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Gordon C.L.,Austin Hospital | Johnson P.D.R.,Austin Hospital | Johnson P.D.R.,University of Melbourne | Permezel M.,Mercy Hospital for Women | And 16 more authors.
Clinical Infectious Diseases | Year: 2010

Background. Severe pandemic 2009 influenza A virus (H1N1) infection is associated with risk factors that include pregnancy, obesity, and immunosuppression. After identification of immunoglobulin G2 (IgG2) deficiency in 1 severe case, we assessed IgG subclass levels in a cohort of patients with H1N1 infection. Methods. Patient features, including levels of serum IgG and IgG subclasses, were assessed in patients with acute severe H1N1 infection (defined as infection requiring respiratory support in an intensive care unit), patients with moderate H1N1 infection (defined as inpatients not hospitalized in an intensive care unit), and a random sample of healthy pregnant women. Results. Among the 39 patients with H1N1 infection (19 with severe infection, 7 of whom were pregnant; 20 with moderate infection, 2 of whom were pregnant), hypoabuminemia (P< .001 ), anemia (P < .001), and low levels of total IgG (P = .01), IgG1 (P = .022), and IgG 2 (15 of 19 vs 5 of 20; P = .001; mean value ± standard deviation [SD], 1.8 ± 1.7 g/L vs 3.4 ± 1.4 g/L; P = .003) were all statistically significantly associated with severe H1N1 infection, but only hypoalbuminemia (P = .02) and low mean IgG2 levels (P = .043) remained significant after multivariate analysis. Follow-up of 15 (79%) surviving IgG2-deficient patients at a mean (±SD) of 90 ± 23 days (R, 38-126) after the initial acute specimen was obtained found that hypoalbuminemia had resolved in most cases, but 11 (73%) of 15 patients remained IgG2 deficient. Among 17 healthy pregnant control subjects, mildly low IgG1 and/or IgG2 levels were noted in 10, but pregnant patients with H1N1 infection had significantly lower levels of IgG 2 (P = .001). Conclusions. Severe H1N1 infection is associated with IgG2 deficiency, which appears to persist in a majority of patients. Pregnancy-related reductions in IgG2 level may explain the increased severity of H1N1 infection in some but not all pregnant patients. The role of IgG2 deficiency in the pathogenesis of H1N1 infection requires further investigation, because it may have therapeutic implications. © 2010 by the Infectious Diseases Society of America. All rights reserved.


PubMed | University of Rome La Sapienza and Respiratory
Type: | Journal: Annals of medicine | Year: 2017

Resistant arterial hypertension (RHT) is defined as poor controlled blood pressure (BP) despite optimal doses of 3 or more antihypertensive agents, including a diuretic. In the development of RHT, hyperactivity of sympathetic (SNS) and renin-angiotensin-aldosterone (SRAA) systems are involved, and SNS is a potent stimulator of vasoactive endothelin-1 (ET1) peptide. Renal sympathetic denervation (RSD) through disrupting renal afferent and efferent nerves attenuates SNS activity.We carried out pilot study investigating the effect of RSD on BP and plasma ET-1 levels in consecutive 9 RHT patients (7 male and 2 female, mean age of 56 13.3).After 12 months of the RSD, we observed a significant reduction of BP office, 24-hr ambulatory BP monitoring (ABPM) (p<0.05, respectively), and non-dipping pattern (from 55% to 35%) (p<0.05). Moreover, RSD significantly decreased plasma ET-1 levels in both renal artery (at right from 21.84.1 to 16.82.9pg/ml; p=0.004; at left from 22.13.7 to 18.93.3pg/ml; p=0.02). We observed positive correlations between plasma renal arteries ET-1 levels and systolic BP values at ABPM [Global-SBP (r=0.58; p<0.01), Diurnal-SBP (r=0.51; p<0.03) and Nocturnal-SBP (r=0.58; p<0.01), respectively].Our data confirmed the positive effects of RSD on BP values in patients with RHT, and showed a possible physio-pathological role of ET-1.


