Heterogeneity of macrophage activation syndrome and treatment progression.

Macrophage activation syndrome (MAS) is a rare complication of autoimmune inflammatory rheumatic diseases (AIIRD) characterized by a progressive and life-threatening condition with features including cytokine storm and hemophagocytosis. Predisposing factors are typically associated with microbial infections, genetic factors (distinct from typical genetically related hemophagocytic lymphohistiocytosis (HLH)), and inappropriate immune system overactivation. Clinical features include unremitting fever, generalized rash, hepatosplenomegaly, lymphadenopathy, anemia, worsening liver function, and neurological involvement. MAS can occur in various AIIRDs, including but not limited to systemic juvenile idiopathic arthritis (sJIA), adult-onset Still's disease (AOSD), systemic lupus erythematosus (SLE), Kawasaki disease (KD), juvenile dermatomyositis (JDM), rheumatoid arthritis (RA), and Sjögren's syndrome (SS), etc. Although progress has been made in understanding the pathogenesis and treatment of MAS, it is important to recognize the differences between different diseases and the various treatment options available. This article summarizes the cell types and cytokines involved in MAS-related diseases, the heterogeneity, and treatment options, while also comparing it to genetically related HLH.

The Role of the IL-33/ST2 Axis in CpG-Induced Macrophage Activation Syndrome.

Background: Macrophage activation syndrome (MAS) is a fatal inflammatory condition, which is often associated with the elevation of multiple proinflammatory cytokines and multiple organ dysfunction. Previous studies have shown that ST2 contributes to T cell overactivation and plays a detrimental role in mouse models of primary hemophagocytic lymphohistiocytosis. The purpose of this study was to investigate the role of the IL-33/ST2 axis in a mouse model of MAS induced by repeated injections of cytosine-phosphate-guanine (CpG). Methods: Serum cytokines were determined using the cytometric bead array by flow cytometry. IL-33 and ST2 were detected by immunohistochemistry and real-time quantitative PCR in the liver and spleen of mice. CD3 and F4/80 in the liver were detected by immunohistochemistry. Inflammatory macrophages and effector memory T lymphocytes were detected by flow cytometry. Result: The CpG-induced MAS model was successfully induced after repeated CpG injections, presenting with hypercytokinemia and hepatosplenomegaly. The numbers of IL-33 positive cells in the liver and spleen decreased significantly, while the expression of ST2 in the liver tended to increase in the mice with MAS. IL-33 and St2 knockout mice showed similar levels of hepatosplenomegaly, peripheral blood count, and cytokine storm when compared with wild-type (WT) mice after induction of MAS. There were also no significant differences in liver pathology (including inflammatory cell infiltration of CD3 and F4/80) and levels of splenic inflammatory macrophages and effector memory T cells between the WT and knockout mice. Conclusion: These results suggested that IL-33 decreased in the liver and spleen tissues of MAS mice. Further results suggest that IL-33 and St2 knockout mice have no treatment potential in CpG-induced MAS. Thus, the IL-33/ST2 axis has little effect on the prognosis of CpG-induced MAS.

Human spinal GABA neurons survive and mature in the injured nonhuman primate spinal cord.

Spinal cord injury (SCI) leads to permanent neural dysfunction without effective therapies. We previously showed that human pluripotent stem cell (hPSC)-derived spinal GABA neurons can alleviate spasticity and promote locomotion in rats after SCI, but whether this strategy can be translated into the clinic remains elusive. Here, a nonhuman primate (NHP) model of SCI was established in rhesus macaques (Macaca mulatta) in which the T10 spinal cord was hemisected, resulting in neural conduction failure and neural dysfunction, including locomotion deficits, pain, and spasms. Grafted human spinal GABA neurons survived for up to 7.5 months in the injured monkey spinal cord and retained their intrinsic properties, becoming mature and growing axons and forming synapses. Importantly, they are functionally alive, as evidenced by designer receptors exclusively activated by designer drug (DREADD) activation. These findings represent a significant step toward the clinical translation of human spinal neuron transplantation for treating SCI.

The aberrant levels of decorin induce damages of human salivary gland epithelial cells and polarization of macrophages.

