Worsened Disease Outcome Research Articles

A systematic review on shared biological mechanisms of depression and anxiety in comorbidity with psoriasis, atopic dermatitis, and hidradenitis suppurativa.

Mental disorders in comorbidity with chronic skin diseases may worsen disease outcome and patients' quality of life. We hypothesized the comorbidity of depression, anxiety syndromes, or symptoms as attributable to biological mechanisms that the combined diseases share. We conducted a systematic review based on the Preferred Reporting Items for Systematic Review and Meta-Analysis statement searching into PubMed, PsycInfo, and Scopus databases. We examined the literature regarding the comorbidity of psoriasis (Ps), atopic dermatitis (AD), or hidradenitis suppurativa with depression and/or anxiety in adults ≥18years and the hypothetical shared underlying biological mechanisms. Sixteen studies were analyzed, mostly regarding Ps and AD. Brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling and nuclear factor kappa-light-chain-enhancer of activated B cells/p38 mitogen-activated protein kinase pathways arose as shared mechanisms in Ps animal models with depression- and/or anxiety-like behaviors. Activated microglia and neuroinflammatory responses emerged in AD depressive models. As to genetic studies, atopic-dermatitis patients with comorbid anxiety traits carried the short variant of serotonin transporter and a polymorphism of the human translocator protein gene. A GA genotype of catechol-O-methyltransferase gene was instead associated with Ps. Reduced natural killer cell activity, IL-4, serotonin serum levels, and increased plasma cortisol and IgE levels were hypothesized in comorbid depressive AD patients. In Ps patients with comorbid depression, high serum concentrations of IL-6 and IL-18, as well as IL-17A, were presumed to act as shared inflammatory mechanisms. Further studies should investigate mental disorders and chronic skin diseases concurrently across patients' life course and identify their temporal relation and biological correlates. Future research should also identify biological characteristics of individuals at high risk of the comorbid disorders and associated complications.

Topical ozone therapy restores microbiome diversity in atopic dermatitis

BackgroundStaphylococcus aureus (S. aureus) accounts for 90% of the microbiome in atopic dermatitis (AD) lesions and plays a role in disease flare-ups and worsens disease outcome. Ozone treatment can improve AD conditions by its bactericidal effect on S. aureus. ObjectiveTo study the effects of topical ozone therapy on microbiome diversity in AD lesions and explore potential probiotic pathogens correlated with AD progression. MethodsPatients with moderate to severe bilateral skin lesions in AD were recruited. Randomized split sides were performed. One side was treated with ozone hydrotherapy followed by ozonated oil; while the contralateral side with tap water and basal oil. Patients’ SCORAD scores and modified EASI were recorded before and after treatments. The microbiological compositions in targeting sites were determined using 16S rDNA sequencing. ResultsAfter three-day ozone therapy, patients showed a significant decrease in SCORAD scores and inflammatory cell infiltration in AD lesions. The micro-ecological diversity was higher in the non-lesional as compared with lesional areas (p < 0.05), which was also negatively correlated with the severity of AD (r = −0.499, p < 0.05). The proportion of S. aureus in AD lesions was positively correlated with the severity of AD (r = 0.564, p = 0.010), which was decreased after ozone treatment (p = 0.07). Ozone therapy showed an increase in microbiological diversity with a significant increase in the proportion of Acinetobacter (p < 0.05). ConclusionTopical ozone therapy is highly effective for treatment for AD. It can change the proportional ratio of Staphylococcus and Acinetobacter, thereby restoring the microbiological diversity in AD lesions.

Host nutritional status affects alphavirus virulence, transmission, and evolution.

