Vasculitis Research Articles

Immunomodulatory treatment of interstitial lung disease.

Interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) have an array of immunomodulatory treatment options compared with IPF, due to their inflammatory component. However, there is a relative paucity of guidance on the management of this heterogeneous group of diseases. In ILDs other than IPF, immunosuppression is the cornerstone of therapy, with varying levels of evidence for different immunomodulatory agents and for each specific ILD. Classification of ILDs is important for guiding treatment decisions. Immunomodulatory agents mainly include corticosteroids, mycophenolate mofetil (MMF), azathioprine, methotrexate, cyclophosphamide and rituximab. In this review, the available evidence for single agents in the most common ILDs is first discussed. We then reviewed practical therapeutic approaches in connective tissue disease–related ILD and interstitial pneumonia with autoimmune features, scleroderma-related ILD, vasculitis and dermatomyositis with hypoxemic respiratory failure, idiopathic non-specific interstitial pneumonia, hypersensitivity pneumonitis sarcoidosis, fibrosing organizing pneumonia and eosinophilic pneumonia. The treatment of acute exacerbations of ILD is also discussed. Therapy augmentation in ILD is dictated by the recognition of progression of disease. Criteria for the evaluation of progression of disease are then discussed. Finally, specific protocol and measures to increase patients’ safety are reviewed as well, including general monitoring and serologic surveillance, Pneumocystis jirovecii prophylaxis, patients’ education, genetic testing for azathioprine, MMF serum levels and cyclophosphamide administration protocols. Immunomodulatory therapies are largely successful in the management of ILDs and can be safely managed with the application of specific protocols, precautions and monitoring.

Male Patients with Takayasu Arteritis and Coronary Artery Involvement are Prone to Have Serious Coronary Stenosis and High Mortality.

Takayasu arteritis (TAK) is a rare autoimmune vasculitis that predominantly affects the aorta and its major branches, including the coronary arteries. Information is limited regarding sex-specific differences in coronary artery involvement among TAK patients. To assess the differences in coronary angiographic findings and long-term outcomes between male and female TAK patients with coronary artery involvement. This retrospective cohort study included 87 TAK patients, grouped by sex, who underwent coronary angiography. General characteristics, clinical features, coronary angiographic findings, and therapeutic strategies were obtained from medical records. Major Adverse Cardiac Events (MACE), including death from any cause, myocardial infarction, repeated coronary artery revascularization, and rehospitalization due to unstable or progressive angina or heart failure occurring during follow-up, were also recorded. A total of 207 coronary lesions with stenosis were found in 87 TAK patients. The prevalence of ostial coronary lesions was lower in men than in women (9.1 vs. 23.9%, p=0.031). We observed less moderate stenosis (6.8 vs. 22.7%, p=0.018) and more severe stenosis or occlusion (70.5 vs. 46.0%, p=0.004) in the coronary lesions of male TAK patients. During the up to 7-year follow- up, death from any cause was greater in men than in women (21.4 vs. 1.5%, p=0.003); no other significant differences in MACE occurrence were observed between sexes. Among TAK patients with coronary artery involvement, males tend to have more serious coronary stenosis and a higher risk for long-term mortality than females.