Henault J.,Respiratory | Martinez J.,St Jude Childrens Research Institute | Riggs J.M.,Respiratory | Tian J.,Respiratory | And 11 more authors.
Immunity | Year: 2012

Toll-like receptor-9 (TLR9) is largely responsible for discriminating self from pathogenic DNA. However, association of host DNA with autoantibodies activates TLR9, inducing the pathogenic secretion of type I interferons (IFNs) from plasmacytoid dendritic cells (pDCs). Here, we found that in response to DNA-containing immune complexes (DNA-IC), but not to soluble ligands, IFN-α production depended upon the convergence of the phagocytic and autophagic pathways, a process called microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP). LAP was required for TLR9 trafficking into a specialized interferon signaling compartment by a mechanism that involved autophagy-related proteins, but not the conventional autophagic preinitiation complex, or adaptor protein-3 (AP-3). Our findings unveil a new role for nonconventional autophagy in inflammation and provide one mechanism by which anti-DNA autoantibodies, such as those found in several autoimmune disorders, bypass the controls that normally restrict the apportionment of pathogenic DNA and TLR9 to the interferon signaling compartment. © 2012 Elsevier Inc.


May R.D.,Respiratory | Fung M.,Respiratory
Cytokine | Year: 2015

IL-4 and IL-13 are pleiotropic Th2 cytokines produced by a wide variety of different cell types and responsible for a broad range of biology and functions. Physiologically, Th2 cytokines are known to mediate host defense against parasites but they can also trigger disease if their activities are dysregulated. In this review we discuss the rationale for targeting the IL-4/IL-13 axes in asthma, atopic dermatitis, allergic rhinitis, COPD, cancer, inflammatory bowel disease, autoimmune disease and fibrotic disease as well as evaluating the associated clinical data derived from blocking IL-4, IL-13 or IL-4 and IL-13 together. © 2015 Elsevier Ltd.


Rowland S.L.,University of Washington | Riggs J.M.,Respiratory | Gilfillan S.,University of Washington | Bugatti M.,University of Brescia | And 6 more authors.
Journal of Experimental Medicine | Year: 2014

Plasmacytoid dendritic cells (pDCs) have long been implicated in the pathogenesis of lupus. However, this conclusion has been largely based on a correlative link between the copiousproduction of IFN-α/β by pDCs and the IFN-α/β "signature" often seen in human lupus patients. The specific contribution of pDCs to disease in vivo has not been investigated in detail. For this reason, we generated a strain of BXSB lupus-prone mice in which pDCs can be selectively depleted in vivo. Early, transient ablation of pDCs before disease initiation resulted in reduced splenomegaly and lymphadenopathy, impaired expansion and activation of T and B cells, reduced antibodies against nuclear autoantigens and improved kidney pathology. Amelioration of pathology coincided with decreased transcription of IFN-α/β- induced genes in tissues. PDC depletion had an immediate impact on the activation of immune cells, and importantly, the beneficial effects on pathology were sustained eventhough pDCs later recovered, indicating an early pDC contribution to disease. Together, our findings demonstrate a critical function for pDCs during the IFN-α/β-dependent initiation of autoimmune lupus and point to pDCs as an attractive therapeutic target for the treatment of SLE. © 2014 Rowland et al.


Sanjuan M.A.,Respiratory | Sagar D.,Respiratory | Kolbeck R.,Respiratory
Journal of Allergy and Clinical Immunology | Year: 2016

There is accumulating evidence to suggest that IgE plays a significant role in autoimmunity. The presence of circulating self-reactive IgE in patients with autoimmune disorders has been long known but, at the same time, largely understudied. However, studies have shown that the increased IgE concentration is not associated with higher prevalence for atopy and allergy in patients with autoimmune diseases, such as systemic lupus erythematosus. IgE-mediated mechanisms are conventionally known to facilitate degranulation of mast cells and basophils and promote TH2 immunity, mechanisms that are not only central to mounting an appropriate defense against parasitic worms, noxious substances, toxins, venoms, and environmental irritants but that also trigger exuberant allergic reactions in patients with allergies. More recently, IgE autoantibodies have been recognized to participate in the self-inflicted damaging immune responses that characterize autoimmunity. Such autoimmune responses include direct damage on tissue-containing autoantigens, activation and migration of basophils to lymph nodes, and, as observed most recently, induction of type 1 interferon responses from plasmacytoid dendritic cells. The importance of IgE as a central pathogenic mechanism in autoimmunity has now been clinically validated by the approval of omalizumab, an anti-IgE mAb, for patients with chronic spontaneous urticaria and for the clinical benefit of patients with bullous pemphigoid. In this review we summarize recent reports describing the prevalence of self-reactive IgE and discuss novel findings that incriminate IgE as central in the pathogenesis of inflammatory autoimmune disorders. © 2016 American Academy of Allergy, Asthma & Immunology.