OBJECTIVES: This study aimed to preliminarily address the levels of decorin (DCN, a critical component of extracellular matrix) and its potential roles in primary Sjögren's syndrome (pSS). METHODS: DCN levels were determined in the salivary glands of experimental SS (ESS) mice and pSS patients by RNA sequencing, bioinformatics analysis, or immunohistochemical staining. Its correlation with interested genes and co-localization with a putative receptor was studied in pSS patients. In addition, its potential roles on salivary gland epithelium and macrophages were tested by exogenous administration to corresponding cell lines, followed by the evaluation of apoptosis using flow cytometry or cytokine expression using quantitative real-time polymerase chain reaction. RESULTS: Our data revealed a significant elevation of DCN in the salivary glands of the ESS mice model and pSS patients. In addition, the bioinformatics analysis of DCN in the GSE40611 (RNA-seq, parotid glands) dataset displayed an elevation of the DCN level in the parotid glands of pSS patients that positively correlated with several chemokines (CXCL13, CXCL9, and CCL20), Interleukin -1 ß (IL1 -ß), and caspase3 but negatively correlated with the proliferation relative gene MKI67. The stimulatory effects of DCN on the salivary gland epithelial cells (A253 cell line) and macrophages have been determined as they are considered active participants in the progression of SS. The data showed that DCN induced the apoptosis of A253 cells and polarization of macrophages towards the M1 phenotype, characterized by the expression of pro-inflammatory cytokines. CONCLUSIONS: Our study provided preliminary evidence to understand the clinical significance of DCN in pSS and broadened our horizons in understanding the mechanism of pSS.

Tertiary lymphoid structures in autoimmune diseases.

Tertiary lymphoid structures (TLSs) are organized lymphoid-like aggregations in non-lymphoid tissues. Tissues with chronic and persistent inflammation infiltration may drive and form ectopic germinal center-like structures, which are very common in autoimmune diseases, chronic infections, and tumor microenvironments. However, the mechanisms governing the formation of TLSs are still being explored. At present, it is not clear whether the formation of TLSs is associated with local uncontrolled immune inflammatory responses. While TLSs suggest a good prognosis in tumors, the opposite is true in autoimmune diseases. This review article will discuss the current views on initiating and maintaining TLSs and the potential therapeutic target in autoimmune diseases.

The Role of Decorin in Autoimmune and Inflammatory Diseases.

Decorin is an extracellular matrix protein that belongs to the family of small leucine-rich proteoglycans. As a matrix protein, the first discovered role of decorin is participating in collagen fibril formation. Many other functions of decorin in various biological processes have been subsequently identified. Decorin is involved in an extensive signaling network and can interact with other extracellular matrix components, growth factors, receptor tyrosine kinases, and various proteases. Decorin has been shown to be involved in wound repair, cell cycle, angiogenesis, tumor metastasis, and autophagy. Recent evidence indicates that it also plays a role in immune regulation and inflammatory diseases. This review summarizes the characteristics of decorin in immune and inflammatory diseases, including inflammatory bowel disease (IBD), Sjögren's syndrome (SS), chronic obstructive pulmonary disease (COPD), IgA nephropathy, rheumatoid arthritis (RA), spondyloarthritis (SpA), osteoarthritis, multiple sclerosis (MS), idiopathic inflammatory myopathies (IIM), and systemic sclerosis (SSc) and discusses the potential role in these disorders.

The IL-33/ST2 Axis Promotes Primary Sjögren's Syndrome by Enhancing Salivary Epithelial Cell Activation and Type 1 Immune Response.

The molecular mechanisms of primary Sjögren's syndrome (pSS) are poorly understood. In this study, we explored the role of the IL-33/ST2 axis in the development of pSS. In the mouse model of experimental Sjögren's syndrome, we found that the saliva flow rate at weeks 4 and 30 was preserved in IL-33-/- and ST2-/- mice, compared with that of wild-type mice. At week 30 of experimental Sjögren's syndrome induction, the histological score, anti-nuclear Ab levels, and numbers of Th1 and B cells in draining lymph nodes of the salivary gland were lower in the IL-33-/- and ST2-/- mice, whereas Th17 cells and regulatory T cells were not changed. Primary salivary gland epithelial cells expressed the IL-33 receptor ST2. After stimulation with rIL-33, salivary gland epithelial cells increased the transcriptional levels of CD86 and CCL2, accompanied by the activation of the NF-κB inflammatory pathway. There was a synergistic effect between rIL-33 and rIL-12 in augmenting the production of IFN-γ in CD4+ T cells. In the pSS patients, the expression of IL-33 was elevated in the labial salivary gland, with the number of IL-33+ cells positively correlated with the score of the EULAR (European Alliance of Associations for Rheumatology) Sjögren's syndrome disease activity index (ESSDAI). ST2 was highly expressed in the cytoplasm of ductal epithelial cells, with low levels of expression in lymphatic infiltration sites. Our data suggest that the IL-33/ST2 axis may promote the development of pSS by enhancing salivary epithelial cell activation and the type 1 immune response.