Malnourishment, specifically overweight/obesity and undernourishment, affects more than 2.5 billion people worldwide, with the number affected ever-increasing. Concurrently, emerging viral diseases, particularly those that are mosquito-borne, have spread dramatically in the past several decades, culminating in outbreaks of several viruses worldwide. Both forms of malnourishment are known to lead to an aberrant immune response, which can worsen disease outcomes and reduce vaccination efficacy for viral pathogens such as influenza and measles. Given the increasing rates of malnutrition and spread of arthropod-borne viruses (arboviruses), there is an urgent need to understand the role of host nutrition on the infection, virulence, and transmission of these viruses. To address this gap in knowledge, we infected lean, obese, and undernourished mice with arthritogenic arboviruses from the genus Alphavirus and assessed morbidity, virus replication, transmission, and evolution. Obesity and undernourishment did not consistently influence virus replication in the blood of infected animals except for reductions in virus in obese mice late in infection. However, morbidity was increased in obese mice under all conditions. Using Mayaro virus (MAYV) as a model arthritogenic alphavirus, we determined that both obese and undernourished mice transmit virus less efficiently to mosquitoes than control (lean) mice. In addition, viral genetic diversity and replicative fitness were reduced in virus isolated from obese compared to lean controls. Taken together, nutrition appears to alter the course of alphavirus infection and should be considered as a critical environmental factor during outbreaks.

The Association of Medication Knowledge and Adherence Scores With Hospital Readmission.

Introduction: Readmission scoring systems are used to predict 30-day hospital readmission. These prediction tools do not considerlack of patient medication knowledge or adherence which can worsen disease outcomes or increase risk of readmissions. Objective: To determine if medication knowledge and adherence, as assessed by validated questionnaires, are associated with an increased rate of 30-day readmission. Methods: Adult medical inpatients were randomly selected for a prospective, single center study that was conducted from January to August 2017. Patients were asked the 4-question Morisky Green Levine Scale (MGLS) and the 4-question Medication Knowledge Score (MKS). Validated readmission score; MKS; and MGLS, as well as baseline information and readmission status within 30 days after the index admission were recorded. Mean or median scores were compared for patients readmitted within 30 days with those not readmitted using descriptive and univariate inferential statistics. Results: Data from 119 patients showed a mean age of 63 years (SD = 16). There was no difference in baseline information: age, sex, or number of scheduled home medications between those readmitted within 30 days and those not readmitted. Patients readmitted within 30 days had a statistically higher readmission score compared to patients not readmitted (66.4 vs 57.1, P = .017). There was no difference in median MKS or mean MGLS between patients readmitted within 30 days and those not readmitted (MKS: 4.0 vs 3.0, P = .753; MGLS: 1 vs 1.3, P = .162). Conclusions: In this prospective study, neither the MKS nor the MGLS scores were associated with 30-day hospital readmission.

Is rectus abdominis thickness associated with survival among patients with liver cirrhosis? A prospective cohort study.

Sarcopenia may affect patients with liver cirrhosis and worsen disease outcomes. To evaluate ultrasound-measured psoas major (PM) and rectus abdominis (RA) thickness for predicting survival among patients with liver cirrhosis. Prospective cohort study in a tertiary-level hospital. 61 patients with liver cirrhosis were prospectively included during a 15-month period and followed up for at least six months. Cirrhosis was classified using the Child-Pugh score. Sarcopenia was assessed using surrogate parameters: handgrip strength (HGS), mid-arm muscle circumference (MAMC) and SGA (subjective global assessment). We used ultrasound to measure RA and PM thickness at admission. There were 41 men. The patients' mean age was 58.03 ± 10.8 years. 26.22% of them were Child-Pugh A, 45.9% B and 27.86% C. The patients were followed up for 11.9 ± 5.63 months. RA thickness correlated moderately with MAMC (r = 0. 596; P < 0.0001) and HGS (r = 0.515; P < 0.0001) and decreased with increasing SGA class (A, 10.6 ± 2.8 mm; B, 8.3 ± 1.9 mm; C, 6.5 ± 1.9 mm; P < 0.0001). Survival at six months was independently predicted by using the model for end-stage liver disease-serum sodium score (odds ratio, OR 1.305; 95% OR confidence interval 1.083-1.572; P = 0.005). Survival during follow-up was independently predicted by RA thickness (hazard ratio, HR 0.701; 95% HR confidence interval 0.533-0.922; P = 0.011) and ascites (HR 1.876; 95% HR confidence interval 1.078-3.267; P = 0.026). PM thickness did not have any predictive value. As a surrogate marker of sarcopenia, RA thickness may predict survival among patients with liver cirrhosis.