Finch D.,Respiratory | Sleeman M.,Respiratory
Current Pharmaceutical Design | Year: 2015

Interleukin-1 inhibitors were tested in large arthritis trials with less than impressive results, despite having convincing disease expression data and pre-clinical animal model supporting the potential pathogenic role of this cytokine in these settings. Despite disappointing beginnings, some IL-1 pathway blocking drugs are now beginning to find a place in the pharmacopoeia of rheumatologists. Drug developers utilised rapidly growing understanding of the molecular pathway and the genetic basis of key diseases to seek out conditions in which IL-1 pathway activation was much more likely to have a pivotal role in disease pathogenesis compared to the major arthritides. This review details the crucial advances in understanding of the IL-1 pathway activation which enabled this progress, particularly the advent of inflammasome biology. The drug development of IL-1 biologics in rheumatological diseases makes a fascinating case study illustrating major changes in drug development strategy encompassing closer synergies between translational biology, underlying molecular pathophysiology of disease, and novel clinical development pathways of biologic therapeutics. © 2015 Bentham Science Publishers.


Pescosolido N.,Respiratory | Buomprisco G.,University of Rome La Sapienza
European Endocrinology | Year: 2014

Retinopathy is a serious and common complication of diabetes that represents the leading cause of blindness, among people of working age, in developed countries. It is estimated that the number of people with diabetic retinopathy (DR) will increase from 126.6 million in 2011 to 191 million by 2030. The visual function that seems to be affected first in the course of DR is probably the contrast sensitivity; in addition, being mainly a macular function, the perception of colour is also compromised. Moreover, the duration of the disease, the levels of glycated haemoglobin (HbA1c) and the presence of cystoid macular oedema are strongly associated with the impairment of fixation stability in patients with diabetes with clinically significant macular oedema, suggesting the possible diagnostic role of microperimetry. The test of contrast sensitivity and the microperimetry and the chromatic sensitivity tests have proved to be useful, safe, reproducible and inexpensive tools to diagnose the disease early. © Touch Medical Media 2014.


PubMed | Respiratory
Type: Journal Article | Journal: Current pharmaceutical design | Year: 2015

Interleukin-1 inhibitors were tested in large arthritis trials with less than impressive results, despite having convincing disease expression data and pre-clinical animal model supporting the potential pathogenic role of this cytokine in these settings. Despite disappointing beginnings, some IL-1 pathway blocking drugs are now beginning to find a place in the pharmacopoeia of rheumatologists. Drug developers utilised rapidly growing understanding of the molecular pathway and the genetic basis of key diseases to seek out conditions in which IL-1 pathway activation was much more likely to have a pivotal role in disease pathogenesis compared to the major arthritides. This review details the crucial advances in understanding of the IL-1 pathway activation which enabled this progress, particularly the advent of inflammasome biology. The drug development of IL-1 biologics in rheumatological diseases makes a fascinating case study illustrating major changes in drug development strategy encompassing closer synergies between translational biology, underlying molecular pathophysiology of disease, and novel clinical development pathways of biologic therapeutics.


PubMed | Respiratory
Type: Journal Article | Journal: The Journal of allergy and clinical immunology | Year: 2016

There is accumulating evidence to suggest that IgE plays a significant role in autoimmunity. The presence of circulating self-reactive IgE in patients with autoimmune disorders has been long known but, at the same time, largely understudied. However, studies have shown that the increased IgE concentration is not associated with higher prevalence for atopy and allergy in patients with autoimmune diseases, such as systemic lupus erythematosus. IgE-mediated mechanisms are conventionally known to facilitate degranulation of mast cells and basophils and promote TH2 immunity, mechanisms that are not only central to mounting an appropriate defense against parasitic worms, noxious substances, toxins, venoms, and environmental irritants but that also trigger exuberant allergic reactions in patients with allergies. More recently, IgE autoantibodies have been recognized to participate in the self-inflicted damaging immune responses that characterize autoimmunity. Such autoimmune responses include direct damage on tissue-containing autoantigens, activation and migration of basophils to lymph nodes, and, as observed most recently, induction of type 1 interferon responses from plasmacytoid dendritic cells. The importance of IgE as a central pathogenic mechanism in autoimmunity has now been clinically validated by the approval of omalizumab, an anti-IgE mAb, for patients with chronic spontaneous urticaria and for the clinical benefit of patients with bullous pemphigoid. In this review we summarize recent reports describing the prevalence of self-reactive IgE and discuss novel findings that incriminate IgE as central in the pathogenesis of inflammatory autoimmune disorders.

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