Long-Term Predictive Validity of the Juvenile Sex Offender Assessment Protocol-II: Research and Practice Implications.

The current study evaluated the predictive validity of the Juvenile Sex Offender Assessment Protocol-II (J-SOAP-II) scores in a sample of juveniles who recidivated sexually or nonsexually as adults. Participants included 166 juveniles who had previously sexually offended and were followed into adulthood for an average of 10.75 years. Results of area under the receiver operating characteristic curve (AUC) analyses supported the predictive validity of the J-SOAP-II Total Score, Scale 1, and Static Score in regard to adult sexual recidivism, and predictive validity was found for all J-SOAP-II scores (except Scale 1) in regard to adult nonsexual recidivism. Implications for future research on the assessment of risk factors and treatment needs for adolescents who commit sexual offenses are discussed.

Respiratory syncytial virus infection of newborn CX3CR1-deficient mice induces a pathogenic pulmonary innate immune response.

Respiratory syncytial virus (RSV) infects almost all infants by 2 years of age, and severe bronchiolitis resulting from RSV infection is the primary cause of hospitalization in the first year of life. Among infants hospitalized due to RSV-induced bronchiolitis, those with a specific mutation in the chemokine receptor CX3CR1, which severely compromises binding of its ligand CX3CL1, were at a higher risk for more severe viral bronchiolitis than those without the mutation. Here, we show that RSV infection of newborn mice deficient in CX3CR1 leads to significantly greater neutrophilic inflammation in the lungs, accompanied by an increase in mucus production compared with that induced in WT mice. Analysis of innate and adaptive immune responses revealed an early increase in the number of IL-17+ γδ T cells in CX3CR1-deficient mice that outnumbered IFN-γ+ γδ T cells as well as IFN-γ+ NK cells, IFN-γ being host protective in the context of RSV infection. This bias toward IL-17+ γδ T cells persisted at a later time. The lungs of CX3CR1-deficient mice expressed higher levels of IL-1ß mRNA and protein, and blockade of IL-1ß signaling using IL-1 receptor antagonist significantly reduced the number of IL-17+ γδ T cells in the lungs of infected mice. Blockade of IL-17RC abolished RSV-induced lung pathology in infected CX3CR1-deficient mice. We propose that, in infants harboring mutant CX3CR1, targeting the IL-17R may minimize disease severity and hospitalization in early life.

Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias.

We previously showed that Th1/type 1 inflammation marked by increased IFN-γ levels in the airways can be appreciated in 50% of patients with severe asthma, despite high dose corticosteroid (CS) treatment. We hypothesized that a downstream target of IFN-γ, CXCL10, which recruits Th1 cells via the cognate receptor CXCR3, is an important contributor to Th1high asthma and CS unresponsiveness. We show high levels of CXCL10 mRNA closely associated with IFNG levels in the BAL cells of 50% of severe asthmatics and also in the airways of mice subjected to a severe asthma model, both in the context of high-dose CS treatment. The inability of CS to dampen IFNG or CXCL10 expression was not because of impaired nuclear translocation of the glucocorticoid receptor (GR) or its transactivational functions. Rather, in the presence of CS and IFN-γ, STAT1 and GR were recruited on critical regulatory elements in the endogenous CXCL10 promoter in monocytes, albeit without any abatement of CXCL10 gene expression. High CXCL10 gene expression was also associated with a mast cell signature in both humans and mice, CXCR3 being also expressed by mast cells. These findings suggest that the IFN-γ-CXCL10 axis plays a central role in persistent type 1 inflammation that may be facilitated by CS therapy through GR-STAT1 cooperation converging on the CXCL10 promoter.

IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice.

Severe asthma (SA) is a significant problem both clinically and economically, given its poor response to corticosteroids (CS). We recently reported a complex type 1-dominated (IFN-γ-dominated) immune response in more than 50% of severe asthmatics despite high-dose CS treatment. Also, IFN-γ was found to be critical for increased airway hyperreactivity (AHR) in our model of SA. The transcription factor IRF5 expressed in M1 macrophages can induce a Th1/Th17 response in cocultured human T cells. Here we show markedly higher expression of IRF5 in bronchoalveolar lavage (BAL) cells of severe asthmatics as compared with that in cells from milder asthmatics or healthy controls. Using our SA mouse model, we demonstrate that lack of IRF5 in lymph node migratory DCs severely limits their ability to stimulate the generation of IFN-γ- and IL-17-producing CD4+ T cells and IRF5-/- mice subjected to the SA model displayed significantly lower IFN-γ and IL-17 responses, albeit showing a reciprocal increase in Th2 response. However, the absence of IRF5 rendered the mice responsive to CS with suppression of the heightened Th2 response. These data support the notion that IRF5 inhibition in combination with CS may be a viable approach to manage disease in a subset of severe asthmatics.

