viral molecular patterns is essential for development of antiviral responses. Like many viruses, SARS-CoV-2 has evolved strategies to circumvent innate immune detection, including low cytosine-phosphate-guanosine (CpG) levels in the genome, glycosylation to shield essential elements including the receptor-binding domain, RNA shielding and generation of viral proteins that actively impede anti-viral interferon responses. Together these strategies allow widespread infection and increased viral load. Despite the efforts of immune subversion, SARS-CoV-2 infection activates innate immune pathways inducing a robust type I/III interferon response, production of proinflammatory cytokines and recruitment of neutrophils and myeloid cells. This may induce hyperinflammation or, alternatively, effectively recruit adaptive immune responses that help clear the infection and prevent reinfection. The dysregulation of the renin-angiotensin system due to down-regulation of angiotensin-converting enzyme 2, the receptor for SARS-CoV-2, together with the activation of type I/III interferon response, and inflammasome response converge to promote free radical production and oxidative stress. This exacerbates tissue damage in the respiratory system, but also leads to widespread activation of coagulation pathways leading to thrombosis. Here, we review the current knowledge of the role of the innate immune response following SARS-CoV-2 infection, much of which is based on the knowledge from SARS-CoV and other coronaviruses. Understanding how the virus subverts the initial immune response and how an aberrant innate immune response contributes to the respiratory and vascular damage in COVID-19 may help to explain factors that contribute to the variety of clinical manifestations and outcome of SARS-CoV-2 infection., (© 2020 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)

Objective: Complement components, including C4d, can be found on activated platelets, a process associated with vascular disease in SLE. We investigated whether platelet C4d (PC4d) adds additional value to traditional and known lupus-associated risk factors when identifying SLE patients with vascular disease., Methods: This cross-sectional study included 308 well-characterized SLE patients and 308 matched general population controls. PC4d deposition was analysed using flow cytometry. Values >95% of controls were considered as PC4d positive (+). aPL were determined by Luminex, and the LA test was performed by DRVVT. History of vascular disease (composite and as separate outcomes) was defined at inclusion., Results: SLE patients had increased PC4d deposition as compared with population controls (50 vs 5%, P < 0.0001). PC4d+ positively associated with any vascular events, and separately with venous and cerebrovascular events, and also with all investigated aPL profiles. The association for any vascular event remained statistically significant after adjustment for traditional and SLE-associated risk factors (odds ratio: 2.3, 95% CI: 1.3, 4.3, P = 0.008). Compared with patients negative for both PC4d and LA, patients with double positivity were more likely to have vascular disease (odds ratio: 12.3, 95% CI: 5.4, 29.3; attributable proportion due to interaction 0.8, 95% CI: 0.4, 1.1)., Conclusion: PC4d+ is associated with vascular events in SLE, independently of traditional and SLE-associated risk factors. Concurrent presence of PC4d and LA seem to interact to further increase the odds for vascular events. Prospective studies should examine whether the aPL/PC4d combination can improve prediction of vascular events in SLE and/or APS., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Microparticles (MPs) are vesicular structures that derive from multiple cellular sources. MPs play important roles in intercellular communication, regulation of cell signaling or initiation of enzymatic processes. While MPs were characterized in Systemic Sclerosis (SSc) patients, their contribution to SSc pathogenesis remains unknown. Our aim was to investigate the potential role of MPs in SSc pathophysiology and their impact on tissue fibrosis., Methods: Ninety-six SSc patients and 37 sex-matched healthy donors (HD) were enrolled in this study in order to quantify and phenotype their plasmatic MPs by flow cytometry. The ability of MPs purified from SSc patients and HD controls to modulate fibroblast's extra-cellular matrix genes expression was evaluated in vitro by reverse transcriptase quantitative polymerase chain reaction., Results: SSc patients exhibited a higher concentration of circulatory MPs compared to HD. This difference was exacerbated when we only considered patients that were not treated with methotrexate or targeted disease-modifying antirheumatic drugs. Total circulatory MPs were associated to interstitial lung disease, lung fibrosis and diminished lung functional capacity, but also to vascular involvement such as active digital ulcers. Finally, contrary to HD MPs, MPs from SSc patients stimulated the production of extracellular matrix by fibroblast, demonstrating their profibrotic potential., Conclusions: In this study, we provide evidence for a direct profibrotic role of MPs from SSc patients, underpinned by strong clinical associations in a large cohort of patients., (Copyright © 2020 Leleu, Levionnois, Laurent, Lazaro, Richez, Duffau, Blanco, Sisirak, Contin-Bordes and Truchetet.)