The Role of HMGB1 in Rheumatic Diseases.

HMGB1, a highly conserved non-histone nuclear protein, is widely expressed in mammalian cells. HMGB1 in the nucleus binds to the deoxyribonucleic acid (DNA) to regulate the structure of chromosomes and maintain the transcription, replication, DNA repair, and nucleosome assembly. HMGB1 is actively or passively released into the extracellular region during cells activation or necrosis. Extracellular HMGB1 as an alarmin can initiate immune response alone or combined with other substances such as nucleic acid to participate in multiple biological processes. It has been reported that HMGB1 is involved in various inflammatory responses and autoimmunity. This review article summarizes the physiological function of HMGB1, the post-translational modification of HMGB1, its interaction with different receptors, and its recent advances in rheumatic diseases and strategies for targeted therapy.

Structural Lesion Progression of the Sacroiliac Joint and Clinical Features in axSpA During TNFi Reduction: A Retrospective Cohort Study.

Objective: In the clinic, some patients with axial spondyloarthritis (axSpA) have to reduce tumor necrosis factor inhibitor (TNFi) for various reasons. However, there are few studies about how to balance the relapse and TNFi reduction. Here we retrospectively analyzed the structural progression of the sacroiliac joint (SIJ) and clinical features in axSpA during TNFi reduction. Methods: A total of 108 patients with axSpA who followed up for 2 years and completed at least baseline, 12-month, and 24-month MRI scans of SIJ were divided into the tapering group (n = 63) and withdrawal group (n = 45) according to whether TNFi was stopped. We divided 2 years into five intervals, calculating the average dose quotient (DQ) for each of 540 intervals from 108 patients. By using generalized estimation equations with inverse probability of treatment weighting, we investigated the unbiased effects of average DQ on structural progression and treatment response. Results: The disease activity (such as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP, and ASDAS-ESR) and relapse rate were lower in the tapering group at 12 and 24 months (p < 0.05). Δerosion (ß = -0.0100, p = 0.00026) and Δthe Spondyloarthritis Research Consortium of Canada (SPARCC; ß = -0.0959, p < 0.0001) were negatively correlated with average DQ. The average DQ 30 (74.8%, 80.0%) or 41.6 (76.5%, 83%) was best to discriminate the status of treatment response or the status of bone marrow edema, but considering operability, the average DQ 25 (78.0%, 63.3%) was also acceptable especially for patients with HLA-B27 negative and non-severe fat metaplasia. Conclusion: Complete TNFi withdrawal was not recommended. Our study provided a referable strategy (tapering then maintained the average DQ over 30 or even 25) for patients who need TNFi reduction. Higher dose usage of TNFi was associated with a slower erosion progression of SIJ.

IL-33 in Rheumatic Diseases.

Interleukin-33 (IL-33) is a nuclear factor mainly expressed in barrier epithelium, endothelial cells, and fibroblast reticular cells. Some inflammatory cells also express IL-33 under certain conditions. The important role of IL-33 in allergic reactions, helminth infection, cancer, tissue fibrosis, chronic inflammation, organ transplantation, and rheumatic immune diseases has been extensively studied in recent years. IL-33 primarily activates various circulating and tissue-resident immune cells, including mast cell, group 2 innate lymphoid cell (ILC2), regulatory T cell (Treg), T helper 2 cell (Th2), natural killer cell (NK cell), and macrophage. Therefore, IL-33 plays an immunomodulatory role and shows pleiotropic activity in different immune microenvironments. The IL-33/serum stimulation-2 (ST2) axis has been shown to have a detrimental effect on rheumatoid arthritis, systemic lupus erythematosus, and other rheumatic diseases. Interestingly, IL-33 also plays a protective role in the repair of barrier epithelium and the activation of Tregs. Therefore, the role of IL-33/ST2 depends on the underlying pathological conditions in rheumatic diseases. This review focuses on the dual role of the IL-33/ST2 axis in rheumatic diseases.

Intratracheal Poly(I:C) Exposure Accelerates the Immunological Disorder of Salivary Glands in Sjogren's-Like NOD/ShiLtJ Mice.