Disruption of splenic nerve‐to‐spleen neurotransmission worsens disease outcome in a murine model of systemic lupus erythematosus

Aberrant chronic inflammation can usually be counteracted by endogenous mechanisms; however, such mechanisms may be impaired in the development of hypertension and renal injury. These anti‐inflammatory pathways involve the autonomic nervous system but it is unclear which branch is primarily responsible for quelling inflammation in chronic inflammatory conditions. The cholinergic anti‐inflammatory pathway is a compensatory mechanism thought to include a direct anatomical connection between the parasympathetic vagus and the sympathetic splenic nerve. Although this route of neurotransmission is controversial, we have evidence that stimulation of both of these nerves individually results in a decrease in the production and release of pro‐inflammatory cytokines from splenic immune cells. Our preliminary findings also indicate that chemical splenic denervation may disrupt anti‐inflammatory mechanisms, suggesting an important sympathetic component. In order to confirm this we removed the spleen from mice with systemic lupus erythematosus (SLE), a model of chronic inflammation, hypertension and renal injury, and hypothesized that splenectomy would further disrupt sympathetic neurotransmission within the cholinergic anti‐inflammatory pathway and result in worsened disease outcome. Female SLE mice were subjected to splenectomy or sham surgery (n = 10–12/group) at 31 weeks of age before being implanted with arterial catheters, blood pressure measurement and subsequently euthanization 4 weeks later. Anti‐double‐stranded autoantibodies, the hallmark of SLE, were not different amongst sham and splenectomized mice (4.8e5 ± 8.1e4 vs. 4.6e5 ± 5.4e4 activity units; p = 0.857), and neither was body weight (41.6 ± 2.0 vs. 40.1 ± 1.1 g; p = 0.497). However the incidence of albuminuria [&gt; 300 mg/dL; 42% (5 out of 12) vs. 33% (3 out of 9)] and leukocytes in the urine [50% (6 out of 12) vs. 33% (3 out of 9)] was elevated in splenectomized SLE mice compared to sham‐operated SLE mice. Although blood pressure was not different between sham‐operated and splenectomized SLE mice (131 ± 2 vs. 134 ± 7 mmHg; p = 0.815), there was an increase in mortality following splenectomy [33% (4 out of 12) vs. 10% (1 out of 10)]. In summary, although further studies are needed to confirm the effect splenectomy on inflammation in SLE mice we found that splenectomy exacerbated the progression of SLE disease. This suggests that the sympathetic component of the cholinergic anti‐inflammatory pathway may be important in combating the inflammation in SLE. Taken together, our studies on vagus nerve stimulation, splenic nerve stimulation and denervation and splenectomy in SLE mice suggest critical interactions between autonomic branches that may be impaired during chronic inflammation. Future studies may use technology like direct vagal stimulation via central injections and designer receptors exclusively activated by designer drugs (DREADDs) to further characterize the importance of these autonomic nervous system‐mediated pathways.Support or Funding InformationFunded by NIH 1K01HL139869 and the Lupus Research Alliance Novel Disease GrantThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

IL-17A/F in Leishmania major-resistant C57BL/6 mice.

Proinflammatory IL-17 plays an important role in various diseases and defence against extracellular microorganisms. Healing of leishmaniasis is promoted by Th1/Tc1 cells, whereas Th2/Treg are associated with worsened disease outcome. In addition, high expression of IL-17A in Leishmania-susceptible BALB/c and artificial overexpression of IL-17A in T cells in resistant C57BL/6 mice worsened disease outcome. Since C57BL/6 mice lacking only IL-17A exhibited no phenotype, and IL-17A and IL-17F share similar receptors, but differentially regulate chemokine secretion, we studied mice lacking both IL-17A and IL-17F (IL-17A/F-/- ) in infections with Leishmania major. Interestingly, lesion volumes and parasite burdens were comparable to controls, IL-17A/F-/- mice developed a Th1/Tc1 phenotype, and exhibited normal lesion resolution. Thus, in C57BL/6 mice, secretion of IL-17A and IL-17F does not influence disease progression. It appears that-depending on the genetic background-cytokines of the IL-17 family might be responsible for disease progression primarily in susceptible mice.

'I should not feed such a weak woman'. Intimate partner violence among women living with podoconiosis: A qualitative study in northern Ethiopia.