Undifferentiated Arthritis Revealing Cogan’s Disease

Background: Cogan’s syndrome is a rare autoimmune vasculitis (less than 300 cases described in the literature) characterized in its typical form by cochleovestibular involvement, interstitial keratitis, and an inflammatory involvement of large vessels. It is frequently accompanied by general signs and cardio-vascular, rheumatologic, and digestive complications. Its management is essentially based on the use of corticosteroids and immunosuppressants. The outcome of the treatment, even if rapid, does not always avoid functional complications. This disease is probably under-diagnosed in Africa. Objective: The objective of this study was to report a case of Cogan syndrome in sub-Saharan Africa. Case report: A 78 year old black African female patient presented with arthritis of the left knee without fever. The examination also revealed a bilateral deafness of rapidly progressive onset. The patient was known to be diabetic and hypertensive, and was regularly monitored. The biology revealed an inflammatory syndrome and an inflammatory joint puncture fluid. Pure tone audiometry confirmed a 77% hearing loss. The ophthalmological examination revealed stromal oedema and hypertensive retinopathy of Kendall stage III. The rheumatological evolution was good under methylprednisolone and methotrexate, but the deafness persisted. The occurrence of a fever on day 12 of treatment required further investigations (blood culture, PCR-Covid 19 test, cytobacteriological examination of sputum, thoracic CT). The evolution was unfavourable with the death of the patient. Conclusion: Cogan’s disease is a rare inflammatory disease. Its diagnosis and management are multidisciplinary. The treatment can be disappointing.

Necrotizing Anterior Scleritis in a Woman with Terrien’s Marginal Degeneration: A Case Report

Purpose: The aim of the study was to report the first case of a patient with Terrien’s Marginal Degeneration (TMD) who developed necrotizing anterior scleritis without systemic disease association, requiring systemic immunosuppressive treatment. Case Report: A 32-year-old female consulted for bilateral ocular burning and hyperemia. Initially, she was diagnosed with conjunctivitis and treated with topical antibiotics and corticosteroids, with mild transitory improvement but the progression of the disease. Years later, she attended the ocular immunology consultation for a second opinion where TMD with ocular inflammatory component OU was diagnosed. Seven months later, she presented with severe pain, decreased visual acuity, and photophobia in OS. At the slit-lamp examination, necrotizing anterior scleritis with a high risk of perforation in OS was observed. The patient was referred to the rheumatologist and started treatment with systemic corticosteroids and cyclophosphamide, exhibiting a clinical improvement. The patient did not meet the criteria for any systemic illness associated with scleritis, such as autoimmune diseases or vasculitis. Thus, scleritis was related to the adjacent inflammatory process associated with TMD, as an atypical presentation of this disease. Conclusion: Although an inflammatory type of TMD has been proposed, it is essential to follow up closely these patients and consider necrotizing anterior scleritis, a severe ocular disease that requires prompt immunosuppressive management, as a possible atypical associated presentation of this disease.

Human Proteinase 3, an important autoantigen of c-ANCA associated vasculitis, shares cross-reactive epitopes with serine protease allergens from mites: an in silico analysis

Background: In autoimmune vasculitis, autoantibodies to Human Proteinase 3 (PR3), a human serine protease, seems to have a role on the inception of c-ANCA associated vasculitis. The origin of this autoreactive response remains unclear. However, for several autoreactive responses, molecular mimicry between environmental antigens and human proteins is key to trigger autoantibodies and finally autoimmunity manifestations. Considering that PR3 is a serine protease and house dust mite (HDM) group 3 allergens share this biochemical activity, the aim of this study was to identify cross-reactive epitopes between serine proteases from human and mites using an in silico approach. Methods: Multi alignment among amino acid sequences of PR3 and HDM group 3 allergens was performed to explore identity and structural homology. ElliPro and BepiPred in silico tools were used to predict B and T cell epitopes. Consurf tool was used to conduct identification of conserved regions in serine proteases family. Results: PR3 and HDM group 3 allergens shared moderate identity and structural homology (root mean square deviation < 1). One B cell cross reactive epitope among serine proteases was identified (29I, 30V, 31G, 32G, 34E, 36K, 37A, 38L, 39A and 54C) and two T cell epitopes. Conclusions: PR3 have structural homology and share cross reactive epitopes with HDM group 3 allergens.

The relationship between equine pastern dermatitis, meteorological factors, and the skin microbiota.

