Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis.

Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that the KMO product 3-hydroxykynurenine primes innate immune signaling to exacerbate systemic inflammation during experimental AP. We find a tissue-specific role for KMO, where mice lacking Kmo solely in hepatocytes have elevated plasma 3-hydroxykynurenine levels that prime inflammatory gene transcription. 3-Hydroxykynurenine synergizes with interleukin-1ß to cause cellular apoptosis. Critically, mice with elevated 3-hydroxykynurenine succumb fatally earlier and more readily to experimental AP. Therapeutically, blockade with the highly selective KMO inhibitor GSK898 rescues the phenotype, reducing 3-hydroxykynurenine and protecting against critical illness and death. Together, our findings establish KMO and 3-hydroxykynurenine as regulators of inflammation and the innate immune response to sterile inflammation. During critical illness, excess morbidity and death from multiple organ failure can be rescued by systemic KMO blockade.

Septic arthritis in an in vivo murine model induced by Staphylococcus aureus : a comparison between actions of the haemolysin toxin and the effects of the host immune response.

AIMS: Staphylococcus aureus is a major cause of septic arthritis, and in vitro studies suggest α haemolysin (Hla) is responsible for chondrocyte death. We used an in vivo murine joint model to compare inoculation with wild type S. aureus 8325-4 with a Hla-deficient strain DU1090 on chondrocyte viability, tissue histology, and joint biomechanics. The aim was to compare the actions of S. aureus Hla alone with those of the animal's immune response to infection. METHODS: Adult male C57Bl/6 mice (n = 75) were randomized into three groups to receive 1.0 to 1.4 × 107 colony-forming units (CFUs)/ml of 8325-4, DU1090, or saline into the right stifle joint. Chondrocyte death was assessed by confocal microscopy. Histological changes to inoculated joints were graded for inflammatory responses along with gait, weight changes, and limb swelling. RESULTS: Chondrocyte death was greater with 8325-4 (96.2% (SD 5.5%); p < 0.001) than DU1090 (28.9% (SD 16.0%); p = 0.009) and both were higher than controls (3.8% (SD 1.2%)). Histology revealed cartilage/bone damage with 8325-4 or DU1090 compared to controls (p = 0.010). Both infected groups lost weight (p = 0.006 for both) and experienced limb swelling (p = 0.043 and p = 0.018, respectively). Joints inoculated with bacteria showed significant alterations in gait cycle with a decreased stance phase, increased swing phase, and a corresponding decrease in swing speed. CONCLUSION: Murine joints inoculated with Hla-producing 8325-4 experienced significantly more chondrocyte death than those with DU1090, which lack the toxin. This was despite similar immune responses, indicating that Hla was the major cause of chondrocyte death. Hla-deficient DU1090 also elevated chondrocyte death compared to controls, suggesting a smaller additional deleterious role of the immune system on cartilage.Cite this article: Bone Joint Res 2022;11(9):669-678.

Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells.

The gut microbiota fundamentally regulates intestinal homeostasis and disease partially through mechanisms that involve modulation of regulatory T cells (Tregs), yet how the microbiota-Treg cross-talk is physiologically controlled is incompletely defined. Here, we report that prostaglandin E2 (PGE2), a well-known mediator of inflammation, inhibits mucosal Tregs in a manner depending on the gut microbiota. PGE2 through its receptor EP4 diminishes Treg-favorable commensal microbiota. Transfer of the gut microbiota that was modified by PGE2-EP4 signaling modulates mucosal Treg responses and exacerbates intestinal inflammation. Mechanistically, PGE2-modified microbiota regulates intestinal mononuclear phagocytes and type I interferon signaling. Depletion of mononuclear phagocytes or deficiency of type I interferon receptor diminishes PGE2-dependent Treg inhibition. Together, our findings provide emergent evidence that PGE2-mediated disruption of microbiota-Treg communication fosters intestinal inflammation.

Cervical epithelial damage promotes Ureaplasma parvum ascending infection, intrauterine inflammation and preterm birth induction in mice.

Around 40% of preterm births are attributed to ascending intrauterine infection, and Ureaplasma parvum (UP) is commonly isolated in these cases. Here we present a mouse model of ascending UP infection that resembles human disease, using vaginal inoculation combined with mild cervical injury induced by a common spermicide (Nonoxynol-9, as a surrogate for any mechanism of cervical epithelial damage). We measure bacterial load in a non-invasive manner using a luciferase-expressing UP strain, and post-mortem by qPCR and bacterial titration. Cervical exposure to Nonoxynol-9, 24 h pre-inoculation, facilitates intrauterine UP infection, upregulates pro-inflammatory cytokines, and increases preterm birth rates from 13 to 28%. Our results highlight the crucial role of the cervical epithelium as a barrier against ascending infection. In addition, we expect the mouse model will facilitate further research on the potential links between UP infection and preterm birth.