BackgroundIntimate Partner Violence (IPV) is a serious, preventable public health problem that affects millions of people worldwide. Research indicates that adults suffering from long term, disabling conditions are more likely to be victims of IPV due to the intersection of disease-associated stigma and discrimination. IPV in turn is known to worsen the overall health and wellbeing of those affected by it. Little research however explores the relationship between neglected tropical diseases such as podoconiosis and IPV. This study explores the relationship between IPV and podoconiosis in northern Ethiopia with the aim of identifying new avenues for limiting disability and promoting the wellbeing of people affected by this neglected tropical disease.MethodsThe study was conducted in East and West Gojjam zones, located in the Amhara Regional State of Ethiopia. Research participants were first screened using the domestic violence screening tool Hurt-Insult-Threaten-Scream (HITS). Data were collected by native speakers of the local language (Amharic) in the form of semi-structured interviews during January and February 2016. Thematic and content data analysis was carried out, using the Open Code 3.4 qualitative data analysis software for coding.ResultsA total of 15 women living with podoconiosis and experiencing IPV were interviewed (aged 31 to 75). Women experienced different forms of IPV, including beatings (with or without an object), insults, name calling, undermining, denial of equal rights over common assets, movement monitoring, cheating, abandonment, forced divorce, obstruction of health care access, inhibition of decision-making and sexual coercion. Podoconiosis increases the frequency and severity of IPV and in occasions shapes a change from physical to psychological and financial violence. In turn, frequent episodes of IPV worsen disease outcomes and contribute to disease persistence in the region, in that these impede women’s ability to manage the disease and help perpetuate the conditions of poverty that influence disease onset.ConclusionsWomen living with podoconiosis are victims of various, overlapping forms of IPV that negatively impact their health and wellbeing. Poverty, scarce IPV prevention services in the area together with a social acceptance of IPV and these women’s decreased ability to work due to the debilitating effects of podoconiosis and childcare responsibilities frequently prompt these women to tolerate IPV and remain in abusive relationships. Tackling disease-associated taboo and stigma, developing accessible IPV interventions, working towards greater gender equality at the household and societal levels and developing sustainable strategies for improving the socio-economic assets of women affected by podoconiosis are all necessary to both prevent IPV and to improve disease outcome.

Early inhibition of endothelial retinoid uptake upon myocardial infarction restores cardiac function and prevents cell, tissue, and animal death

Physiologically, following myocardial infarction (MI), retinoid levels elevate locally in the infarcted area. Whereas therapeutic systemic application of retinoids was shown to reduce the progression of ventricular dilatation and the onset of heart failure, the role of acute physiologically increased retinoids in the infarction zone is unknown to date. To reveal the role of local retinoids in the MI zone is the central aim of this study. Using human cell culture and co-culture models for hypoxia as well as various assays systems, lentivirus-based transgene expression, in silico molecular docking studies, and an MI model in rats, we analysed the impact of the retinoid all-trans retinoic acid (ATRA) on cell signalling, cell viability, tissue survival, heart function, and MI-induced death in rats. Based on our results, ATRA-mediated signalling does aggravate the MI phenotype (e.g. 2.5-fold increased mortality compared to control), whereas 5′-methoxyleoligin (5ML), a new agent which interferes with ATRA-signalling rescues the ATRA-dependent phenotype. On the molecular level, ATRA signalling causes induction of TXNIP, a potent inhibitor of the physiological antioxidant thioredoxin (TRX1) and sensitizes cells to necrotic cell death upon hypoxia. 5ML-mediated prevention of ATRA effects were shown to be based on the inhibition of cellular ATRA uptake by interference with the cholesterol (and retinol) binding motif of the transmembrane protein STRA6. 5ML-mediated inhibition of ATRA uptake led to a strong reduction of ATRA-dependent gene expression, reduced ROS formation, and protection from necrotic cell death. As 5ML exerted a cardioprotective effect, also independent of its inhibition of cellular ATRA uptake, the agent likely has another cardioprotective property, which may rely on the induction of TRX1 activity. In summary, this is the first study to show i) that local retinoids in the early MI zone may worsen disease outcome, ii) that inhibition of endothelial retinoid uptake using 5ML may constitute a novel treatment strategy, and iii) that targeting endothelial and myocardial retinoid uptake (e.g. via STRA6 inhibition) may constitute a novel treatment target in acute MI.

