IL-37 regulates allergic inflammation by counterbalancing pro-inflammatory IL-1 and IL-33.

BACKGROUND: Children with asthma have impaired production of interleukin (IL) 37; in mice, IL-37 reduces hallmarks of experimental allergic asthma (EAA). However, it remains unclear how IL-37 exerts its inhibitory properties in asthma. This study aimed to identify the mechanism(s) by which IL-37 controls allergic inflammation. METHODS: IL-37 target cells were identified by single-cell RNA-seq of IL-1R5 and IL-1R8. Airway tissues were isolated by laser-capture microdissection and examined by microarray-based gene expression analysis. Mononuclear cells (MNC) and airway epithelial cells (AECs) were isolated and stimulated with allergen, IL-1ß, or IL-33 together with recombinant human (rh) IL-37. Wild-type, IL-1R1- and IL-33-deficient mice with EAA were treated with rhIL-37. IL-1ß, IL-33, and IL-37 levels were determined in sputum and nasal secretions from adult asthma patients without glucocorticoid therapy. RESULTS: IL-37 target cells included AECs, T cells, and dendritic cells. In mice with EAA, rhIL-37 led to differential expression of >90 genes induced by IL-1ß and IL-33. rhIL-37 reduced production of Th2 cytokines in allergen-activated MNCs from wild-type but not from IL-1R1-deficient mice and inhibited IL-33-induced Th2 cytokine release. Furthermore, rhIL-37 attenuated IL-1ß- and IL-33-induced pro-inflammatory mediator expression in murine AEC cultures. In contrast to wild-type mice, hIL-37 had no effect on EAA in IL-1R1- or IL-33-deficient mice. We also observed that expression/production ratios of both IL-1ß and IL-33 to IL-37 were dramatically increased in asthma patients compared to healthy controls. CONCLUSION: IL-37 downregulates allergic airway inflammation by counterbalancing the disease-amplifying effects of IL-1ß and IL-33.

Region-specific effects of the cysteine protease papain on gastric motility.

BACKGROUND: Papaya is a traditional remedy for gastrointestinal complaints in the folk medicine. On this basis, papain, a cysteine protease of the fruit, is sold as a nutritional supplement, although scientific data on its effects in the gastrointestinal tract are lacking. We aimed to explore the effect of papain on gastric motility in vitro. METHODS: Guinea pig antrum and corpus strips were mounted in organ bath. KEY RESULTS: Papain reversibly increased the amplitude of ongoing phasic contractions in both circular and longitudinal antrum strips without having an effect on the frequency or on the muscle tone. All three tested doses of papain (end cc.: 12.5 mg L-1 , 50 mg L-1 , 100 mg L-1 ) were similarly effective. Contrarily, in the corpus circular and longitudinal muscle strips, papain caused a dose-dependent relaxation, which was preceded by a transient contraction in most tissues. The effect was resistant to tetrodotoxin (1 µM), but diminished by the cysteine protease inhibitor E64 (4.5 µM) in both regions. In the corpus, L-NAME (100 µM) and the protease-activated receptor (PAR)-1 antagonist SCH79797 (5 µM) or the PAR-2 antagonist GB 83 (3 µM) did not change the effect of papain significantly. This demonstrates that the effects of papain are not neurally mediated and nitrergic pathways are not involved in the mechanism. The effects are linked to the enzymatic activity, but not executed via PAR-1 or 2. CONCLUSIONS AND INFERENCES: Papain alters gastric motility in a region-specific manner, which could at least partly explain its claimed beneficial effects in functional gastrointestinal disorders.

The alpha-melanocyte-stimulating hormone acts as a local immune homeostasis factor in experimental allergic asthma.