Giant cell arteritis (GCA) is a common form of primary systemic vasculitis in adults, with no reliable indicators of prognosis or treatment responses. We used single cell technologies to comprehensively map immune cell populations in the blood of patients with GCA and identified the CD66b+CD15+CD10lo/-CD64- band neutrophils and CD66bhiCD15+CD10lo/-CD64+/bright myelocytes/metamyelocytes to be unequivocally associated with both the clinical phenotype and response to treatment. Immature neutrophils were resistant to apoptosis, remained in the vasculature for a prolonged period of time, interacted with platelets, and extravasated into the tissue surrounding the temporal arteries of patients with GCA. We discovered that immature neutrophils generated high levels of extracellular reactive oxygen species, leading to enhanced protein oxidation and permeability of endothelial barrier in an in vitro coculture system. The same populations were also detected in other systemic vasculitides. These findings link functions of immature neutrophils to disease pathogenesis, establishing a clinical cellular signature of GCA and suggesting different therapeutic approaches in systemic vascular inflammation.

Ab cross-linking of HLA class I (HLA I) molecules on the surface of endothelial cells (EC) triggers proliferative and prosurvival intracellular signaling, which is implicated in the process of chronic allograft rejection, also known as transplant vasculopathy. Despite the importance of Ab-mediated rejection in transplantation, the mechanisms involved remain incompletely understood. In this study, we examined the regulation of yes-associated protein (YAP) localization, phosphorylation, and transcriptional activity in human ECs challenged with Abs that bind HLA I. In unstimulated ECs, YAP localized mainly in the cytoplasm. Stimulation of these cells with Ab W6/32 induced marked translocation of YAP to the nucleus. The nuclear import of YAP was associated with a rapid decrease in YAP phosphorylation at Ser 127 and Ser 397 , sites targeted by LATS1/2 and with the expression of YAP-regulated genes, including connective tissue growth factor ( CTGF ), and cysteine-rich angiogenic inducer 61 (CYR61). Transfection of small interfering RNAs targeting YAP/TAZ blocked the migration of ECs stimulated by ligation of HLA I, indicating that YAP mediates the increase in EC migration induced by HLA I ligation. Treatment of intact ECs with Src family inhibitors induced cytoplasmic localization of YAP in unstimulated ECs and, strikingly, blocked the nuclear import of YAP induced by Ab-induced HLA I activation in these cells and the increase in the expression of the YAP-regulated genes CTGF and CYR61 induced by HLA I stimulation. Our results identify the Src/YAP axis as a key player in promoting the proliferation and migration of ECs that are critical in the pathogenesis of transplant vasculopathy., (Copyright © 2020 by The American Association of Immunologists, Inc.)

After the emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in the last two decades, the world is facing its new challenge in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic with unprecedented global response. With the expanding domain of presentations in COVID-19 patients, the full range of manifestations is yet to unfold. The classical clinical symptoms for SARS-CoV-2 affected patients are dry cough, high fever, dyspnoea, lethal pneumonia whereas many patients have also been found to be associated with a few additional signs and clinical manifestations of isolated vasculopathy. Albeit a deep and profound knowledge has been gained on the clinical features and management of COVID-19, less clear association has been provided on SARS-CoV-2 mediated direct or indirect vasculopathy and its possible correlation with disease prognosis. The accumulative evidences suggest that novel coronavirus, apart from its primary respiratory confinement, may also invade vascular endothelial cells of several systems including cerebral, cardio-pulmonary as well as renal microvasculature, modulating multiple visceral perfusion indices. Here we analyse the phylogenetic perspective of SARS-CoV-2 along with other strains of β-coronaviridae from a standpoint of vasculopathic derangements. Based on the existing case reports, literature and open data bases, we also analyse the differential pattern of vasculopathy related changes in COVID-19 positive patients. Besides, we debate the need of modulation in clinical approach from a hemodynamical point of view, as a measure towards reducing disease transmission, morbidity and mortality in SARS-CoV-2 affected patients.

