Interleukin-17A Serves a Priming Role in Autoimmunity by Recruiting IL-1ß-Producing Myeloid Cells that Promote Pathogenic T Cells.

Interleukin-17A (IL-17A) is a major mediator of tissue inflammation in many autoimmune diseases. Anti-IL-17A is an effective treatment for psoriasis and is showing promise in clinical trials in multiple sclerosis. In this study, we find that IL-17A-defective mice or mice treated with anti-IL-17A at induction of experimental autoimmune encephalomyelitis (EAE) are resistant to disease and have defective priming of IL-17-secreting γδ T (γδT17) cells and Th17 cells. However, T cells from Il17a-/- mice induce EAE in wild-type mice following in vitro culture with autoantigen, IL-1ß, and IL-23. Furthermore, treatment with IL-1ß or IL-17A at induction of EAE restores disease in Il17a-/- mice. Importantly, mobilization of IL-1ß-producing neutrophils and inflammatory monocytes and activation of γδT17 cells is reduced in Il17a-/- mice. Our findings demonstrate that a key function of IL-17A in central nervous system (CNS) autoimmunity is to recruit IL-1ß-secreting myeloid cells that prime pathogenic γδT17 and Th17 cells.

PD-1 regulation of pathogenic IL-17-secreting γδ T cells in experimental autoimmune encephalomyelitis.

The PD-1-PD-L1 immune checkpoint helps to maintain self-tolerance and prevent the development of autoimmune diseases. Immune checkpoint inhibitors are successful immunotherapeutics for several cancers, but responding patients can develop immune-mediated adverse events. It is well established that PD-1 regulates CD4 and CD8 T-cell responses, but its role in controlling the activation of pathogenic γδ T cells is less clear. Here we examined the role of PD-1 in regulating γδ T cells in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We found that PD-1 was highly expressed on CD27- Vγ4 γδ T cells in the lymph node (LN) and CNS of mice with EAE. Treatment of mice with anti-PD-1 significantly augmented IL-17A-producing CD27- Vγ4 γδ T cells in the LN and CNS and enhanced the severity of EAE. The exacerbating effect of anti-PD-1 on EAE was lost in Tcrd-/- mice. Conversely, ligation of PD-1 suppressed Il17a and Rorc gene expression and IL-17A production by purified Vγ4 γδ T cells stimulated via the TCR, but not with IL-1ß and IL-23. Our study demonstrates that PD-1 regulates TCR-activated CD27- Vγ4 γδ T cells, but that cytokine-activated IL-17A producing γδ T cells escape the regulatory effects of the PD-1-PD-L1 pathway.

Therapeutic potential of targeting IL-17.

A June 2012 meeting in Dublin, Ireland, showcased advances in the understanding of the role of IL-17 and related cytokines in host immunity and how these cytokines have been successfully targeted for the treatment of autoimmunity.

Landscape Fire Air Pollution as a Mediator in Drought and Childhood Stunting Pathway in Low- and Middle-Income Countries.

Drought induces dry hazards, including wildfire, and increased air pollution from wildfire may be a mechanism by which drought increases health risks. We examined whether the drought-wildfire pathway increases the risk of childhood stunting. We analyzed all geocoded children under five across 44 low- and middle-income countries (LMICs). We first conducted mixed-effect regressions to examine the three pairwise associations between standardized precipitation evapotranspiration index (SPEI), fire-sourced PM2.5, and childhood stunting. We then employed a causal mediation analysis to determine whether compounding drought-wildfire (cascading or co-occurring) events significantly impact the drought-stunting pathway. We found that each 1-unit decrease in SPEI exposure was associated with a 2.16% [95% confidence interval (CI): 0.79, 3.49%] increase in stunting risk and 0.57 (95% CI 0.55, 0.59%) µg/m3 increase in fire-sourced PM2.5. Additionally, each 1 µg/m3 increase in 24 month average fire-sourced PM2.5 was associated with an increased risk of 2.46% (95% CI: 2.16, 2.76%) in stunting. Drought-mediated fires accounted for 26.7% (95% CI: 14.5, 36.6%) of the linkage between SPEI and stunting. Our study revealed fire-sourced PM2.5 is a mediator in the drought-stunting pathway in LMICs. To protect child health under increasing drought conditions, personal interventions against wildfire should be considered to enhance climate resilience.

Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity.

Th17 cells, CD4(+) T cells that secrete interleukin-17 (IL-17), are pathogenic in autoimmune diseases and their development and expansion is driven by the cytokines IL-6, TGF-beta, IL-21, IL-1, and IL-23. However, there are also innate sources of IL-17. Here, we show that gammadelta T cells express IL-23R and the transcription factor RORgammat and produce IL-17, IL-21, and IL-22 in response to IL-1beta and IL-23, without T cell receptor engagement. IL-17-producing gammadelta T cells were found at high frequency in the brain of mice with experimental autoimmune encephalomyelitis (EAE). gammadelta T cells activated by IL-1beta and IL-23 promoted IL-17 production by CD4(+) T cells and increased susceptibility to EAE, suggesting that gammadelta T cells act in an amplification loop for IL-17 production by Th17 cells. Our findings demonstrate that gammadelta T cells activated by IL-1beta and IL-23 are an important source of innate IL-17 and IL-21 and provide an alternative mechanism whereby IL-1 and IL-23 may mediate autoimmune inflammation.

Relative contribution of Th1 and Th17 cells in adaptive immunity to Bordetella pertussis: towards the rational design of an improved acellular pertussis vaccine.

Whooping cough caused by Bordetella pertussis is a re-emerging infectious disease despite the introduction of safer acellular pertussis vaccines (Pa). One explanation for this is that Pa are less protective than the more reactogenic whole cell pertussis vaccines (Pw) that they replaced. Although Pa induce potent antibody responses, and protection has been found to be associated with high concentrations of circulating IgG against vaccine antigens, it has not been firmly established that host protection induced with this vaccine is mediated solely by humoral immunity. The aim of this study was to examine the relative contribution of Th1 and Th17 cells in host immunity to infection with B. pertussis and in immunity induced by immunization with Pw and Pa and to use this information to help rationally design a more effective Pa. Our findings demonstrate that Th1 and Th17 both function in protective immunity induced by infection with B. pertussis or immunization with Pw. In contrast, a current licensed Pa, administered with alum as the adjuvant, induced Th2 and Th17 cells, but weak Th1 responses. We found that IL-1 signalling played a central role in protective immunity induced with alum-adsorbed Pa and this was associated with the induction of Th17 cells. Pa generated strong antibody and Th2 responses, but was fully protective in IL-4-defective mice, suggesting that Th2 cells were dispensable. In contrast, Pa failed to confer protective immunity in IL-17A-defective mice. Bacterial clearance mediated by Pa-induced Th17 cells was associated with cell recruitment to the lungs after challenge. Finally, protective immunity induced by an experimental Pa could be enhanced by substituting alum with a TLR agonist that induces Th1 cells. Our findings demonstrate that alum promotes protective immunity through IL-1ß-induced IL-17A production, but also reveal that optimum protection against B. pertussis requires induction of Th1, but not Th2 cells.

Total mercury concentrations in Tasman Sea mesopelagic fish: Exploring biotic and abiotic drivers.

Understanding mercury (Hg) concentrations in mesopelagic and mid-trophic fishes is important for assessing Hg accumulation in oceanic ecosystems and higher-order predators. This study measured total Hg (THg) concentrations in the whole body of 16 abundant mesopelagic fish species sampled in two distinct sites within the Tasman Sea. Across all species, total Hg concentrations ranged from 0.02 to 0.48 µg g-1 dry weight (0.01 to 0.15 µg g-1 wet weight). Total Hg concentrations varied with vertical migration patterns, with shallower migrators exhibiting higher THg. Females typically had statistically higher THg concentrations than males. Positive correlations between THg concentration and standard length were observed for some but not all species. At the community level, THg concentrations correlated positively with estimated trophic position and foraging habitat, as inferred by stable isotope values. These findings contribute to our understanding of Hg cycling in oceanic ecosystems and the potential for biomagnification in oceanic top-order predators.

IL-17-producing γδ T cells and innate lymphoid cells.

