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Hidradenitis suppurativa (HS) is a debilitating inflammatory skin disorder characterized by abscess-like nodules and boils resulting in fistulas and tissue scarring. We previously reported evidence of an autoimmune signature in HS, characterized by enhanced neutrophil extracellular trap (NET) infiltration in HS skin lesions and dysregulation of the adaptive immune system characterized by the presence of autoantibodies. Timely removal of NETs is critical for tissue homeostasis to prevent a dysregulated generation of modified autoantigens and tissue damage. DNases 1 and 1L3 play important roles in proper NET removal. We tested the hypothesis that NETs in patients with HS are not effectively cleared owing to the presence of antibodies against DNase 1 and DNase 1L3. We report that HS serum poorly degraded NETs. Addition of exogenous DNase 1 restored NET degradation capabilities in a subset of HS samples. DNase 1 activity was significantly decreased in HS sera. Anti‒DNase 1 and ‒DNase 1L3 antibodies were detected in serum samples and skin lesions from patients with HS. Purified IgGs from HS decreased DNase 1 activity and NET degradation. Taken together, this identification of neutralizing antibodies against nucleases in HS expands the understanding of the pathogenesis of this disease to support an autoimmune mechanism in its underlying pathogenesis., (Published by Elsevier Inc.)

Hidradenitis suppurativa (HS), also known as acne inversa, is a debilitating inflammatory skin disorder that is characterized by nodules that lead to the development of connected tunnels and scars as it progresses from Hurley stages I to III. HS has been associated with several autoimmune diseases, including inflammatory bowel disease and spondyloarthritis. We previously reported dysregulation of humoral immune responses in HS, characterized by elevated serum total IgG, B-cell activation, and antibodies recognizing citrullinated proteins. In this study, we characterized IgG autoreactivity in HS sera and lesional skin compared with those in normal healthy controls using an array-based high-throughput autoantibody screening. The Cy3-labeled anti-human assay showed the presence of autoantibodies against nuclear antigens, cytokines, cytoplasmic proteins, extracellular matrix proteins, neutrophil proteins, and citrullinated antigens. Most of these autoantibodies were significantly elevated in stages II‒III in HS sera and stage III in HS skin lesions compared with those of healthy controls. Furthermore, immune complexes containing both native and citrullinated versions of antigens can activate M1 and M2 macrophages to release proinflammatory cytokines such as TNF-α, IL-8, IL-6, and IL-12. Taken together, the identification of specific IgG autoantibodies that recognize circulating and tissue antigens in HS suggests an autoimmune mechanism and uncovers putative therapeutic targets., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Dysregulation in the phenotype and function of neutrophils may play important roles in the initiation and perpetuation of autoimmune responses, including conditions affecting the skin. Neutrophils can have local and systemic effects on innate and adaptive immune cells as well as on resident cells in the skin, including keratinocytes (KCs). Aberrant formation/clearance of neutrophil extracellular traps (NETs) in systemic autoimmunity and chronic inflammatory diseases have been associated with the externalization of modified autoantigens in peripheral blood and tissues. NETs can impact the function of many cells, including macrophages, lymphocytes, dendritic cells, fibroblasts, and KCs. Emerging evidence has unveiled the pathogenic key roles of neutrophils in systemic lupus erythematosus, idiopathic inflammatory myopathies, psoriasis, hidradenitis suppurativa, and other chronic inflammatory conditions. As such, neutrophil-targeting strategies represent promising therapeutic options for these diseases., (Published by Elsevier Inc.)

The recent identifications of a subset of proinflammatory neutrophils, low-density granulocytes, and their ability to readily form neutrophil extracellular traps led to a resurgence of interest in neutrophil dysregulation in the pathogenesis of systemic lupus erythematosus (SLE). This article presents an overview on how neutrophil dysregulation modulates the innate and adaptive immune responses in SLE and their putative roles in disease pathogenesis. The therapeutic potential of targeting this pathogenic process in the treatment of SLE is also discussed., Competing Interests: Disclosure The authors have nothing to disclose., (Published by Elsevier Inc.)