BACKGROUND: Originally, the neuropeptide α-melanocyte-stimulating hormone (α-MSH) has been described as a mediator of skin pigmentation. However, recent studies have shown that α-MSH is able to modulate inflammation in various tissues including the lung. So far, it is still not clear whether α-MSH also plays a role in allergic bronchial asthma. OBJECTIVE: This study aimed at investigating the role and regulatory mechanisms of α-MSH in asthma pathogenesis. METHODS: α-MSH levels were measured in bronchoalveolar lavage (BAL) fluid of asthmatic and non-asthmatic individuals as well as of healthy mice and mice with experimental asthma. Wild-type mice were sensitized to ovalbumin (OVA) and exposed to an OVA aerosol in order to induce experimental allergic asthma. α-MSH was administrated intratracheally, the α-MSH antibody intraperitoneally prior each OVA challenge. Airway inflammation, cytokine production, mucus production, airway hyperresponsiveness and receptor expression were assessed. RESULTS: α-MSH levels in BAL of asthmatic individuals and mice were significantly higher compared to healthy controls. In a mouse model of experimental asthma, α-MSH neutralization increased airway inflammation and mucus production, whereas local administration of α-MSH significantly reduced inflammation of the airways. The beneficial effects were further associated with decreased levels of eosinophilic chemoattractant factors that are released by MC5R-positive T helper 2 and airway epithelial cells. CONCLUSION AND CLINICAL RELEVANCE: α-MSH acts as a regulatory factor to maintain local immune homeostasis in allergic bronchial asthma.

Effect of IL-37 on Allergic Airway Inflammation.

RATIONALE: The new cytokine IL-37 has been described as a negative regulator of innate immunity. It reduces activation of dendritic cells and the production of proinflammatory mediators in murine and human immune cells. Although recent results from the CLARA childhood asthma cohort suggested an impact of IL-37 on human asthma pathogenesis, the receptor for IL-37 and its implication in adaptive immune responses have not been determined. OBJECTIVES: This study aimed to clarify whether IL-37 also provides antiinflammatory effects on adaptive immune responses and through which receptor it exerts its effects. METHODS: IL-37 levels in supernatants of restimulated peripheral blood mononuclear cells isolated from children with asthma and healthy children were determined. Mice (wild-type, IL-18Rα(-/-), and SIGIRR/IL-1R8(-/-)) were sensitized to ovalbumin (OVA) and challenged with OVA aerosol to induce acute allergic experimental asthma, and IL-37 was applied intranasally during OVA challenge. Airway hyperresponsiveness was determined. A cytometric bead array was used to assess cytokine levels in bronchoalveolar lavage fluid. Epithelial mucus was quantified on the basis of lung sections stained with periodic acid-Schiff reagent, using the newCAST microscope system. MEASUREMENTS AND MAIN RESULTS: Human peripheral blood mononuclear cells of subjects with allergic asthma produce less IL-37 compared with healthy control subjects. In mice, intranasal administration of IL-37 dampened allergic airway inflammation as well as proinflammatory cytokine production, mucus hyperproduction, and airway hyperresponsiveness. However, the antiinflammatory effects of IL-37 were completely abolished in mice deficient for IL-18Rα or SIGIRR/IL-1R8. CONCLUSIONS: This study demonstrates that IL-37 reduces allergic airway inflammation directed by type 2 helper T cells and the hallmarks of experimental asthma in mice, suggesting that IL-37 may be critical for asthma pathogenesis in particular and may have an impact on adaptive immunity in general. Furthermore, these data suggest a mode of action of IL-37 that involves binding to IL-18Rα and subsequent heterodimerization with or activation of SIGIRR/IL-1R8. Therefore, IL-37 or its receptors could be potential targets for asthma intervention.

Allergic airway inflammation: unravelling the relationship between IL-37, IL-18Rα and Tir8/SIGIRR.