The inflammatory cytokine IL-17 plays a critical role in immunity to infection and is involved in the inflammatory pathology associated with certain autoimmune diseases, such as psoriasis and rheumatoid arthritis. While CD4(+) and CD8(+) T cells are important sources of this cytokine, recent evidence has suggested that γδ T cells and a number of families of innate lymphoid cells (ILCs) can secrete IL-17 and related cytokines. The production of IL-17 by γδ T cells appears to be largely independent of T-cell receptor activation and is promoted through cytokine signalling, in particular by IL-23 in combination with IL-1ß or IL-18. Therefore IL-17-secreting γδ T cells can be categorised as a family of cells similar to innate-like lymphoid cells. IL-17-secreting γδ T cells function as a part of mucosal defence against infection, with most studies to date focusing on their response to bacterial pathogens. γδ T cells also play a pathological role in certain autoimmune diseases, where they provide an early source of IL-17 and IL-21, which initiate responses mediated by conventional IL-17-secreting CD4(+) T cells (Th17 cells). ILCs lack an antigen receptor or other lineage markers, and ILC subsets that express the transcriptional factor RORγt have been found to secrete IL-17. Evidence is emerging that these newly recognised sources of IL-17 play both pathological and protective roles in inflammatory diseases as discussed in this article.

Escherichia coli heat-labile enterotoxin promotes protective Th17 responses against infection by driving innate IL-1 and IL-23 production.

Escherichia coli heat-labile enterotoxin (LT) is a powerful mucosal adjuvant; however, it is associated with toxic effects when delivered intranasally, and its mechanism of action is poorly understood. In this article, we demonstrate that LT acts as a highly effective adjuvant when administered parenterally, promoting Ag-specific IL-17, as well as IFN-γ, IL-4, and IL-10 production in response to coadministered Ags. We found that the adjuvant activity of LT was mediated in part by inducing dendritic cell (DC) activation; LT promoted CD80 and CD86 expression by DCs and enhanced IL-1α, IL-1ß, and IL-23 production. An LT mutant, LTK63, that lacks enzyme activity was less effective than the wild-type toxin in promoting DC maturation and the development of Ag-specific Th17 cells. LT enhanced IL-23 and IL-1α production from DCs via activation of ERK MAPK and IL-1ß secretion through activation of caspase-1 and the NLRP3 inflammasome. These cytokines played a major role in promoting Th17 responses by LT and LTK63. The induction of Th17 cells in vivo in response to LT and LTK63 as adjuvants was significantly reduced in IL-1RI-deficient mice. Finally, using a murine respiratory infection model, we demonstrated that LT can act as a highly effective adjuvant for a pertussis vaccine, promoting Ag-specific Th17 cells and protection against Bordetella pertussis challenge, which was significantly reduced in IL-17-defective mice. Our findings provide clear evidence that LT can promote protective immune responses in part through induction of innate IL-1 and, consequently, Th17 cells.

Caspase-1-processed cytokines IL-1beta and IL-18 promote IL-17 production by gammadelta and CD4 T cells that mediate autoimmunity.

IL-1ß plays a critical role in promoting IL-17 production by γδ and CD4 T cells. However, IL-1-targeted drugs, although effective against autoinflammatory diseases, are less effective against autoimmune diseases. Conversely, gain-of-function mutations in the NLRP3 inflammasome complex are associated with enhanced IL-1ß and IL-18 production and Th17 responses. In this study, we examined the role of caspase-1-processed cytokines in IL-17 production and in induction of experimental autoimmune encephalomyelitis (EAE). Killed Mycobacterium tuberculosis, the immunostimulatory component in CFA used for inducing EAE, stimulated IL-1ß and IL-18 production by dendritic cells through activation of the inflammasome complex and caspase-1. Dendritic cells stimulated with M. tuberculosis and myelin oligodendrocyte glycoprotein promoted IL-17 production by T cells and induced EAE following transfer to naive mice, and this was suppressed by a caspase-1 inhibitor and reversed by administration of IL-1ß or IL-18. Direct injection of the caspase-1 inhibitor suppressed IL-17 production by CD4 T cells and γδ T cells in vivo and attenuated the clinical signs of EAE. γδ T cells expressed high levels of IL-18R and the combination of IL-18 and IL-23, as with IL-1ß and IL-23, stimulated IL-17 production by γδ T cells, but also from CD4 T cells, in the absence of TCR engagement. Our findings demonstrate that caspase-1-processed cytokines IL-1ß and IL-18 not only promote autoimmunity by stimulating innate IL-17 production by T cells but also reveal redundancy in the functions of IL-1ß and IL-18, suggesting that caspase-1 or the inflammasome may be an important drug target for autoimmune diseases.