BackgroundEquine pastern dermatitis (EPD) is a multifactorial syndrome, with prolonged exposure to moisture assumed to be a predisposing or primary factor.Hypothesis/ObjectivesTo examine the course of EPD lesion severity, changes in bacterial skin microbiota, and the influence of meteorological factors.AnimalsProspective, longitudinal cohort study over a one‐year period, with six Franches‐Montagnes stallions, four affected by EPD and two unaffected, that were kept under the same conditions.Methods and materialsPasterns were scored for lesion severity and sampled once a month for 12 consecutive months. Lesion severity, the skin microbiota and meteorological factors were examined for associations.ResultsEPD lesions tended to worsen in autumn and at the beginning of spring. The relationship between lesion severity and the meteorological factor precipitation was not clearly evident; high scores were preceded by both low or high rates of precipitation. Microbiota in affected pasterns appeared to have experienced a reduction in alpha diversity. Beta diversity analyses demonstrated that bacterial community structures were altered in affected versus unaffected pasterns, and that alterations were more pronounced with higher EPD scores (P = 0.005). Meteorological factors also had considerable influences on the bacterial composition, whereby these influences appeared to be more marked in the affected pasterns (P = 0.001, F = 3.19) than in unaffected ones (P = 0.005, F = 1.83).Conclusions and clinical relevanceOur study provides preliminary observations of the relationships between lesion severity, meteorological factors and cutaneous bacteria. The population was too small to draw firm conclusions, and further studies on environmental factors and the involvement of bacteria in this multifactorial disease are needed.

Ultrasound Technologies and the Diagnosis of Giant Cell Arteritis.

Giant cell arteritis (GCA) is a primary autoimmune vasculitis that specifically affects medium-sized extracranial arteries, like superficial temporal arteries (TAs). The most important data to be considered for the ultrasound (US) diagnosis of temporal arteritis are stenosis, acute occlusions and “dark halo” sign, which represent the edema of the vascular wall. The vessel wall thickening of large vessels in GCA can be recognized by the US, which has high sensitivity and is facile to use. Ocular complications of GCA are common and consist especially of anterior arterial ischemic optic neuropathies or central retinal artery occlusion with sudden, painless, and sharp loss of vision in the affected eye. Color Doppler imaging of the orbital vessels (showing low-end diastolic velocities and a high resistance index) is essential to quickly differentiate the mechanism of ocular involvement (arteritic versus non-arteritic), since the characteristics of TAs on US do not correspond with ocular involvement on GCA. GCA should be cured immediately with systemic corticosteroids to avoid further visual loss of the eyes.

Abstract 13880: Autoimmune Connective Tissue Diseases and Cardiac Surgery

Introduction: The results of cardiac surgery in patients affected by autoimmune connective tissue diseases (ACTD) have not been extensively reported. Accordingly, we sought to assess the outcomes of ACTD patients after cardiac surgery, focusing on postoperative complications and survival at short and long term. Methods: Since 2008, 1002 cardiac surgical patients affected by ACTD (rheumatoid arthritis (RA) 59%, autoimmune vasculitis 14%, autoimmune inflammatory disease 12%, psoriatic arthritis 9%, and systemic lupus erythematosus (SLE) 6%), were retrospectively analysed in two centres. Demographics, clinical characteristics and specific treatment were recorded. Type of surgery, postoperative complications, early and late mortality were analysed. Results: Median age was 71 (22-92) years, and 48% were female. Most patients presented severe comorbidities (shown in the table) and required urgent surgery in 17% of cases, most frequently CABG (56%). Perioperative mortality was 2% but 60% of patients developed postoperative complications (mainly acute renal failure 15%). Patients affected by systemic inflammatory autoimmune diseases needed longer time of mechanical ventilation (p&lt;0.01), while those with vasculitis more frequently had pneumonia (p=0.05). SLE patients had higher 30-day mortality (7%, p=0.04). Survival at 1, 5 and 10 years was 97±1%, 82±1% and 59±2%, respectively, and most common causes of death were not cardiac related (75%). By multivariate analysis, RA (HR 1.30, 1.00-1.70) was a risk factor for late mortality while both SLE and vasculitis were risk factors for re-operation (p=0.04 and p&lt;0.01, respectively), at a median follow up of 59 months (1-184). Conclusions: Cardiac surgery in ACTD patients can achieve satisfactory short- and long-term results despite higher rate of postoperative complications, mainly renal failure and infections.