The hallmarks of allergic bronchial asthma arise from chronic airway inflammation. Thus, elucidating the mechanisms regulating the maintenance of this chronic inflammatory response is key to understanding asthma pathogenesis. To date, it is not clear whether a predominance of proinflammatory factors or a reduced capacity of counterbalancing anti-inflammatory mediators is the pivotal factor predisposing individuals towards asthma development. The IL-1 cytokine family and its receptor systems comprise a variety of proinflammatory cytokines like IL-1ß and IL-18 and anti-inflammatory molecules such as the Toll/interleukin-1 receptor 8/single Ig IL-1 receptor (IL-R)-related molecule (Tir8/SIGIRR) and the recently established cytokine IL-37. This article reviews the functions of these IL-1 cytokine family members in the regulation of allergic airway inflammation and asthma as they have been assessed clinically, in vitro and in mouse models.

Increase of angiotensin II type 1 receptor auto-antibodies in Huntington's disease.

BACKGROUND: In the recent years, a role of the immune system in Huntington's disease (HD) is increasingly recognized. Here we investigate the presence of T cell activating auto-antibodies against angiotensin II type 1 receptors (AT1R) in all stages of the disease as compared to healthy controls and patients suffering from multiple sclerosis (MS) as a prototype neurologic autoimmune disease. RESULTS: As compared to controls, MS patients show higher titers of anti-AT1R antibodies, especially in individuals with active disease. In HD, anti-AT1R antibodies are more frequent than in healthy controls or even MS and occur in 37.9% of patients with relevant titers ≥ 20 U/ml. In a correlation analysis with clinical parameters, the presence of AT1R antibodies in the sera of HD individuals inversely correlated with the age of onset and positively with the disease burden score as well as with smoking and infection. CONCLUSIONS: These data suggest a dysfunction of the adaptive immune system in HD which may be triggered by different stimuli including autoimmune responses, infection and possibly also smoking.

Differential surface expression of ADAM10 and ADAM17 on human T lymphocytes and tumor cells.

A disintegrin and metalloproteases (ADAMs) have been implicated in many processes controlling organismic development and integrity. Important substrates of ADAM proteases include growth factors, cytokines and their receptors and adhesion proteins. The inducible but irreversible cleavage of their substrates alters cell-cell communication and signaling. The crucial role of ADAM proteases (e.g. ADAM10 and 17) for mammalian development became evident from respective knockout mice, that displayed pre- or perinatal lethality with severe defects in many organs and tissues. Although many substrates for these two ADAM proteases were identified over the last decade, the regulation of their surface appearance, their enzymatic activity and their substrate specificity are still not well understood. We therefore analyzed the constitutive and inducible surface expression of ADAM10 and ADAM17 on a variety of human T cell and tumor cell lines. We demonstrate that ADAM10 is constitutively present at comparably high levels on the majority of the tested cell types. Stimulation with phorbol ester and calcium ionophore does not significantly alter the amount of surface ADAM10, except for a slight down-regulation from T cell blasts. Using FasL shedding as a readout for ADAM10 activity, we show that PKC activation and calcium mobilization are both prerequisite for activation of ADAM10 resulting in a production of soluble FasL. In contrast to ADAM10, the close relative ADAM17 is detected at only low levels on unstimulated cells. ADAM17 surface expression on T cell blasts is rapidly induced by stimulation. Since this inducible mobilization of ADAM17 is sensitive to inhibitors of actin filament formation, we propose that ADAM17 but not ADAM10 is prestored in a subcellular compartment that is transported to the cell surface in an activation- and actin-dependent manner.

Successful treatment of anti-Caspr2 syndrome by interleukin 6 receptor blockade through tocilizumab.

IMPORTANCE: A patient with a Caspr2 autoantibodies-associated syndrome had an unusual clinical triad and an excellent response to B-cell-anergizing therapy using the humanized monoclonal antibody tocilizumab directed against the interleukin 6 (IL-6) receptor. OBSERVATIONS: A 55-year-old man had an atypical clinical triad of epilepsy, dysarthria, and paroxysmal kinesigenic dystonia, and a high titer of Caspr2 antibodies was detected in his serum and cerebrospinal fluid. Screening for underlying neoplasias was negative. With initial methylprednisolone sodium succinate and alternate treatment using plasma exchange and immunoabsorption as well as subsequent IL-6 receptor blockade through tocilizumab, a complete and stable remission of symptoms has been achieved throughout the follow-up period of 7 months. CONCLUSIONS AND RELEVANCE: In our patient, the implementation of a B-cell-anergizing therapy using tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, has shown an excellent response. Larger case series or even controlled studies are needed to confirm the efficacy of tocilizumab in autoimmune synaptic or presynaptic diseases.

Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy.

OBJECTIVE: To report first experiences with interleukin 6 receptor inhibition in therapy-resistant neuromyelitis optica (NMO). DESIGN: Retrospective case series. SETTING: Neurology department at a tertiary referral center. PATIENTS: Patients with an aggressive course of NMO switched to tocilizumab after failure of anti-CD20 therapy. MAIN OUTCOME MEASURES: Annualized relapse rate and disability progression measured by the Expanded Disability Status Scale. RESULTS: We report 3 female patients with a median age of 39 years (range, 26-40 years) and aquaporin 4-positive NMO. All patients had been treated with different immunosuppressive and immunomodulating agents, followed by 1 to 3 cycles of rituximab. Despite complete CD20-cell depletion during rituximab therapy, the median annualized relapse rate was 3.0 (range, 2.3-3.0) and the median Expanded Disability Status Scale score increased from 5.0 (range, 4.5-7.0) to 6.5 (range, 5.0-7.0). After the switch to tocilizumab (median duration of therapy, 18 months), the median annualized relapse rate decreased to 0.6 (range, 0-1.3). A total of 2 relapses occurred; however, they were mild and there were no changes in clinical disability. CONCLUSIONS: Interleukin 6 receptor-blocking therapy can be effective in therapy-resistant cases of NMO. Larger controlled studies are needed to confirm the efficacy of tocilizumab.

Stability of cognitive functions under mitoxantrone therapy in patients with progressive multiple sclerosis: a pilot analysis.

OBJECTIVE: Mitoxantrone (MX) is a potent immunosuppressant that is licensed as escalation therapy for the treatment of active multiple sclerosis (MS). METHODS: In an open-label, retrospective analysis, we investigated effects of MX therapy on parameters of cognitive functions in patients with progressive MS and significant disability. Twenty patients received a total of 42 mg/m(2) MX in 4 cycles. Six patients who fulfilled the criteria for MX therapy, yet did not receive this treatment, served as controls. Before initiation of therapy and after a mean observation period of 24 months, neurological examination and a neuropsychological test battery were performed. Neuropsychological analyses comprised tests for cognitive flexibility as a part of executive functioning, and verbal as well as non-verbal tests for memory and attention. Additionally, intelligence and symptoms of depression were investigated. RESULTS: While there was stability of EDSS over time, there were no differences in cognitive functions before and after MX treatment. In contrast, patients not receiving MX showed a worsening of verbal short term memory and cognitive flexibility over the same time period. CONCLUSION: In conclusion, this preliminary observational study points at stability of cognitive functions under MX therapy in patients with progressive multiple sclerosis.

Successful management of natalizumab-associated progressive multifocal leukoencephalopathy and immune reconstitution syndrome in a patient with multiple sclerosis.

OBJECTIVE: To describe a case of successful clinical management of natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution syndrome (IRIS) in a patient with multiple sclerosis. DESIGN: Case report. SETTING: University hospital. PATIENT: A 41-year-old woman with relapsing-remitting multiple sclerosis developed PML after 29 natalizumab infusions. INTERVENTIONS: Immediate plasma exchange was combined for removal of natalizumab with application of mefloquine and mirtazapine to limit viral replication and oligodendrocyte infection. A subsequent IRIS was treated with glucocorticosteroids. RESULTS: After 3 months of treatment, cerebrospinal fluid tested negative for JC virus. There was a favorable outcome, and the Expanded Disability Status Scale score remained stable at 3.5 compared with before PML. CONCLUSIONS: In the setting of early diagnosis and consequent treatment, natalizumab-associated PML can be well managed in some cases. This situation differs from the course of PML in other conditions, eg, after the application of depleting monoclonal antibodies, in which irreversible cellular effects are associated with very high mortality.