PYHIN protein IFI207 regulates cytokine transcription and IRF7 and contributes to the establishment of K. pneumoniae infection.

PYHIN proteins AIM2 and IFI204 sense pathogen DNA, while other PYHINs have been shown to regulate host gene expression through as-yet unclear mechanisms. We characterize mouse PYHIN IFI207, which we find is not involved in DNA sensing but rather is required for cytokine promoter induction in macrophages. IFI207 co-localizes with both active RNA polymerase II (RNA Pol II) and IRF7 in the nucleus and enhances IRF7-dependent gene promoter induction. Generation of Ifi207-/- mice shows no role for IFI207 in autoimmunity. Rather, IFI207 is required for the establishment of a Klebsiella pneumoniae lung infection and for Klebsiella macrophage phagocytosis. These insights into IFI207 function illustrate that PYHINs can have distinct roles in innate immunity independent of DNA sensing and highlight the need to better characterize the whole mouse locus, one gene at a time.

A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis.

It was recently demonstrated that interleukin (IL)-23-driven IL-17-producing (ThIL-17) T cells mediate inflammatory pathology in certain autoimmune diseases. We show that the induction of antigen-specific ThIL-17 cells, but not T helper (Th)1 or Th2 cells, by immunization with antigens and adjuvants is abrogated in IL-1 receptor type I-deficient (IL-1RI(-/-)) mice. Furthermore, the incidence of experimental autoimmune encephalomyelitis (EAE) was significantly lower in IL-1RI(-/-) compared with wild-type mice, and this correlated with a failure to induce autoantigen-specific ThIL-17 cells, whereas induction of Th1 and Th2 responses was not substantially different. However, EAE was induced in IL-1RI(-/-) mice by adoptive transfer of autoantigen-specific cells from wild-type mice with EAE. IL-23 alone did not induce IL-17 production by T cells from IL-1RI(-/-) mice, and IL-23-induced IL-17 production was substantially enhanced by IL-1alpha or IL-1beta, even in the absence of T cell receptor stimulation. We demonstrate essential roles for phosphatidylinositol 3-kinase, nuclear factor kappaB, and novel protein kinase C isoforms in IL-1- and IL-23-mediated IL-17 production. Tumor necrosis factor alpha also synergized with IL-23 to enhance IL-17 production, and this was IL-1 dependent. Our findings demonstrate that IL-1 functions upstream of IL-17 to promote pathogenic ThIL-17 cells in EAE.

Interleukin-1 accounts for intrarenal Th17 cell activation during ureteral obstruction.

Interleukin 17A-secreting T-helper 17 (Th17) cells are pathogenic in inflammatory kidney diseases, but their intrarenal regulation is poorly understood. In order to better define Th17 cell dynamics during interstitial inflammation, we utilized the mouse unilateral ureteral obstruction model to analyze inflammatory cell subtypes by multicolor flow cytometry and cell sorting and by effects on in vitro-generated Th17 cells. Interleukin 17A expression localized to CCR6(+)CCR4(+/-)CD4(+) T-cells and progressively increased in obstructed kidneys. The number of CCR6(+)CD4(+) T-cells increased over 10-fold by 72 h, were enriched for interleukin 17A production, and were highly proliferative based on in vivo bromodeoxyuridine incorporation. Secreted products of leukocytes isolated from obstructed kidneys enhanced the interleukin 17A production of in vitro-generated Th17 cells. This Th17-enhancing activity was identified as interleukin-1 produced by renal dendritic cells and monocytes. The in vivo validity of these findings was confirmed in mice lacking the interleulin-1 receptor and in mice treated with a recombinant interleukin-1 receptor antagonist, each of which exhibited reduced intrarenal Th17 activity compared with control mice. Thus, the inflamed kidney accumulates CCR6(+) Th17 cells that undergo activation and proliferation. Production of interleukin 1 family cytokines by resident dendritic cells and infiltrating monocytes enhances intrarenal Th17 activation in acute kidney injury.