Evidences have suggested that Sjogren's syndrome (SS) is associated with viral infection. The aim of this study was to investigate the involvement of respiratory viral poly(I:C) in the pathogenesis of SS and potential mechanisms using a SS-like NOD/ShiLtJ (NOD) mouse model. 5-week female NOD mice were intratracheally administered poly(I:C) every other day for 5 times to mimic viral infection. Pilocarpine induced saliva secretion was determined every 8 days. Submandibular glands (SMG) and lungs were harvested for the detection of pathological changes. We found that intratracheal administration of poly(I:C) significantly advanced and enhanced the reduction of saliva flow rate in NOD mice. Furthermore, poly(I:C) treatment aggravated the histopathological lesions and inflammatory cells infiltration in SMG. Accompanied by elevated expression of IFN cytokines and IL-33, Th1 activation was enhanced in SMG of poly(I:C)-treated NOD mice, but Th17 cells activation was unchanged among the groups. In addition, intratracheal poly(I:C) exposure promoted the expression of IL-33 and increased T cells proportion in the lung, which were consistent with the change in SMG. Therefore, intratracheal poly(I:C) exposure aggravated the immunological and function disorder of SMG in NOD mice.

Clinical characteristics of IgG4-RD patients infected with COVID-19 in Hubei, China.

Objective: IgG4-related disease (IgG4-RD) is an immune-mediated multi-organ, chronic and progressive disease. Therefore, we conducted a study to investigate the susceptibility of COVID-19 in IgG4-RD patients in Hubei province, and to characterize the clinical manifestation of COVID-19 in IgG4-RD patients. Methods: A follow-up system that includes over 200 IgG4-RD patients across the country during the past ten years. A total of ninety-one patients with IgG4-RD who live in Hubei, China were identified and responded to our survey. Medical history, clinical symptoms, laboratory tests, CT imaging, and treatment were obtained through a standardized data collection form, and then independently reviewed by two investigators. Results: 2 of 91 cases were infected with COVID-19. Both of them were classified as moderate type. The symptoms such as fever and cough and radiologic features were similar to other COVID-19 patients. Neither of them episode recurrent of IgG4-RD nor progressed to severe or critical condition of COVID-19 under the condition of continuous oral low-dose of glucocorticoids. Besides, patient 2 took a long time for SARS-CoV-2 nucleic acid to turn negative. Conclusion: IgG4-RD patients may belongs to the susceptible population of COVID-19 infection, and thus need more careful personal protection. Early identification and properly treatment are very important to prevent IgG4-RD patients with COVID-19 from progression to severe condition.

The clinical value of the albumin quotient in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: The disruption of the blood-brain barrier (BBB) is common in patients with neuromyelitis optica spectrum disorder (NMOSD), causing pro-inflammatory immune cells to migrate into the central nervous system (CNS) and active demyelinating lesions. Albumin quotient is commonly used as an indicator for BBB permeability or dysfunction, but its potential clinical value in NMOSD treatment has never been explored. The present study investigated the differences in the albumin quotient level among NMOSD patients with different antibodies (AQP4-IgG and MOG-IgG) and the relationship between the albumin quotient and neurological dysfunction. METHODS: We retrospectively collected data from 141 patients with NMOSD (104 with AQP4-IgG and 37 with MOG-IgG) and reviewed their clinical features and albumin quotient levels. RESULTS: The percentage of patients with an abnormal albumin quotient was significantly higher in the MOG-IgG group than in the AQP4-IgG group (48.6% vs 27.9%, P = 0.026); albumin quotient levels in the AQP4-IgG-positive group were similar to those in the MOG-IgG groups (5.65 vs 5.8, P = 0.23). Among those with an abnormal quotient, no differences in the proportions of severe neurological disability across treatment were found between patients with AQP4-IgG and those with MOG-IgG (pre-treatment: AQP4-IgG group vs MOG-IgG group: 58.6% vs 38.9%, P = 0.24; post-treatment: AQP4-IgG group vs MOG-IgG group: 31.0% vs 22.2%, P = 0.74). CONCLUSIONS: The BBB breakdown in NMOSD patients with MOG-IgG may be more common than in those with AQP4-IgG. AQP4-IgG-positive patients and MOG-IgG-positive patients with severe neurological disability tend to exhibit similar disruptions to the BBB.

Characterization of the Fine Particle Emissions from the Use of Two Fischer-Tropsch Fuels in a CFM56-2C1 Commercial Aircraft Engine.