Plasmapheresis for neurological disorders.

Apheresis is a general term that describes removal of abnormal blood constituents by extracorporeal blood purification methods. To date, therapeutic plasma exchange (PE) is the most common apheresis procedure. Here, plasma is separated from corpuscular blood constituents and replaced with a substitution fluid. In contrast to immunoadsorption, PE is a nonspecific treatment modality with elimination of the entire plasma. The therapeutic effect is based on the removal of circulating, pathogenic immune factors including autoantibodies. Currently, PE is used for treatment of several immune-mediated neurological disorders. While first experiences relate to acute life-threatening conditions, such as treatment of Guillain-Barré syndrome or myasthenic crisis, therapeutic success was also shown in chronic diseases where immunosuppressive therapy is often required for long-term management. PE has been applied successfully in chronic inflammatory demyelinating polyneuropathy, paraproteinemic polyneuropathy, stiff person syndrome, and may also be tried in several diseases of paraneoplastic origin. In recent years, PE was also established as an escalation therapy for steroid-unresponsive relapses of multiple sclerosis, and thus has gained more widespread attention. Adding to its increasing application in clinical practice, the procedure is usually well tolerated. Possible adverse reactions mainly relate to vascular access, the use of replacement fluids and the need for anticoagulation.

Violência contra o médico / Violence against the doctor

Os autores relatam e analisam a relação médico-paciente abalada por situações que colocam o médico como sujeito vulnerável quando vítima de agressões, sejam elas físicas ou morais, exercidas por seus pacientes. Questionam a capacidade deste profissional de oferecer condições de saúde, quando lhe falta à própria segurança por se encontrar em condições de violência emocional.

Contrast-enhanced ultrasonic parametric perfusion imaging detects dysfunctional tissue at risk in acute MCA stroke.

Ultrasonic perfusion imaging predicts size and localization of acute stroke. It is unclear whether irreversibly damaged tissue can be differentiated from tissue at risk. Thirty-four patients (ischemic stroke <12 h) were included (Phase Inversion Harmonic Perfusion Imaging; bolus kinetic; fitted model function). Three patterns of perfusion were defined in 14 prespecified regions of interest (ROI): 'normal', 'hypoperfusion', and 'no perfusion'. Clinical status was assessed using the National Institutes of Health Stroke Scale (NIHSS) (at baseline and at days 2 to 4). Cranial Computed Tomography (CCT) (days 2 to 4) displayed final infarction. The pattern 'hypoperfusion' (ROIs presumably representing tissue at risk) was tested twofold: (i) Functional impairment by correlating their number with baseline NIHSS. (ii) Viability by correlating their recruitment rate to infarction with clinical course (DeltaNIHSS days 2 to 4). In addition, various predictive values were assessed. Twenty-seven patients were eligible for analysis. The sum of ROIs with 'no perfusion' and 'hypoperfusion' correlated highest with baseline NIHSS (rho=0.78, P<0.001). Recruitment of hypoperfused ROIs to infarction highly correlated with clinical course (rho=0.79, P<0.001). Clinical course dichotomized the patients into subgroups A ('stable', DeltaNIHSS>or=-3) and B ('improved', DeltaNIHSS

Osteossarcoma / Osteosarcoma

Os autores têm por objetivo neste estudo fazer uma revisão bibliográfica referente ao osteossarcoma. enfatizam aspectos gerais da doença, tais como fisiopatogenia, sinais e sintomas, tratamentos e prognóstico. além disso, comentam os últimos estudos relacionados principalmente aos fatores prognósticos da doença. valem-se destas ferramentas para tentar facilitar o compreendimento da patologia, assim como orientar o diagnóstico e a abordagem terapêutica.