P31 Cogan's syndrome—a neglected autoimmune vasculitis

P31 Cogan's syndrome—a neglected autoimmune vasculitis

ACUTE MULTIPLE CEREBRAL WATERSHED INFARCTIONS AS THE FIRST PRESENTATION OF COVID-19 IN A YOUNG MALE PATIENT: A CASE REPORT

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Novel Coronavirus disease 2019 (COVID-19) pandemic represents the greatest global public health crisis since the influenza outbreak in 1918. It has been associated with hypercoagulability causing life-threatening cardiovascular and neurovascular complications. The pathogenesis of this predisposition is not well understood, and one of its consequences is an increased risk of stroke. Patients with patent foramen ovale (PFO), atrial fibrillation, previous history of stroke, and elderly patients with uncontrolled hypertension, may be at a higher risk of developing strokes with COVID-19. We present a rare case of acute multiple cerebral watershed infarctions in a COVID-19 patient. CASE PRESENTATION: 38 year-old obese male with past medical history of hypertension presented with confusion, left sided weakness, right lower extremity weakness, and right gaze preference. MRI brain demonstrated multiple patchy small areas of acute ischemic infarcts bilaterally consistent with watershed infarcts. An echocardiogram with bubble study was negative for PFO. Lower extremity venous Doppler ultrasound was negative for DVT. Telemetry didn't record any arrhythmias. Laboratory work-up ruled out autoimmune diseases, hypercoagulable states, and vasculitis including: antiphospholipid antibodies, lupus anticoagulants, anti-neutrophil cytoplasmic antibodies, anti-nuclear antibodies, anti-factor Xa, Anti-thrombin, Protein S and C, and rapid plasma regain. The patient was screened for COVID-19 due to increased reports of stroke in young patients nationwide, and surprisingly, the test was positive. Aspirin, clopidogrel, high-intensity statins, along with enoxaparin for DVT prophylaxis were initiated. DISCUSSION: Evidence increasingly shows that COVID-19 it is not always confined to the respiratory tract but can also induce neurologic diseases with increased risk of stroke in young patients. The reported incidence of stroke in COVID-19 positive patients is about 1-6%. The plausible proposed mechanisms include: viral neurotropism, coagulopathy from systemic inflammation and cytokine storm, and endothelial dysfunction leading to angiopathic thrombosis. There are handful of cases linking COVID-19 to large vessel macrothrombosis and antiphospholipid syndrome. We herein report an even more unusual case that presented with multiple focal neurologic symptoms and was found to have watershed infarctions secondary to COVID-19 with only mild respiratory symptoms, without typical vascular risk factors, PFO or arrhythmia, after excluding autoimmune diseases, hypercoagulability diseases, and vasculitis, shedding the light on the importance of suspecting this devastating disease in an otherwise healthy young patient who presents with focal neurological symptoms. CONCLUSIONS: In COVID-19 patients with mild respiratory symptoms, a low threshold for investigation for stroke should be adopted with any new neurological symptoms. REFERENCE #1: Tan YK, Goh C, Leow AST, et al. COVID-19 and ischemic stroke: a systematic review and meta-summary of the literature. J Thromb Thrombolysis. 2020;50(3):587-595. doi:10.1007/s11239-020-02228-y DISCLOSURES: No relevant relationships by Ramy Abdelmaseih, source=Web Response No relevant relationships by Randa Abdelmasih, source=Web Response

Coronary Artery Aneurysm in Kawasaki Disease: Coronary CT Angiography through the Lens of Pathophysiology and Differential Diagnosis.