STING-associated vasculopathy with onset in infancy (SAVI) is an autosomal dominant disorder due to gain-of-function mutations in STING1 , also known as TMEM173 , encoding for STING. It was reported as a vasculopathy of infancy. However, since its description a wider spectrum of associated manifestations and disease-onset has been observed. We report a kindred with a heterozygous STING mutation (p.V155M) in which the 19-year-old proband suffered from isolated adult-onset ANCA-associated vasculitis. His father suffered from childhood-onset pulmonary fibrosis and renal failure attributed to ANCA-associated vasculitis, and died at the age of 30 years due to respiratory failure. In addition, an overview of the phenotypic spectrum of SAVI is provided highlighting (a) a high phenotypic variability with in some cases isolated manifestations, (b) the potential of adult-onset disease, and (c) a novel manifestation with ANCA-associated vasculitis., (Copyright © 2020 Staels, Betrains, Doubel, Willemsen, Cleemput, Vanderschueren, Corveleyn, Meyts, Sprangers, Crow, Humblet-Baron, Liston and Schrijvers.)

Objective: Systemic sclerosis (SSc) is characterized by fibrosis, vascular disease, and inflammation. Adenosine signaling plays a central role in fibroblast activation. We undertook this study to evaluate the therapeutic effects of adenosine depletion with PEGylated adenosine deaminase (PEG-ADA) in preclinical models of SSc., Methods: The effects of PEG-ADA on inflammation, vascular remodeling, and tissue fibrosis were analyzed in Fra-2 mice and in a B10.D2→BALB/c (H-2 d ) model of sclerodermatous chronic graft-versus-host disease (GVHD). The effects of PEG-ADA were confirmed in vitro in a human full-thickness skin model., Results: PEG-ADA effectively inhibited myofibroblast differentiation and reduced pulmonary fibrosis by 34.3% (with decreased collagen expression) (P = 0.0079; n = 6), dermal fibrosis by 51.8% (P = 0.0006; n = 6), and intestinal fibrosis by 17.7% (P = 0.0228; n = 6) in Fra-2 mice. Antifibrotic effects of PEG-ADA were also demonstrated in sclerodermatous chronic GVHD (reduced by 38.4%) (P = 0.0063; n = 8), and in a human full-thickness skin model. PEG-ADA treatment decreased inflammation and corrected the M2/Th2/group 2 innate lymphoid cell 2 bias. Moreover, PEG-ADA inhibited proliferation of pulmonary vascular smooth muscle cells (reduced by 40.5%) (P < 0.0001; n = 6), and prevented thickening of the vessel walls (reduced by 39.6%) (P = 0.0028; n = 6) and occlusions of pulmonary arteries (reduced by 63.9%) (P = 0.0147; n = 6). Treatment with PEG-ADA inhibited apoptosis of microvascular endothelial cells (reduced by 65.4%) (P = 0.0001; n = 6) and blunted the capillary rarefication (reduced by 32.5%) (P = 0.0199; n = 6). RNA sequencing demonstrated that treatment with PEG-ADA normalized multiple pathways related to fibrosis, vasculopathy, and inflammation in Fra-2 mice., Conclusion: Treatment with PEG-ADA ameliorates the 3 cardinal features of SSc in pharmacologically relevant and well-tolerated doses. These findings may have direct translational implications, as PEG-ADA has already been approved by the Food and Drug Administration for the treatment of patients with ADA-deficient severe combined immunodeficiency disease., (© 2020, American College of Rheumatology.)

Cardiovascular and cerebrovascular diseases caused by atherosclerosis have a high disability rate and reduce the quality of life of the population. Therefore, understanding the mechanism of atherosclerosis and its control may interfere with the progression of atherosclerosis and thus control the occurrence of diseases closely related to atherosclerosis. TSP-1 is a factor that has been found to have an antiangiogenic effect, and CD47, as the receptor of TSP-1, can participate in the regulation of antiangiogenesis of atherosclerosis. VEGF is an important regulator of angiogenesis, and TSP-1/CD47 can cause VEGF and its downstream expression. Therefore, the TSP-1/CD47/VEGF/VEGFR2 signal may have an important influence on atherosclerosis. In addition, some inflammatory factors, such as IL-1 and NLRP3, can also affect atherosclerosis. This review will be expounded focusing on the pathogenesis and influencing factors of atherosclerosis., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Manman Dou et al.)