The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia.

Bacterial pneumonia is a significant healthcare burden worldwide. Failure to resolve inflammation after infection precipitates lung injury and an increase in morbidity and mortality. Gram-negative bacteria are common in pneumonia and increased levels of the mito-damage-associated molecular pattern (DAMP) cardiolipin can be detected in the lungs. Here we show that mice infected with Klebsiella pneumoniae develop lung injury with accumulation of cardiolipin. Cardiolipin inhibits resolution of inflammation by suppressing production of anti-inflammatory IL-10 by lung CD11b+Ly6GintLy6CloF4/80+ cells. Cardiolipin induces PPARγ SUMOylation, which causes recruitment of a repressive NCOR/HDAC3 complex to the IL-10 promoter, but not the TNF promoter, thereby tipping the balance towards inflammation rather than resolution. Inhibition of HDAC activity by sodium butyrate enhances recruitment of acetylated histone 3 to the IL-10 promoter and increases the concentration of IL-10 in the lungs. These findings identify a mechanism of persistent inflammation during pneumonia and indicate the potential of HDAC inhibition as a therapy.

Mitochondrial H2O2 in Lung Antigen-Presenting Cells Blocks NF-κB Activation to Prevent Unwarranted Immune Activation.

Inhalation of environmental antigens such as allergens does not always induce inflammation in the respiratory tract. While antigen-presenting cells (APCs), including dendritic cells and macrophages, take up inhaled antigens, the cell-intrinsic molecular mechanisms that prevent an inflammatory response during this process, such as activation of the transcription factor NF-κB, are not well understood. Here, we show that the nuclear receptor PPARγ plays a critical role in blocking NF-κB activation in response to inhaled antigens to preserve immune tolerance. Tolerance induction promoted mitochondrial respiration, generation of H2O2, and suppression of NF-κB activation in WT, but not PPARγ-deficient, APCs. Forced restoration of H2O2 in PPARγ-deficient cells suppressed IκBα degradation and NF-κB activation. Conversely, scavenging reactive oxygen species from mitochondria promoted IκBα degradation with loss of regulatory and promotion of inflammatory T cell responses in vivo. Thus, communication between PPARγ and the mitochondria maintains immune quiescence in the airways.

High IFN-γ and low SLPI mark severe asthma in mice and humans.

Severe asthma (SA) is a challenge to control, as patients are not responsive to high doses of systemic corticosteroids (CS). In contrast, mild-moderate asthma (MMA) is responsive to low doses of inhaled CS, indicating that Th2 cells, which are dominant in MMA, do not solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and SA patients and determined that IFN-γ (Th1) immune responses are exacerbated in the airways of individuals with SA, with reduced Th2 and IL-17 responses. We developed a protocol that recapitulates the complex immune response of human SA, including the poor response to CS, in a murine model. Compared with WT animals, Ifng-/- mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. Conversely, AHR was not reduced in Il17ra-/- mice, although airway inflammation was lower. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells, and IFN-γ inversely correlated with SLPI expression in SA patients and the mouse model. In mice subjected to our SA model, forced SLPI expression decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Our study identifies a distinct immune response in SA characterized by a dysregulated IFN-γ/SLPI axis that affects lung function.

Cutting Edge: MMP-9 inhibits IL-23p19 expression in dendritic cells by targeting membrane stem cell factor affecting lung IL-17 response.

We reported previously that c-kit ligation by membrane-bound stem cell factor (mSCF) boosts IL-6 production in dendritic cells (DCs) and a Th17-immune response. However, Th17 establishment also requires heterodimeric IL-23, but the mechanisms that regulate IL-23 gene expression in DCs are not fully understood. We show that IL-23p19 gene expression in lung DCs is dependent on mSCF, which is regulated by the metalloproteinase MMP-9. Th1-inducing conditions enhanced MMP-9 activity, causing cleavage of mSCF, whereas the opposite was true for Th17-promoting conditions. In MMP-9(-/-) mice, a Th1-inducing condition could maintain mSCF and enhance IL-23p19 in DCs, promoting IL-17-producing CD4(+) T cells in the lung. Conversely, mSCF cleavage from bone marrow DCs in vitro by rMMP-9 led to reduced IL-23p19 expression under Th17-inducing conditions, with dampening of intracellular AKT phosphorylation. Collectively, these results show that the c-kit/mSCF/MMP-9 axis regulates IL-23 gene expression in DCs to control IL-17 production in the lung.