Regulation of interleukin-1beta by interferon-gamma is species specific, limited by suppressor of cytokine signalling 1 and influences interleukin-17 production.

Reports describing the effect of interferon-gamma (IFNgamma) on interleukin-1beta (IL-1beta) production are conflicting. We resolve this controversy by showing that IFNgamma potentiates IL-1beta release from human cells, but transiently inhibits the production of IL-1beta from mouse cells. Release from this inhibition is dependent on suppressor of cytokine signalling 1. IL-1beta and Th17 cells are pathogenic in mouse models for autoimmune disease, which use Mycobacterium tuberculosis (MTB), in which IFNgamma and IFNbeta are anti-inflammatory. We observed that these cytokines suppress IL-1beta production in response to MTB, resulting in a reduced number of IL-17-producing cells. In human cells, IFNgamma increased IL-1beta production, and this might explain why IFNgamma is detrimental for multiple sclerosis. In mice, IFNgamma decreased IL-1beta and subsequently IL-17, indicating that the adaptive immune response can provide a systemic, but transient, signal to limit inflammation.

Inflammasome activation by adenylate cyclase toxin directs Th17 responses and protection against Bordetella pertussis.

Inflammasome-mediated IL-1beta production is central to the innate immune defects that give rise to certain autoinflammatory diseases and may also be associated with the generation of IL-17-producing CD4(+) T (Th17) cells that mediate autoimmunity. However, the role of the inflammasome in driving adaptive immunity to infection has not been addressed. In this article, we demonstrate that inflammasome-mediated IL-1beta plays a critical role in promoting Ag-specific Th17 cells and in generating protective immunity against Bordetella pertussis infection. Using a murine respiratory challenge model, we demonstrated that the course of B. pertussis infection was significantly exacerbated in IL-1R type I-defective (IL-1RI(-/-)) mice. We found that adenylate cyclase toxin (CyaA), a key virulence factor secreted by B. pertussis, induced robust IL-1beta production by dendritic cells through activation of caspase-1 and the NALP3-containing inflammasome complex. Using mutant toxins, we demonstrate that CyaA-mediated activation of caspase-1 was not dependent on adenylate cyclase enzyme activity but was dependent on the pore-forming capacity of CyaA. In addition, CyaA promoted the induction of Ag-specific Th17 cells in wild-type but not IL-1RI(-/-) mice. Furthermore, the bacterial load was enhanced in IL-17-defective mice. Our findings demonstrate that CyaA, a virulence factor from B. pertussis, promotes innate IL-1beta production via activation of the NALP3 inflammasome and, thereby, polarizes T cell responses toward the Th17 subtype. In addition to its known role in subverting host immunity, our findings suggest that CyaA can promote IL-1beta-mediated Th17 cells, which promote clearance of the bacteria from the respiratory tract.

Urine CA125 and HE4 for the Triage of Symptomatic Women with Suspected Endometrial Cancer.

A simple, noninvasive and accurate detection tool that can triage women with suspected endometrial cancer for definitive testing will transform patient care. The aim of this study was to evaluate urine CA125 and HE4 levels for the detection of endometrial cancer in symptomatic women. This was a cross-sectional diagnostic accuracy study of 153 symptomatic women who underwent urgent diagnostic investigations for suspected endometrial cancer at a large gynecological cancer center. Urine samples were collected prior to routine clinical procedures. Urine CA125 and HE4 levels were determined using automated chemiluminescent enzyme immunoassays. Univariate and multivariable receiver operating characteristic (ROC) curve analyses were performed. Urine CA125 and HE4 were discovered to be significantly elevated in women with endometrial cancer, compared to controls (p < 0.001 and p = 0.01, respectively). Urine CA125 and HE4 detected endometrial cancer with an area under the ROC curve (AUC) of 0.89 (0.81, 0.98) and 0.69 (0.55, 0.83), respectively. CA125 exhibited good discriminatory potential for Type I and early-stage tumors (AUC 0.93 and 0.90, respectively). A diagnostic model that combined urine CA125 and transvaginal ultrasound-measured endometrial thickness predicted endometrial cancer with an AUC of 0.96 (0.91, 1.00). Urine CA125 displays potential as a diagnostic tool for symptomatic women with suspected endometrial cancer. When combined with transvaginal ultrasound-measured endometrial thickness, this patient-friendly, urine-based test could help triage women for invasive diagnostics or safe reassurance, reducing costs and improving patient experience.