Kawasaki disease (KD) is an inflammatory autoimmune vasculitis affecting the coronary arteries of very young patients, which can result in coronary artery aneurysms (CAAs) with lifelong manifestations. Accurate identification and assessment of CAAs in the acute phase and sequentially during the chronic phase of KD is fundamental to the treatment plan for these patients. The differential diagnosis of CAA includes atherosclerosis, other vasculitic processes, connective tissue disorders, fistulas, mycotic aneurysms, and procedural sequelae. Understanding of the initial pathophysiology and evolutionary arterial changes is important to interpretation of imaging findings. There are multiple applicable imaging modalities, each with its own strengths, limitations, and role at various stages of the disease process. Coronary CT angiography is useful for evaluation of CAAs as it provides assessment of the entire coronary tree, CAA size, structure, wall, and lumen characteristics and visualization of other cardiothoracic vasculature. Knowledge of the natural history of KD, the spectrum of other conditions that can cause CAA, and the strengths and limitations of cardiovascular imaging are all important factors in imaging decisions and interpretation. Keywords: Pediatrics, Coronary Arteries, Angiography, Cardiac © RSNA, 2021.

A Comprehensive Review on Autoimmune Diseases

Abstract: Immunity refers to the inbuilt ability of the organism to resist a particular disease or to be able to protect itself from disease causing microorganisms by preventing its development. Immune system includes WBCs which includes all the neutrophils, lymphocytes including the T-cells, the B-cells &amp; the natural killer cells, all together make up the lymphatic system, antibodies, the spleen, the thymus, the bone marrow; our skin, mucous glands, hair, tears etc. also protect our body. By autoimmunity we understand that it is misallocated response of our immune system when it releases autoantibodies to attack the healthy cells of the body. Scientists have studied a lot about autoimmunity and its disorders. By the end of the 19th century, it was first believed that our immune system has the inability to react against its own body tissue until in 20th century the concept of “horror autotoxicus” was proposed by the German immunologist Paul Ehrlich. The autoimmune disease occurs when the immune system reacts and attacks its own cells in the body as a result of breakdown of immunologic tolerance to auto reactive immune cells. Many times, genetic as well as environmental factors are the key reason for autoimmune diseases. Many kinds of research are going through as to find out the actual cause of autoimmunity; till now no actual or exact cause is known. There are at least 80 types of autoimmune diseases recognized by our scientists; some of the commonly known autoimmune diseases are: type 1 diabetes, systemic lupus erythematosus, scleroderma, thyroiditis, multiple sclerosis, autoimmune vasculitis, rheumatoid arthritis, and many more. With unusual autoimmune diseases, diagnosis may not be done instantly; the patients may suffer years before getting diagnosed properly. Most of the diseases don't have any cure; some even need lifelong treatment to ease the symptoms. The diseases will be discussed in detail in the further sections. Keywords: autoimmunity, immune system, cells, disease, disorder, diabetes, arthritis, lupus, ITP

Radiological aspects of idiopathic lumbosacral plexitis

Idiopathic Lumbosacral Plexitis is a disease that do not have definitive causes but even starts to be studied by Sander Evans et al. in 1981 hypotheses were put forward related to viral infections, vaccines and heterologous serum. Although more recently studies have showed that the disease can develop without immunological history. Multiple roots and nerves are affected and it can be bilateral. The diferential diagnosis of other pathologies must involves research for tumours, traumas and diabetes. The findings of the disease include: autoimmune demyelination and vasculitis with axonal lesion. The clinicalconditionare characterized by intensive pain, paresis, hypoesthesia in lower members, and a limping gait. The prognosis is positive, however do not have a completely remission without squeals. The treatment has not been defined but is common to uses corticosteroids and immunoglobulin.

Characterisation of an enhanced preclinical model of experimental MPO-ANCA autoimmune vasculitis.

Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO-ANCA, pulmonary haemorrhage, and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub-nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone - with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci-immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub-nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non-classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a 4-day treatment period. We believe that this enhanced model of MPO-AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

COVID-19 skin lesions are rarely positive at RT-PCR test: the macrophage activation with vascular impact and SARS-CoV-2-induced cytokine storm.