Objective: To investigate whether toll-like receptor 7 (TLR7) activation induces an increase in blood pressure and vascular damage in wild-type mice treated with the TLR7 agonist imiquimod (IMQ)., Methods: Female BALB/c mice (7-9 week old) were randomly assigned to two experimental groups: an untreated control group and a group treated topically with IMQ (IMQ-treated) for 4 or 8 weeks. A group of IMQ-treated mice that take a combination of the antioxidants tempol and apocynin, and another treated IL-17-neutralizing antibody were also performed., Results: TLR7 activation gradually increased blood pressure, associated with elevated plasma levels of anti-dsDNA autoantibodies, splenomegaly, hepatomegaly, and severe expansion of splenic immune cells with an imbalance between proinflammatory T cells and regulatory T cells. TLR7 activation induced a marked vascular remodeling in mesenteric arteries characterized by an increased media--lumen ratio (≈40%), and an impaired endothelium-dependent vasorelaxation in aortas from wild-type mice after 8 weeks of treatment. In addition, an increased ROS production, as a result of the upregulation of NADPH oxidase subunits, and an enhanced vascular inflammation were found in aortas from IMQ-treated mice. These functional and structural vascular alterations induced by IMQ were improved by antioxidant treatment. Anti-IL-17 treatment reduced blood pressure and improved endothelial dysfunction in IMQ-treated mice., Conclusion: Our results demonstrate that TLR7 activation induces the development of hypertension and vascular damage in BALB/c mice, and further underscore the increased vascular inflammation and oxidative stress, mediated in part by IL-17, as key factors contributing to cardiovascular complications in this TLR7-driven lupus autoimmunity model.

STING-associated vasculopathy with onset in infancy (SAVI) is an autoimmune disease caused by heterozygous gain of function mutations of STING (stimulator of interferon genes) that had initially been classified as a type I interferonopathy. We recently reported a genetically engineered mouse strain carrying a common SAVI-associated STING mutation. These STING N153S/WT mice reproduce key features of SAVI, including lung inflammation, loss of T cells in spleen and blood, splenomegaly and thymic hypoplasia. Here we show that αβ T lymphocytopenia is due to disrupted T cell development and is associated with impaired T cell activation and a relative increase in γδ T cell numbers. These alterations were not rescued by additional knockout of the type I IFN receptor (IFNAR1). Collectively, our findings consolidate the concept that constitutive STING signalling leads to a SCID-like phenotype in STING N153S/WT mice., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate the impact of high-intensity strength training (ST) or low-intensity strength training with blood flow restriction (ST-BFR) on monocyte subsets, the expression of C-C chemokine receptor 5 (CCR5), and CD16 on monocytes, and tumor necrosis factor alpha (TNF-α) production of overweight men. Thirty overweight men were randomly assigned to conventional ST or ST-BFR. Both groups performed exercises of knee extension and biceps curl with equal volume (3 sessions/week) over 8 weeks, and the peripheral frequency of monocytes (CD14+CD16-, classical monocytes; CD14+CD16+, intermediate monocytes; CD14-CD16+, nonclassical monocytes), the mean fluorescence intensity (MFI) of CCR5 and CD16 on CD14+ monocytes; and the production of TNF-α by lipopolysaccharide (LPS)-stimulated cells were quantified. Eight weeks of ST increased the frequency of CD14+CD16- monocytes ( p = 0.04) and reduced the percentage of CD14-CD16+ ( p = 0.02) and the production of TNF-α by LPS-stimulated cells ( p = 0.03). The MFI of CD16 on CD14+ monocytes decreased after the ST intervention ( p = 0.02). No difference in monocyte subsets, CCR5 or CD16 expression, and TNF-α production were identified after ST-BFR intervention ( p > 0.05). The adoption of ST promotes anti-inflammatory effects on monocyte subsets of overweight men, but this effect was lost when BFR was adopted. Novelty High-intensity strength training reduces the production of TNF-α and the peripheral frequency of CD16+ monocytes in overweight men. Blood flow restriction method blunts the strength training adaptations on monocyte subsets and pro-inflammatory TNF-α production in overweight men.