Disruption of GPR35 Exacerbates Dextran Sulfate Sodium-Induced Colitis in Mice.

G protein-coupled receptor 35 (GPR35) is an orphan receptor and is vastly expressed in immune cells and gastrointestinal cells, suggesting the potential physiological importance of GPR35 in these cells. Here, we tested the hypothesis that the lack of GPR35 expression in the colon mucosa exacerbates the severity of dextran sulfate sodium (DSS)-induced experimental colitis in mice. Colitis was induced in GPR35 wild-type (GPR35+/+) and GPR35 knockout (GPR35-/-) mice through the administration of DSS in drinking water for 5days followed by regular facility water for 1day. Induction of colitis was evaluated by measuring relative body weight loss, clinical illness scores, and morphological changes in the colon. Abolition of Gpr35 gene expression in the colon mucosa of GPR35-/- mice was confirmed by quantitative real-time PCR (qPCR). Gene expressions of inflammatory and tissue remodeling cytokines were detected by qPCR. Human colorectal epithelial Caco cells were transfected with siRNA against GPR35 before treated with 1% DSS in vitro. Protein expressions were measured using Western blot. GPR35-/- mice receiving DSS showed a significantly worsened colitis disease with profound loss of body weight and a considerable amount of severe clinical illness compared to GPR35+/+ mice that received DSS. The histology of colon sections from GPR35-/- mice showed extensive pathological changes including submucosal edema, diffuse ulcerations, and evidence of complete loss of crypts compared to wild-type mice. The mean histopathological score was significantly higher in GPR35-/- mice as compared to GPR35+/+ mice. The qPCR data revealed significant expression of pro-inflammatory and tissue remodeling cytokines in GPR35-/- colon mucosa, including IL-1β, CXCL1, CXCL2, CCL2, HMGB1, TGFβ1, TGFβ3, MMP1/9/12. The protein expressions of Zonula occludens-1, E-cadherin, Claudin1 were decreased upon knocking down GPR35 with or without 1% DSS treatment. Our experimental data suggest that lack of GPR35 resulted in worsened disease outcome in DSS-induced experimental colitis, indicating that GPR35 could play a crucial role in protecting from colonic inflammation and serve as a therapeutic target.

In Atp7b−/− Mice Modeling Wilson’s Disease Liver Repopulation With Bone Marrow-Derived Myofibroblasts or Inflammatory Cells and Not Hepatocytes Is Deleterious

In Wilson's disease, Atp7b mutations impair copper excretion with liver or brain damage. Healthy transplanted hepatocytes repopulate the liver, excrete copper, and reverse hepatic damage in animal models of Wilson's disease. In Fah-/- mice with tyrosinemia and α-1 antitrypsin mutant mice, liver disease is resolved by expansions of healthy hepatocytes derived from transplanted healthy bone marrow stem cells. This potential of stem cells has not been defined for Wilson's disease. In diseased Atp7b-/- mice, we reconstituted bone marrow with donor cells expressing green fluorescent protein reporter from healthy transgenic mice. Mature hepatocytes originating from donor bone marrow were identified by immunostaining for green fluorescence protein and bile canalicular marker, dipeptidylpeptidase-4. Mesenchymal and inflammatory cell markers were used for other cells from donor bone marrow cells. Gene expression, liver tests, and tissues were analyzed for outcomes in Atp7b-/- mice. After bone marrow transplantation in Atp7b-/- mice, donor-derived hepatocytes containing bile canaliculi appeared within weeks. Despite this maturity, donor-derived hepatocytes neither divided nor expanded. The liver of Atp7b-/- mice was not repopulated by donor-derived hepatocytes: Atp7b mRNA remained undetectable; liver tests, copper content, and fibrosis actually worsened. Restriction of proliferation in hepatocytes accompanied oxidative DNA damage. By contrast, donor-derived mesenchymal and inflammatory cells extensively proliferated. These contributed to fibrogenesis through greater expression of inflammatory cytokines. In Wilson's disease, donor bone marrow-derived cells underwent different fates: hepatocytes failed to proliferate; inflammatory cells proliferated to worsen disease outcomes. This will help guide stem cell therapies for conditions with proinflammatory or profibrogenic microenvironments.