BackgroundSeveral skin manifestations have been reported since the start of the COVID‐19 pandemic: chilblains‐like, livedoid lesions, urticaria‐like, pseudo‐Kawasaki disease, and others. Histopathologic images of these lesions most often show aspects of endothelitis, images similar to autoimmune vasculitis. Cutaneous lesions are often negative at RT‐PCR for SARS‐CoV‐2 virus.Method and ResultsWe reviewed recent articles on the mechanisms of COVID‐19 and we synthesized main pathways of inflammatory cascade. After the penetration into the cells of the respiratory epithelium, SARS‐CoV‐2 virus initiates a “cytokine storm” well described in previous publications: the expression of interferon type I (IFN‐I) is one of the key elements of the antiviral response in COVID‐19 patients, IFN‐I expression seems to play an important role in the induction of interleukin 6 (IL‐6), chemotactic factors such as Granulocyte‐Macrophage Colony‐Stimulating Factor (GM‐CSF) and the consequent activation of monocyte‐macrophage system followed by the expression of TNF‐alpha, and finally by the induction of coagulation factors by both extrinsic and intrinsic pathways.ConclusionsThe simplified synthesis of the main pathophysiological mechanisms of COVID‐19 could help us to understand at least partially the importance of macrophage activation and its vascular involvement in many skin lesions that remain often negative at in situ tests for SARS‐CoV‐2.

Commentary

Commentary

McH-lpr/lpr-RA1 mice: A novel spontaneous mouse model of autoimmune sialadenitis

Many studies of the autoimmune disease Sjögren's syndrome have been performed using spontaneous mouse models. In the present study, we describe the characteristics of McH/lpr-RA1 mice and propose their use as a novel murine model of autoimmune sialadenitis. The McH/lpr-RA1 mouse is a recombinant congenic strain derived from generation F54 or more of MRL-Faslpr x (MRL- Faslpr x C3H- Faslpr) F1. We show for the first time that this mouse spontaneously develops autoimmune sialadenitis and vasculitis in submandibular gland tissues. Sialadenitis was accompanied by extensive inflammatory cell infiltration and tissue destruction. Immunohistochemical studies revealed that the salivary gland lesions strongly expressed four sialadenitis-related molecules: SSA and SSB (autoantigens of Sjögren's syndrome), gp91phox (an accelerator of reactive oxygen species production) and single strand DNA (a marker of apoptotic cells). In contrast, expression of aquaporin-5 (AQP5), which stimulates salivary secretion was weak or negligible. Statistical correlation analyses indicated that the apoptosis of salivary gland cells provoked by oxidative stress contributed to the severe sialadenitis and reduced expression of AQP5. Our study has demonstrated that McH/lpr-RA1 mice spontaneously develop the pathognomonic features of autoimmune sialadenitis and thus could be used as a new animal model of Sjögren's syndrome.

MicroRNA-340-5p inhibits endothelial apoptosis, inflammatory response, and pro-coagulation by targeting KDM4C in anti-neutrophil cytoplasmic antibody (ANCA)-mediated glomerulonephritis through activation of B cells