Background: STING-associated vasculopathy with onset in infancy (SAVI) is a type 1 interferonopathy manifesting as a pulmonary and vascular syndrome resulting from gain-of-function mutations in TMEM173, the gene encoding STING. Familial reports in the literature are sparse., Case Presentation: We report a case series of SAVI in a three generation kindred, with a phenotype of interstitial lung disease (ILD) and rheumatoid factor positive polyarticular juvenile idiopathic arthritis (JIA). Current and historical medical records were reviewed for clinical and laboratory information. Whole blood from cases 1 and 2, plus stored appendicectomy tissue from case 3, underwent DNA sequencing of the TMEM173 gene. Peripheral blood RNA was obtained from cases 1 and 2 for functional assessment of the TMEM173 mutation. DNA sequencing identified the same heterozygous TMEM173 mutation (c.463G > A; p.Val155Met) in all three cases, consistent with a diagnosis of the autosomal dominant condition SAVI. Functional assessment of this mutation identified a prominent interferon signature which was confirmed on repeat testing., Conclusions: SAVI presented in this family as ILD with early onset juvenile rheumatoid arthritis. This condition should be considered in all rheumatoid arthritis patients with early-onset ILD and in all JIA patients with ILD.

Background: Juvenile dermatomyositis (JDM) is a systemic autoimmune disease with a prominent interferon (IFN) signature, but the pathogenesis of JDM and the etiology of its IFN signature remain unknown. The Mendelian autoinflammatory interferonopathies, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) and STING-Associated Vasculopathy with onset in Infancy (SAVI), are caused by genetic mutations and have extremely elevated IFN signatures thought to drive pathology. The phenotypic overlap of some clinical features of CANDLE and SAVI with JDM led to the comparison of a standardized interferon-regulated gene score (IRG-S) in JDM and myositis-specific autoantibody (MSA) JDM subgroups, with CANDLE and SAVI., Methods: A peripheral 28-component IRG-S assessed by NanoString™ in 57 JDM patients subtyped by MSA was compared with IRG-S in healthy controls (HC) and CANDLE/SAVI patients. Principal component analysis (PCA) was performed, and individual genes were evaluated for their contribution to the score. IRG-S were correlated with disease assessments and patient characteristics., Results: IRG-S in JDM patients were significantly higher than in HC but lower than in CANDLE or SAVI. JDM IRG-S overlapped more with SAVI than CANDLE by PCA. Among MSA groups, anti-MDA5 autoantibody-positive patients' IRG-S overlapped most with SAVI. The IFI27 proportion was significantly higher in SAVI and CANDLE than JDM, but IFIT1 contributed more to IRG-S in JDM. Overall, the contribution of individual interferon-regulated genes (IRG) in JDM was more similar to SAVI. IRG-S correlated moderately with JDM disease activity measures (r s  = 0.33-0.47) and more strongly with skin activity (r s  = 0.58-0.79) in anti-TIF1 autoantibody-positive patients. Weakness and joint disease activity (multinomial OR 0.91 and 3.3) were the best predictors of high IRG-S., Conclusions: Our findings demonstrate peripheral IRG expression in JDM overlaps with monogenic interferonopathies, particularly SAVI, and correlates with disease activity. Anti-MDA5 autoantibody-positive JDM IRG-S were notably more similar to SAVI. This may reflect both a shared IFN signature, which is driven by IFN-β and STING pathways in SAVI, as well as the shared phenotype of vasculopathy in SAVI and JDM, particularly in anti-MDA5 autoantibody-positive JDM, and indicate potential therapeutic targets for JDM.

Stimulator of interferon genes associated vasculopathy with onset in infancy (SAVI), caused by heterozygote gain-of-function mutations in TMEM173, is characterized by fever attacks with ulcerating cutaneous manifestations on cold-sensitive areas and interstitial lung disease. A six-month-old boy was admitted to our hospital with fever, cough, and rash on the external surface of both upper and lower extremities. Respiratory symptoms consistent with ILD developed and skin lesions evolved to eschar formation particularly on acral regions. Ultimately, diagnosis of SAVI was confirmed at the age of 10 months due to the high level of interferon-score and a heterozygous N154S mutation in TMEM173. Since systemic corticosteroid and ruxolitinib were not effective, baricitinib was initiated at the age of 15 months, resulting in alleviation of fever attacks, cutaneous manifestations and respiratory symptoms within 2 months. In conclusion, we reported an infant diagnosed with SAVI at the age of 10 months and treated with baricitinib., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Renal microvascular lesions, common in lupus nephritis (LN), are associated with long-term poor outcomes. There are mainly five pathological types of renal microvascular lesions in LN: (1) vascular immune complex deposits (ICD), (2) arteriosclerosis (AS), (3) thrombotic microangiopathy (TMA), (4) non-inflammatory necrotizing vasculopathy (NNV), and (5) true renal vasculitis (TRV). The pathogenesis of renal microvascular lesions in LN remains to be elucidated. The activation and dysfunction of endothelial cells, in addition to the contribution of immune system dysfunction, especially the immune complex-induced vascular inflammation and antiphospholipid antibody-associated thrombotic events, are key mechanisms in the development of vascular lesions in LN that need to be further investigated. Alteration of the microvascular environment produces an acute immunological response that recruits immune cells, such as T cells, monocytes, and macrophages, which induces platelet aggregation with microthrombus formation. There is also increased cytotoxicity caused by cytokines produced by immune cells in the kidney. Identifying the mechanism underlying the pathogenesis of renal microvascular lesions in LN might provide potential targets for the development of novel therapies.