The fine particulate matter (PM) emissions from the use of two types of Fischer-Tropsch aviation fuels and their 50:50 blends with military JP-8 were quantified as part of the first Alternative Aviation Fuel Experiment (AAFEX). Measurements were made at 30-m downstream of a CFM56-2C1 engine for PM mass and number, particle size distribution, black carbon (BC), and volatile PM (sulfate + organics) using selected on-line instrumentation. The PM number emission index (EI N ) ranged from ~ 2 × 1015 to 7 × 1016 particles/kg fuel burned depending on fuel flow, fuel composition, and sampling temperature with the magnitude of the emissions inversely correlated to fuel flow. The PM mass emissions (EI M ) measured in the study varied from ~ 5 to 680 mg/kg fuel again depending on fuel flow, fuel type, and sampling temperature with a characteristic U-shaped curve of EI M with respect to fuel flow observed from the data. At low fuel flow (corresponding to low engine power), particle number and volume size distributions contained a single mode whereas at higher engine power, a bi-modal distribution was observed. The BC emissions varied from ~ 3 to 415 mg/kg fuel depending on fuel type and were found to exponentially increase with engine power (fuel flow). The volatile PM varied with sample temperature, fuel type, and increasing fuel flow within the range of EIs from ~ 0.4 to 11 mg/kg fuel with the highest values being at low fuel flow. Finally, the use of the two neat alternative fuels reduced the EI N by a median value of 70-73% and the EI M by ~ 94% as compared to JP-8 across all power conditions tested.

Expression of human Tau40 in the medial entorhinal cortex impairs synaptic plasticity and associated cognitive functions in mice.

Entorhinal cortex (EC) is the initial brain region that suffers abnormal tau in Alzheimer's disease (AD). Whether overexpression of human tau (htau40) in EC disrupts cognitive function and synaptic plasticity in AD has not been fully elucidated. To investigate the effects of htau40 on the pathology and associated mechanisms of early stage of AD in mice, an adeno-associated virus-based htau40 transduced in medial EC (mEC) mouse model was established. The results showed that htau40 restrictedly expressed in mEC after transduction. The memory function and long-term potentiation (LTP) of dentate gyrus (DG) were significantly impaired by overexpression of htau40 in mEC after transduction at 3 and 6 months. However, the abnormities of neurons and neurotransmitters in mEC started at just 1 month after transduction. The resting membrane potential was increased and paired pulse facilitates was depressed, but the action potential amplitude, threshold, and half width did not alter after htau40 transduction at 1 month. The levels of inhibitory neurotransmitters were up regulated whereas level of lactate was decreased. Our study demonstrated that htau40 in mEC impaired cognition and synaptic plasticity of perforant path (PP)-DG, which simulated early stage of AD and elucidated the mechanism of that htau40 overexpression in mEC may be associated with the development of AD.

Physical and chemical characterization of residential oil boiler emissions.

The toxicity of emissions from the combustion of home heating oil coupled with the regional proximity and seasonal use of residential oil boilers (ROB) is an important public health concern. Yet scant physical and chemical information about the emissions from this source is available for climate and air quality modeling and for improving our understanding of aerosol-related human health effects. The gas- and particle-phase emissions from an active ROB firing distillate fuel oil (commonly known as diesel fuel) were evaluated to address this deficiency. Ion chromatography of impactor samples showed that the ultrafine ROB aerosol emissions were approximately 45% (w/w) sulfate. Gas chromatography-mass spectrometry detected various n-alkanes at trace levels, sometimes in accumulation mode particles, and out of phase with the size distributions of aerosol mass and sulfate. The carbonaceous matter in the ROB aerosol was primarily light-adsorbing elemental carbon. Gas chromatography-atomic emission spectroscopy measured a previously unrecognized organosulfur compound group in the ROB aerosol emissions. High-resolution transmission electron microscopy of ROB soot indicated the presence of a highly ordered primary particle nanostructure embedded in larger aggregates. Organic gas emissions were measured using EPA Methods TO-15 and TO-11A. The ROB emitted volatile oxygenates (8 mg/(kg of oil burned)) and olefins (5 mg/(kg of oil burned)) mostly unrelated to the base fuel composition. In the final analysis, the ROB tested was a source of numerous hazardous air pollutants as defined in the Clean Air Act Amendments. Approximations conducted using emissions data from the ROB tests show relatively low contributions to a regional-level anthropogenic emissions inventory for volitile organic compounds, PM2.5, and SO2 mass.