Correction: Macrophages, but not neutrophils, are critical for proliferation of Burkholderia cenocepacia and ensuing host-damaging inflammation.

[This corrects the article DOI: 10.1371/journal.ppat.1006437.].

Macrophages, but not neutrophils, are critical for proliferation of Burkholderia cenocepacia and ensuing host-damaging inflammation.

Bacteria of the Burkholderia cepacia complex (Bcc) can cause devastating pulmonary infections in cystic fibrosis (CF) patients, yet the precise mechanisms underlying inflammation, recurrent exacerbations and transition from chronic stages to acute infection and septicemia are not known. Bcc bacteria are generally believed to have a predominant extracellular biofilm life style in infected CF lungs, similar to Pseudomonas aeruginosa, but this has been challenged by clinical observations which show Bcc bacteria predominantly in macrophages. More recently, Bcc bacteria have emerged in nosocomial infections of patients hospitalized for reasons unrelated to CF. Research has abundantly shown that Bcc bacteria can survive and replicate in mammalian cells in vitro, yet the importance of an intracellular life style during infection in humans is unknown. Here we studied the contribution of innate immune cell types to fatal pro-inflammatory infection caused by B. cenocepacia using zebrafish larvae. In strong contrast to the usual protective role for macrophages against microbes, our results show that these phagocytes significantly worsen disease outcome. We provide new insight that macrophages are critical for multiplication of B. cenocepacia in the host and for development of a fatal, pro-inflammatory response that partially depends on Il1-signalling. In contrast, neutrophils did not significantly contribute to disease outcome. In subcutaneous infections that are dominated by neutrophil-driven phagocytosis, the absence of a functional NADPH oxidase complex resulted in a small but measurably higher increase in bacterial growth suggesting the oxidative burst helps limit bacterial multiplication; however, neutrophils were unable to clear the bacteria. We suggest that paradigm-changing approaches are needed for development of novel antimicrobials to efficiently disarm intracellular bacteria of this group of highly persistent, opportunistic pathogens.

YO-10 - ROS is the boss

The production of reactive oxygen species (ROS) via the oxidative burst has been connected with promotion of inflammation and tissue damage, but in recent years has been implicated in regulation of inflammation. We investigated the effects of ROS on the murine model of lupus and in patients (SLE). The aim of this project was to elucidate the impact of the oxidative burst on the development of lupus-like autoimmunity. Lupus was induced by i.p. injection of pristane oil. Ex vivo phagocytosis assays were deployed to assess the uptake of cell debris in ROS deficient mice. The formation of neutrophil extracellular traps (NETs) was analysed by immune fluorescence microscopy. ROS activators were injected into mice to investigate the possible beneficial clinical effects on lupus pathology. The absence of ROS gives rise to dramatically exacerbated lupus. Aberrant phagocytosis in ROS-deficient animals leading to production of inflammatory mediators, accompanied by diminished pristane-induced but higher spontaneous formation of NETs could be responsible for this phenotype. Treatment with NOX2 agonists ameliorated the clinical course in mice, while application of a ROS scavenger worsened disease outcome. A fine-tuned balance of ROS-production is necessary to prevent autoimmunity and to avert the development of lupus in mice and men.

Species dependent impact of helminth-derived antigens on human macrophages infected with Mycobacterium tuberculosis: Direct effect on the innate anti-mycobacterial response.

BackgroundIn countries with a high prevalence of tuberculosis there is high coincident of helminth infections that might worsen disease outcome. While Mycobacterium tuberculosis (Mtb) gives rise to a pro-inflammatory Th1 response, a Th2 response is typical of helminth infections. A strong Th2 response has been associated with decreased protection against tuberculosis.Principal findingsWe investigated the direct effect of helminth-derived antigens on human macrophages, hypothesizing that helminths would render macrophages less capable of controlling Mtb. Measuring cytokine output, macrophage surface markers with flow cytometry, and assessing bacterial replication and phagosomal maturation revealed that antigens from different species of helminth directly affect macrophage responses to Mtb. Antigens from the tapeworm Hymenolepis diminuta and the nematode Trichuris muris caused an anti-inflammatory response with M2-type polarization, reduced macrophage phagosome maturation and ability to activate T cells, along with increased Mtb burden, especially in T. muris exposed cells which also induced the highest IL-10 production upon co-infection. However, antigens from the trematode Schistosoma mansoni had the opposite effect causing a decrease in IL-10 production, M1-type polarization and increased control of Mtb.ConclusionWe conclude that, independent of any adaptive immune response, infection with helminth parasites, in a species-specific manner can influence the outcome of tuberculosis by either enhancing or diminishing the bactericidal function of macrophages.