Accumulating evidence suggests a role for the complement system in the pathogenesis of diabetes and the vascular complications that characterise this condition. Complement proteins contribute to the development of type 1 diabetes (T1D) by enhancing the underlying organ-specific autoimmune processes. Complement upregulation and activation is also an important feature of insulin resistance and the development of type 2 diabetes (T2D). Moreover, animal and human studies indicate that complement proteins are involved in the pathogenic mechanisms leading to diabetic microvascular and macrovascular complications. The adverse vascular effects of complement appear to be related to enhancement of the inflammatory process and the predisposition to a thrombotic environment, eventually leading to vascular occlusion. Complement proteins have been considered as therapeutic targets to prevent or treat vascular disease but studies have been mainly conducted in animal models, while human work has been both limited and inconclusive so far. Further studies are needed to understand the potential role of complement proteins as therapeutic targets for reversal of the pathological processes leading to T1D and T2D and for the prevention/treatment of diabetic vascular complications., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Adaptive immunity has gained importance in transplant immunology for years, based on models in which T-cells orchestrate the immune responses during rejection. Most recently, researches revealed that innate immune cells, including mast cells (MCs) also play a pivotal role in allograft rejection. MC mediated immunoregulatory responses influence the innate and adaptive immune responses. Their capability to produce an array of both pro-inflammatory and anti-inflammatory mediators, expressing a wide range of costimulatory molecules in addition to acting as antigen-presenting cells (APCs), make them effective immune cells far beyond their classical role as primary orchestrator cells of allergy. Activated regulatory Tcells (Treg) cells contribute to MC recruitment into grafts by releasing interleukin (IL)-9. Tregs are capable of stabilizing MCs and suppressing IgE mediated degranulation through interaction of Treg expressing OX40 with MCs expressing OX40L. MCs in turn release transforming growth factor (TGF)-β and IL-10 which possess suppressive properties. Thus, these cells can suppress the proliferation of T-cells and support the generation of Tregs. MCs in addition to orchestrating immune responses in grafts by cell-to-cell interactions with variety of immune cells, cause histologic changes, mainly fibrosis by releasing mediators such as histamine, fibroblast growth factor-2 (FGF-2), TGF-β, chymase, and cathepsin G. The role of MCs in transplant rejection remains controversial. The accumulation of MCs in rejected grafts suggests that they play a role in preventing graft tolerance, and contribute to the progression of chronic rejection of allografts. However, high expression of MC-related gene products in tolerant grafts and their known interaction with Tregs on the other hand, support the notion that they are an integral component in achieving peripheral tolerance., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Mechanisms of chronic rejection of vascularized composite allografts (VCA) remain poorly understood and likely present along a spectrum of highly varied clinicopathological findings. Across both animal and human VCA however, graft vasculopathy (GV) has been the most consistent pathological finding resulting clinically in irreversible allograft dysfunction and eventual loss. A literature review of all reported clinical VCA cases with documented GV up to December 2018 was thus performed to elucidate the possible mechanisms involved. Relevant data extracted include C4d deposition, donor-specific antibody (DSA) formation, extent of human leukocyte antigen (HLA) mismatch, pretransplant panel reactive antibody levels, induction and maintenance immunosuppression used, the number of preceding acute rejection episodes, and time to histological confirmation of GV. Approximately 6% (13 of 205) of all VCA patients reported to date developed GV at a mean of 6 years post-transplantation. 46% of these patients have either lost or had their VCAs removed. Neither C4d nor DSA alone was predictive of GV development; however, when both are present, VCA loss appears inevitable due to progressive GV. Of utmost concern, GV in VCA does not appear to be abrogated by currently available immunosuppressive treatment and is essentially irreversible by the time of diagnosis with allograft loss a likely eventuality., (© 2019 Steunstichting ESOT.)