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, a class of systemic autoimmune diseases, results in damage of various critical organs including kidneys, lungs, eyes, and nervous system. MicroRNA-340-5p was confirmed to be downregulated in autoimmune pathogenesis. However, the role of miR-340-5p remains unknown in ANCA-induced glomerulonephritis (GN). The current study aimed to explore the role of miR-340-5p in ANCA-induced GN. The animal models of ANCA-induced GN was established by experimental autoimmune vasculitis (EAV) operation. The primary glomerular endothelial cells (PGEnCs) were treated with anti-myeloperoxidase (anti-MPO) to mimic cell injury in vitro. The renal function was analysed by measuring serum creatinine, blood urea nitrogen, urine blood, urine protein and urine leukocytes. The levels of RNA and proteins were examined by RT-qPCR and western blot analysis, respectively. The binding capacity between miR-340-5p and KDM4C was detected by luciferase reporter assay. Cell apoptosis was analysed by flow cytometry in vitro. Cell viability was determined by CCK-8 assay. The cleaved caspase-3 activity was analysed by immunofluorescent assay. Cell inflammation was measured by western blot. Cell procoagulant activity was assessed by FXa generation assay. The histological changes of renal tissues were assessed by Haematoxylin and eosin (H&E) staining assay. The correlation between miR-340-5p and KDM4C level (or content of TNF-α and IL-6) was analysed by Pearson correlation analysis. The injection of anti-MPO IgG induced a significant elevation of Serum creatinine and blood urea nitrogen in serum, as well as urine blood, urine protein and urine leukocytes. Importantly, KDM4C was downregulated in model group. In mechanism, we identified that miR-340-5p bound with KDM4C 3'untranslated region (UTR), negatively regulated KDM4C in endothelial cells and negatively correlated with KDM4C in serum of GN rats. In function, we found that miR-340-5p promoted B cell activation and proliferation by downregulating KDM4C. The in vitro assays showed that the decrease of cell viability induced by anti-MPO was reversed by miR-340-5p overexpression, and further reduced by KDM4C overexpression. Inversely, the suppressive effects of miR-340-5p mimics on cell apoptosis, cleaved caspase-3 activity, inflammatory response and pro-coagulation were countervailed by KDM4C overexpression in anti-MPO-treated cells. The in vivo assays validated that miR-340-5p overexpression mitigated the impairment of renal function, and histological changes induced by anti-MPO IgG injection in model group. Finally, we found the negative correlation between miR-340-5p and TNF-α (or IL-6) content in serum of GN rats. In conclusion, we found that miR-340-5p inhibited endothelial apoptosis and inflammatory response by targeting KDM4C in ANCA-mediated GN through activation of B cells, implying a potential novel insight for treatment of ANCA-mediated GN.

CMTM6-Deficient Monocytes in ANCA-Associated Vasculitis Fail to Present the Immune Checkpoint PD-L1.

ObjectivesANCA-associated vasculitides (AAV) affect small- and medium-sized blood vessels. In active disease, vessel wall infiltrates are mainly composed of monocytes and macrophages. Immune checkpoint molecules are crucial for the maintenance of self-tolerance and the prevention of autoimmune diseases. After checkpoint inhibitor therapy, the development of autoimmune vasculitis has been observed. However, defects of immune checkpoint molecules in AAV patients have not been identified yet.MethodsMonocytes and monocyte-derived macrophages from AAV patients and healthy age-matched controls were tested for surface expression of immunoinhibitory checkpoint programmed cell death ligand-1 (PD-L1). Using in vitro co-culture approaches, the effect of monocyte PD-L1 expression on CD4+ T cell activation and proliferation was tested.ResultsMonocytes from AAV patients displayed lower PD-L1 expression and a defective PD-L1 presentation upon activation, an effect that was correlated with disease activity. Lower PD-L1 expression was due to increased lysosomal degradation of PD-L1 in AAV monocytes. We identified a reduced expression of CMTM6, a protein protecting PD-L1 from lysosomal breakdown, as the underlying molecular defect. PD-L1low AAV monocytes showed increased stimulatory capacity and induced T cell activation and proliferation. Inhibiting lysosomal function corrected this phenotype by increasing PD-L1, thus normalizing the pro-stimulatory behavior of AAV monocytes.ConclusionsThis study identifies a defect of the immunoinhibitory checkpoint PD-L1 in monocytes from patients with AAV. Low expression of CMTM6 results in enhanced lysosomal degradation of PD-L1, thus providing insufficient negative signaling to T cells. Correcting this defect by targeting lysosomal function may represent a novel strategy to treat AAV.

Therapy response evaluation in large-vessel vasculitis: a new role for [18F]FDG-PET/CT?

Therapy response evaluation in large-vessel vasculitis: a new role for [18F]FDG-PET/CT?