Reduction of adenosine deaminase 2 (ADA2) activity due to autosomal-recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1 ) results in a systemic vasculitis known as deficiency of ADA2 (DADA2). Neutrophils and a subset of neutrophils known as low-density granulocytes (LDGs) have been implicated in the pathogenesis of vasculitis, at least in part, through the formation of neutrophil extracellular traps (NETs). The study objective was to determine whether neutrophils and NETs play a pathogenic role in DADA2. In vivo evidence demonstrated NETs and macrophages in affected gastrointestinal tissue from patients with DADA2. An abundance of circulating LDGs prone to spontaneous NET formation was observed during active disease in DADA2 and were significantly reduced after remission induction by anti-tumor necrosis factor (TNF) therapy. Increased circulating LDGs were identified in unaffected family members with monoallelic ADA2 mutations. Adenosine triggered NET formation, particularly in neutrophils from female patients, by engaging A 1 and A 3 adenosine receptors (ARs) and through reactive oxygen species- and peptidylarginine deiminase-dependent pathways. Adenosine-induced NET formation was inhibited by recombinant ADA2, A 1 /A 3 AR antagonists, or by an A 2A agonist. M1 macrophages incubated with NETs derived from patients with DADA2 released significantly greater amounts of TNF-α. Treatment with an A 2A AR agonist decreased nuclear translocation of NF-κB and subsequent production of inflammatory cytokines in DADA2 monocyte-derived macrophages. These results suggest that neutrophils may play a pathogenic role in DADA2. Modulation of adenosine-mediated NET formation may contribute a novel and directed therapeutic approach in the treatment of DADA2 and potentially other inflammatory diseases., (© 2019 by The American Society of Hematology.)

Objective: Molecular characterization of ameloblastoma has indicated a high frequency of driver mutations in BRAF and SMO. Preclinical data suggest that Food and Drug Administration-approved BRAF-targeted therapies may be immediately relevant for patients with ameloblastoma positive for the BRAF V600E mutation., Methods: A neoadjuvant treatment regime of dabrafenib was given to a patient with recurrent BRAF-mutant mandibular ameloblastoma. The patient subsequently underwent left mandible composite resection of the tumor and pathologic evaluation of treatment response., Results: The ameloblastoma had a slow but dramatic response with >90% tumor volume reduction. The inner areas of the tumor underwent degeneration and squamous differentiation, and intact ameloblastoma was present in the outer areas associated with bone., Conclusions: Targeted neoadjuvant therapy for ameloblastoma may be useful in certain clinical settings of primary ameloblastoma. These might include tumors of advanced local stage when a neoadjuvant reduction could alter the extent of surgery and instances of local recurrence when surgical options are limited., (Copyright © 2016 Elsevier Inc. All rights reserved.)

NETosis is a newly recognized mechanism of programmed neutrophil death. It is characterized by a stepwise progression of chromatin decondensation, membrane rupture, and release of bactericidal DNA-based structures called neutrophil extracellular traps (NETs). Conventional 'suicidal' NETosis has been described in pathogenic models of systemic autoimmune disorders. Recent in vivo studies suggest that a process of 'vital' NETosis also exists, in which chromatin is condensed and membrane integrity is preserved. Techniques to assess 'suicidal' or 'vital' NET formation in a specific, quantitative, rapid and semiautomated way have been lacking, hindering the characterization of this process. Here we have developed a new method to simultaneously assess both 'suicidal' and 'vital' NETosis, using high-speed multi-spectral imaging coupled to morphometric image analysis, to quantify spontaneous NET formation observed ex-vivo or stimulus-induced NET formation triggered in vitro. The use of imaging flow cytometry allows automated, quantitative and rapid analysis of subcellular morphology and texture, and introduces the potential for further investigation using NETosis as a biomarker in pre-clinical and clinical studies., (Published by Elsevier B.V.)

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints in which systemic overproduction of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) may accelerate cardiovascular (CV) complications. Synovial inflammation in RA spreads systemically and transforms silently into chronic inflammation manifested by increased cytokine release and abnormally high levels of acute reactive proteins (ARPs) such as C-reactive protein (CRP), suggesting inflammation as a connecting link between RA and CV dysfunction. While the treatment to improve CV function in RA patients is being validated, it is timely to propose and test two-pronged therapies that ameliorate arthritis concomitant to improving CV functions. In this review, we summarized the pre-clinical and clinical studies validating the cardiovascular and anti-rheumatic activities of epigallocatechin-3 gallate (EGCG), a potent anti-inflammatory molecule found in green tea. The review also draws many parallels that have emerged between the paradigm of cytokine-driven inflammation in the pathogenesis of RA and its CV complications. Finally, based on extensive clinical evidence of the 'synovial inflammation-systemic inflammation' link and the benefits of EGCG in regulating these two pathologies via common driving factors, authors put forward an argument that EGCG may be tested for its potential CV benefit along with anti-rheumatic activity in animal models of human RA., (© 2013.)

Morbidity and mortality rates are higher in individuals with rheumatoid arthritis (RA) than in the general population. Ischemic heart disease and heart failure now represent one of the most common causes of death in RA. Indeed, RA appears to represent an independent risk factor for ischemic heart disease, similar to diabetes mellitus. However, no clear guidelines with regard to cardiovascular disease diagnosis and prevention in RA have been developed. This review highlights recent investigations on the assessment, prevention, and treatment of cardiovascular disease in RA.