Dietary choline and its containing foods are biotransformed to trimethylamine (TMA) via gut microbial metabolism. Subsequently, as an intermediate molecule, TMA is quickly transported and oxidized in the liver by hepatic flavin monooxygenases to form trimethylamine oxide (TMAO). TMAO was treated as a waste byproduct from choline metabolism, but recent convincing evidence demonstrated the association between the small molecule TMAO and inflammation-related diseases, including blood vessel inflammation and vascular diseases. The scope of this study is to investigate the preventive effect of nobiletin on TMAO-induced blood vessel inflammation. Our results from Western blot showed that the inhibition of TMAO-induced cardiovascular inflammation was correlated with nobiletin-mediated inhibitory effects on NF-κB and MAPK/ERK related pathways. More specifically, nobiletin prevented the oxidative damage of vascular sites (proximal aorta), inhibited the activity of MAPK/ERK, reduced the expression of NF-κB p65 and phospho-NF-κB p65, and consequently decreased the inflammatory response. Flow cytometry analyses showed that nobiletin decreased TMAO-induced apoptosis of HUVEC cells and counteracted TMAO-induced HUVEC cell proliferation. Results from HE staining and immunohistochemical results also showed that nobiletin reduced the degree of inflammation of the proximal aorta in Sprague-Dawley rats. In summary, nobiletin significantly reduced TMAO-induced vascular inflammation via inhibition of the NF-κB/MAPK pathways.

Objective: Based on the antibody profiles of inflammatory myositis patients, we investigated the type 1 IFN (T1-IFN) signature in serum and DM skin to determine the relationship between T1-IFN and vasculopathy in anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive DM patients., Methods: We examined 47 patients with new-onset inflammatory myositis. We divided them into three groups: the anti-MDA5 antibody-positive patients (MDA5 group, n = 16), the anti-aminoacyl-tRNA synthetase antibody-positive patients (aminoacyl-tRNA synthetase group, n = 12), and the double-negative patients (n = 19). Serum T1-IFN signatures were revealed by a functional reporter assay, and we evaluated the T1-IFN signatures of skin based on Mx1 expression by immunohistochemistry., Results: The numbers of patients with classical DM, clinically amyopathic DM and interstitial lung disease were 1, 15 and 13 in the MDA5 group, 2, 3 and 11 in the aminoacyl-tRNA synthetase group, and 10, 1 and 4 in the double-negative group, respectively. The signs of vasculopathies (i.e. palmer papules, skin ulcers and mononeuritis multiplex) were identified only in the MDA5 patients. Most of the MDA5 group showed the highest serum T1-IFN signatures among the three groups. In the histological analysis of DM skin, perivascular inflammations were significant in the MDA5 group. The MDA5 group's Mx1 expression was significantly strong, distributed in blood vessels and interstitial fibroblasts, and had spread to deep dermis., Conclusion: Anti-MDA5 antibody-positive DM patients showed high T1-IFN signatures in serum and affected skin. The high T1-IFN signatures of the MDA5 antibody-positive DM patients in serum and deep vasculatures suggested that T1-IFN may have important roles in the vasculopathy of these patients., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Annexin-A1 (ANXA1) was first discovered in the early 1980's as a protein, which mediates (some of the) anti-inflammatory effects of glucocorticoids. Subsequently, the role of ANXA1 in inflammation has been extensively studied. The biology of ANXA1 is complex and it has many different roles in both health and disease. Its effects as a potent endogenous anti-inflammatory mediator are well-described in both acute and chronic inflammation and its role in activating the pro-resolution phase receptor, FPR2, has been described and is now being exploited for therapeutic benefit. In the present mini review, we will endeavor to give an overview of ANXA1 biology in relation to inflammation and functions that mediate pro-resolution that are independent of glucocorticoid induction. We will focus on the role of ANXA1 in diseases with a large inflammatory component focusing on diabetes and microvascular disease. Finally, we will explore the possibility of exploiting ANXA1 as a novel therapeutic target in diabetes and the treatment of microvascular disease.