Chronic high-dose glucocorticoid therapy triggers the development of chronic organ damage and worsens disease outcome in systemic lupus erythematosus.

Long-term survival of patients with systemic lupus erythematosus (SLE) improved worldwide; thus, prevention of cumulative organ damage became a major goal in disease management. The aim of our study was to investigate the chronic organ damages and their influence on disease outcome in SLE. We evaluated clinical conditions, laboratory findings and medications of 357 consecutive SLE patients and assessed their impact on Systemic Lupus Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI) and disease outcome. We detected one or more SDI scores in 77.87% of patients. Patients with disease duration of more than 10years and subjects diagnosed at age above 40 had significantly higher SDI values. The most frequent damages were valvulopathies, cognitive dysfunction, angina pectoris and venous thrombosis. Higher cumulative glucocorticoid dose increased SDI, while chloroquin treatment was favourable for patients. Male gender, elevated SDI scores and higher cumulative doses of glucocorticoids increased mortality risk. Our data confirmed that disease duration, age at diagnosis and chronic high-dose glucocorticoid therapy have significant effects on the development of chronic organ damage. Higher SDI score is characterized with worse survival ratios. The most common chronic organ damages affected the cardiovascular or neuropsychiatric system. As long-term survival in SLE improves, it becomes increasingly important to identify the determinants of chronic organ damage. Most of the chronic organ damage occurs in the cardiovascular and the neuropsychiatric systems; thus, regular follow-up, screening and adequate therapy are essential for the best clinical outcome.

106 - ROS Ameriolates the Clinical Course of Murine Lupus

The production of reactive oxygen species (ROS) via the oxidative burst has in the traditional view been connected with promotion of inflammation and tissue damage, but has in recent years also been implicated in regulation of inflammation and protection from autoimmunity. We have investigated the effects of ROS on the autoimmunity in a mouse model of lupus and in patients with systemic lupus erythematosus (SLE). Aims The aim of this project was to elucidate the impact of the oxidative burst on the development of lupus-like autoimmunity in wild type and Ncf1** mice which carry a point mutation in one of the subunits of the phagocyte NADPH oxidase 2 complex that abrogates ROS-production. Lupus was induced by intraperitoneal injection of 0.5 ml pristane oil and the clinical course was compared by analysis of serological markers and organ involvement. Ex vivo phagocytosis assays and flow cytometry were deployed to assess uptake of cell debris in ROS deficient mice. The formation of neutrophil extracellular traps (NETs) was analysed by immune fluorescence microscopy. Potential activators of ROS production were injected into mice to investigate the possible beneficial clinical effects on lupus pathology. Results Our results show that the absence of ROS in Ncf1** mice gives rise to dramatically exacerbated lupus. Aberrant phagocytosis in ROS-deficient animals leading to production of inflammatory mediators, accompanied by diminished pristane-induced but higher spontaneous formation of NETs could be responsible for this phenotype. Treatment of pristane-induced lupus with NOX2 agonists ameliorated the clinical course in BALB/c mice, while application of a ROS scavenger worsened disease outcome. Further, downstream nrf2 signalling was decreased in Ncf1** mice. Patients with SLE showed similar aberrant phagocytosis as in murine lupus, and were characterized by higher spontaneous formation of NETs. A fine-tuned balance of ROS-production is necessary to prevent autoimmunity and to avert the development of lupus in mice and men.