Myctobase, a circumpolar database of mesopelagic fishes for new insights into deep pelagic prey fields.

The global importance of mesopelagic fish is increasingly recognised, but they remain poorly studied. This is particularly true in the Southern Ocean, where mesopelagic fishes are both key predators and prey, but where the remote environment makes sampling challenging. Despite this, multiple national Antarctic research programs have undertaken regional sampling of mesopelagic fish over several decades. However, data are dispersed, and sampling methodologies often differ precluding comparisons and limiting synthetic analyses. We identified potential data holders by compiling a metadata catalogue of existing survey data for Southern Ocean mesopelagic fishes. Data holders contributed 17,491 occurrence and 11,190 abundance records from 4780 net hauls from 72 different research cruises. Data span across 37 years from 1991 to 2019 and include trait-based information (length, weight, maturity). The final dataset underwent quality control processes and detailed metadata was provided for each sampling event. This dataset can be accessed through Zenodo. Myctobase will enhance research capacity by providing the broadscale baseline data necessary for observing and modelling mesopelagic fishes.

Inhibition of ERK MAPK suppresses IL-23- and IL-1-driven IL-17 production and attenuates autoimmune disease.

IL-17-producing CD4(+) T (Th17) cells are pathogenic in many autoimmune diseases. The induction and expansion of Th17 cells is directed by cytokines, including IL-23 and IL-1beta, produced by innate immune cells through activation of pathogen recognition receptors. The NF-kappaB and IFN regulatory factor families of transcriptional factors mediate IL-12 production; however, distinct signaling pathways appear to be required for IL-23 production. In this study, we show that inhibition of ERK MAPK suppressed IL-23 and IL-1beta production by dendritic cells stimulated with TLR or dectin-1 agonists but did not affect IL-12p70 production. Furthermore, an ERK inhibitor suppressed the ability of Ag-pulsed TLR-activated dendritic cells to induce Ag-specific Th17 cells in vivo, but interestingly also inhibited the induction of Th1 cells. Treatment with an ERK inhibitor attenuated experimental autoimmune encephalomyelitis (EAE), when administered either at the induction phase of acute EAE or during remission in the relapsing-remitting EAE model. This was associated with significant suppression of autoantigen-specific Th17 and Th1 responses. The suppressive effect of the ERK inhibitor on attenuation of EAE was reversed by administration of IL-1beta and IL-23. Our findings suggest that ERK MAPK plays a critical and hitherto undescribed role in activating innate production of IL-23 and IL-1beta, which promote pathogenic T cell responses, and therefore represents an important target for therapeutic intervention against autoimmune diseases.

Community-Acquired, Extended-Spectrum ß-Lactamase-Producing and Extensively Drug-Resistant Escherichia coli in a 28-Year-Old Pyelonephritis Patient Lacking Risk Factors.

While Escherichia coli is a common cause of urinary tract infections and pyelonephritis, there are few documented cases of extended-spectrum ß-lactamase (ESBL)-producing and extensively drug-resistant (XDR) isolates from the community resulting in infection requiring hospitalization, especially in individuals lacking risk factors. In the United States, exposure to ESBL-producing E. coli is typically nosocomial, whereas patients from developing countries often encounter ESBL-producing E. coli in the community through the consumption of contaminated food or water. Considering the rarity at which XDR E. coli isolates are encountered, there is also a scarcity of literature describing the successful treatment of ESBL-producing XDR E. coli. Here we present a case of an otherwise healthy 28-year-old female delicatessen worker infected with ESBL-producing and XDR E. coli without recent travel, antibiotic use, or healthcare contact, who required admission to the intensive care unit (ICU) with pyelonephritis and septic shock. Treatment with intravenous meropenem through a peripherally inserted central catheter (PICC) line at home was curative and follow up thereafter unremarkable. Given the patient's lack of obvious exposure to and risk factors for an ESBL-producing XDR E. coli infection and the specific lack of risk factors for severe pyelonephritis requiring hospitalization, this case represents a unique addition to the literature and is of value to clinicians by describing successful treatment.