Systemic lupus erythematosus (SLE) is associated with an increase in the risk of premature cardiovascular complications caused by accelerated atherosclerosis, which significantly contributes to morbidity and mortality. Standard Framingham risk factors seem to be less important predictors of cardiovascular events than the presence of active SLE, and the immune dysregulation characteristic of lupus seems to play a dominant role in atherogenesis. Although both SLE-specific and nonspecific mechanisms have been proposed to play a prominent role in the induction of premature vascular damage in this disease, the exact etiology remains unclear. This review summarizes some of the proposed mechanisms that may promote accelerated vascular damage in lupus and explores potential targets for cardiovascular risk prevention in this patient population.

Individuals with systemic lupus erythematosus (SLE) have a striking increase in premature atherosclerosis of unclear etiology. Accelerated endothelial cell apoptosis occurs in SLE and correlates with endothelial dysfunction. Endothelial progenitor cells (EPCs) and myelomonocytic circulating angiogenic cells (CACs) are crucial in blood vessel repair after vascular damage, and decreased levels or abnormal function of EPCs/CACs are established atherosclerosis risk factors. We investigated if vascular repair is impaired in SLE. We report that SLE patients display abnormal phenotype and function of EPCs/CACs. These abnormalities are characterized by significant decreases in the number of circulating EPCs (310 +/- 50 EPCs/mL of blood in SLE versus 639 +/- 102 in controls) and significant impairments in the capacity of EPCs/CACs to differentiate into mature ECs and synthesize adequate levels of the proangiogenic molecules vascular endothelial growth factor (VEGF) and hepatic growth factor (HGF). These abnormalities are triggered by interferon-alpha (IFN-alpha), which induces EPC and CAC apoptosis and skews myeloid cells toward nonangiogenic phenotypes. Lupus EPCs/CACs have increased IFN-alpha expression and their supernatants promote higher induction of IFN-inducible genes. Importantly, neutralization of IFN pathways restores a normal EPC/CAC phenotype in lupus. SLE is characterized by an imbalance between endothelial cell damage and repair triggered by type I IFNs, which might promote accelerated atherosclerosis.

Women with systemic lupus erythematosus (SLE) are at risk for premature atherothrombosis independent of Framingham risk factors. We investigated whether endothelial cell (EC) apoptosis predicts abnormal vasomotor tone and contributes to circulating tissue factor (TF) levels in this disease. Brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation were determined in women with SLE, healthy control subjects, and subjects with coronary artery disease (CAD) (n = 43/group). Quantification of circulating apoptotic ECs was performed by flow cytometry (CD146(+) cells that stained for Annexin V [CD146(AnnV+)]) and immunofluorescent microscopy. Plasma TF was measured by enzyme-linked immunosorbent assay (ELISA). Compared with healthy control and CAD subjects, patients with SLE had higher numbers of circulating CD146(AnnV+) cells (10 +/- 3, 18 +/- 5, and 89 +/- 32 cells/mL, respectively, mean +/- SEM; P <.01). Increased CD146(AnnV+) cells correlated strongly with abnormal vascular function (P =.037). After adjusting for known predictors of endothelial function, CD146(AnnV+) was the only variable that predicted FMD (beta = -4.5, P <.001). Increased CD146(AnnV+) was strongly associated with elevated levels of circulating TF (r =.46, P =.002). Circulating apoptotic ECs are elevated in young women with SLE and strongly correlate with markedly abnormal vascular function and elevated TF levels. Heightened endothelial apoptosis may represent an important mechanism for development of atherothrombosis in SLE.

Injuries to the posterior cruciate ligament (PCL) are an uncommon but significant instability pattern that eventually deteriorates the articular surface of the PLC-deficient knee. Although controversy persists regarding the appropriate treatment for the isolated PCL tear, patients with combined ligament injuries are best served by reconstruction of the PCL and surgical correction of the other injured tissues. The authors outline their experience with these complex ligamentous derangements.

Enlargement of the cerebral third ventricle appears to be a replicable finding in groups of patients with psychotic illnesses, and there is evidence for an association of third ventricle enlargement with poorer response to treatment. Third ventricle area and width were measured from computed tomography (CT) scans in 24 mood-incongruent psychotic patients and 14 controls age and gender matched to schizophrenic patients. Patients were treated with a fixed dose of haloperidol and classified as rapid responders (55% symptom reduction on New Haven Schizophrenic Index (NHSI) within 4.5 +/- 1.3 days) or delayed responders (55% symptom reduction on NHSI within 18.6 +/- 10.5 days). The significant enlargement of third ventricle area was isolated among the 12 delayed neuroleptic responders (19.3 +/- 9.0 mm2) compared with the 14 controls (11.7 +/- 4.8 mm2, p = 0.01), and 12 other mood-incongruent psychotics. Third ventricle width also showed a trend towards larger width in the delayed responders. There was a clear positive correlation between ventricular size and patient's age exclusively in the delayed responders (r = 0.78); a comparable relationship between ventricular size and age was not present in controls, or in the other psychotics. This finding is consistent with an age-related progressive degenerative process in the central nervous system (CNS) isolated to the neuroleptic-delayed responsive psychotics.