Leishmaniavirus-Dependent Metastatic Leishmaniasis Is Prevented by Blocking IL-17A

Cutaneous leishmaniasis has various outcomes, ranging from self-healing reddened papules to extensive open ulcerations that metastasise to secondary sites and are often resistant to standard therapies. In the case of L. guyanensis (L.g), about 5–10% of all infections result in metastatic complications. We recently showed that a cytoplasmic virus within L.g parasites (LRV1) is able to act as a potent innate immunogen, worsening disease outcome in a murine model. In this study, we investigated the immunophenotype of human patients infected by L.g and found a significant association between the inflammatory cytokine IL-17A, the presence of LRV1 and disease chronicity. Further, IL-17A was inversely correlated to the protective cytokine IFN-γ. These findings were experimentally corroborated in our murine model, where IL-17A produced in LRV1+ L.g infection contributed to parasite virulence and dissemination in the absence of IFN-γ. Additionally, IL-17A inhibition in mice using digoxin or SR1001, showed therapeutic promise in limiting parasite virulence. Thus, this murine model of LRV1-dependent infectious metastasis validated markers of disease chronicity in humans and elucidated the immunologic mechanism for the dissemination of Leishmania parasites to secondary sites. Moreover, it confirms the prognostic value of LRV1 and IL-17A detection to prevent metastatic leishmaniasis in human patients.

Abstract 1888: Protein kinase C beta II suppresses colorectal cancer by regulating IGF1 mediated cell survival

Abstract Despite extensive efforts, cancer therapies directed at the Protein Kinase C (PKC) family of serine/threonine kinases have failed in clinical trials. These therapies have been directed at inhibiting PKC and have, in some cases, worsened disease outcome. Here we examine colon cancer patients and show not only that PKC Beta II is a tumour suppressor, but patients with low levels of this isozyme have significantly decreased disease free survival. Specifically, analysis of gene expression levels of all PKC genes in matched normal and cancer tissue samples from colon cancer patients revealed a striking down-regulation of the gene coding PKC Beta in the cancer tissue (n = 21). Tissue microarray analysis revealed a dramatic down-regulation of PKC Beta II protein levels in both the epithelial and stromal diseased tissue (n = 166). Of clinical significance, low levels of the protein in the normal tissue of patients is associated with a low (10%) 10 year survival compared with a much higher (60%) survival in patients with relatively high levels of the protein. Consistent with PKC Beta II levels protecting against colon cancer, overexpression of PKC Beta II in colon cancer cell lines reveals that PKC Beta II reverses transformation in cell based assays. Further to this, activation of PKC Beta II in an IGF-1 dependent manor showed a downregulation of AKT, indicating a role for PKCs in regulating IGF-1 mediated cell survival. Thus, PKC Beta II is a tumour suppressor in colon cancer and low levels serve as a predictor for poor survival outcome. Citation Format: Catriona M. Dowling, James Phelan, Julia A. Callender, Mary Clare Cathcart, Brian Mehigan, Paul McCormick, Tara Dalton, John C. Coffey, Alexandra C. Newton, Jacintha O’Sullivan, Patrick A. Kiely. Protein kinase C beta II suppresses colorectal cancer by regulating IGF1 mediated cell survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1888.

Protein kinase C beta II suppresses colorectal cancer by regulating IGF-1 mediated cell survival.

Despite extensive efforts, cancer therapies directed at the Protein Kinase C (PKC) family of serine/threonine kinases have failed in clinical trials. These therapies have been directed at inhibiting PKC and have, in some cases, worsened disease outcome. Here we examine colon cancer patients and show not only that PKC Beta II is a tumour suppressor, but patients with low levels of this isozyme have significantly decreased disease free survival. Specifically, analysis of gene expression levels of all PKC genes in matched normal and cancer tissue samples from colon cancer patients revealed a striking down-regulation of the gene coding PKC Beta in the cancer tissue (n = 21). Tissue microarray analysis revealed a dramatic down-regulation of PKC Beta II protein levels in both the epithelial and stromal diseased tissue (n = 166). Of clinical significance, low levels of the protein in the normal tissue of patients is associated with a low (10%) 10 year survival compared with a much higher (60%) survival in patients with relatively high levels of the protein. Consistent with PKC Beta II levels protecting against colon cancer, overexpression of PKC Beta II in colon cancer cell lines reveals that PKC Beta II reverses transformation in cell based assays. Further to this, activation of PKC Beta II results in a dramatic downregulation of IGF-I-induced AKT, indicating a role for PKCs in regulating IGF-1 mediated cell survival. Thus, PKC Beta II is a tumour suppressor in colon cancer and low levels serve as a predictor for poor survival outcome.