Intrapulmonary Autoantibodies to HSP72 Are Associated with Improved Outcomes in IPF.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease, with high mortality. Currently, the aetiology and the pathology of IPF are poorly understood, with both innate and adaptive responses previously being implicated in the disease pathogenesis. Heat shock proteins (Hsp) and antibodies to Hsp in patients with IPF have been suggested as therapeutic targets and prognostic biomarkers, respectively. We aimed to study the relationship between the expression of Hsp72 and anti-Hsp72 antibodies in the BAL fluid and serum Aw disease progression in patients with IPF. METHODS: A novel indirect ELISA to measure anti-Hsp72 IgG was developed and together with commercially available ELISAs used to detect Hsp72 IgG, Hsp72 IgGAM, and Hsp72 antigen, in the serum and BALf of a cohort of IPF (n = 107) and other interstitial lung disease (ILD) patients (n = 66). Immunohistochemistry was used to detect Hsp72 in lung tissue. The cytokine expression from monocyte-derived macrophages was measured by ELISA. RESULTS: Anti-Hsp72 IgG was detectable in the serum and BALf of IPF (n = 107) and other ILDs (n = 66). Total immunoglobulin concentrations in the BALf showed an excessive adaptive response in IPF compared to other ILDs and healthy controls (p = 0.026). Immunohistochemistry detection of C4d and Hsp72 showed that these antibodies may be targeting high expressing Hsp72 type II alveolar epithelial cells. However, detection of anti-Hsp72 antibodies in the BALf revealed that increasing concentrations were associated with improved patient survival (adjusted HR 0.62, 95% CI 0.45-0.85; p = 0.003). In vitro experiments demonstrate that anti-Hsp72 complexes stimulate macrophages to secrete CXCL8 and CCL18. CONCLUSION: Our results indicate that intrapulmonary anti-Hsp72 antibodies are associated with improved outcomes in IPF. These may represent natural autoantibodies, and anti-Hsp72 IgM and IgA may provide a beneficial role in disease pathogenesis, though the mechanism of action for this has yet to be determined.

Kynurenine 3-monooxygenase is a critical regulator of renal ischemia-reperfusion injury.

Acute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking kynurenine 3-monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active kynurenine metabolites 3-hydroxykynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.

An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade.

A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a ß-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3-/- mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3-/- mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8+ T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. SIGNIFICANCE: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1480/F1.large.jpg.

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury.

Inflammatory bowel disease (IBD) is a condition of chronic inflammatory intestinal disorder with increasing prevalence but limited effective therapies. The purine metabolic pathway is involved in various inflammatory processes including IBD. However, the mechanisms through which purine metabolism modulates IBD remain to be established. Here, we found that mucosal expression of genes involved in the purine metabolic pathway is altered in patients with active ulcerative colitis (UC), which is associated with elevated gene expression signatures of the group 3 innate lymphoid cell (ILC3)-interleukin (IL)-22 pathway. In mice, blockade of ectonucleotidases (NTPDases), critical enzymes for purine metabolism by hydrolysis of extracellular adenosine 5'-triphosphate (eATP) into adenosine, exacerbates dextran-sulfate sodium-induced intestinal injury. This exacerbation of colitis is associated with reduction of colonic IL-22-producing ILC3s, which afford essential protection against intestinal inflammation, and is rescued by exogenous IL-22. Mechanistically, activation of ILC3s for IL-22 production is reciprocally mediated by eATP and adenosine. These findings reveal that the NTPDase-mediated balance between eATP and adenosine regulates ILC3 cell function to provide protection against intestinal injury and suggest potential therapeutic strategies for treating IBD by targeting the purine-ILC3 axis.

Host chemokine signature as a biomarker for the detection of pre-cancerous cervical lesions.

BACKGROUND: The ability to distinguish which hrHPV infections predispose to significant disease is ever more pressing as a result of the increasing move to hrHPV testing for primary cervical screening. A risk-stratifier or "triage" of infection should ideally be objective and suitable for automation given the scale of screening. RESULTS: CCL2, CCL3, CCL4, CXCL1, CXCL8 and CXCL12 emerged as the strongest, candidate biomarkers to detect underlying disease [cervical intraepithelial neoplasia grade 2 or worse (CIN2+)]. For CIN2+, CCL2 had the highest area under the curve (AUC) of 0.722 with a specificity of 82%. A combined biomarker panel of six chemokines CCL2, CCL3, CCL4, CXCL1, CXCL8, and CXCL12 provides a sensitivity of 71% and specificity of 67%. CONCLUSION: The present work demonstrates that the levels of five chemokine-proteins are indicative of underlying disease. We demonstrate technical feasibility and promising clinical performance of a chemokine-based biomarker panel, equivalent to that of other triage options. Further assessment in longitudinal series is now warranted. METHODS: A panel of 31 chemokines were investigated for expression in routinely taken archived and prospective cervical liquid based cytology (LBC) samples using Human Chemokine Proteomic Array kit. Nine chemokines were further validated using Procartaplex assay on the Luminex platform.

Facilitation of IL-22 production from innate lymphoid cells by prostaglandin E2 prevents experimental lung neutrophilic inflammation.

Acute lung injury is a neutrophil-dominant, life-threatening disease without effective therapies and better understanding of the pathophysiological mechanisms involved is an urgent need. Here we show that interleukin (IL)-22 is produced from innate lymphoid cells (ILC) and is responsible for suppression of experimental lung neutrophilic inflammation. Blocking prostaglandin E2 (PGE2) synthesis reduces lung ILCs and IL-22 production, resulting in exacerbation of lung neutrophilic inflammation. In contrast, activation of the PGE2 receptor EP4 prevents acute lung inflammation. We thus demonstrate a mechanism for production of innate IL-22 in the lung during acute injury, highlighting potential therapeutic strategies for control of lung neutrophilic inflammation by targeting the PGE2/ILC/IL-22 axis.

Prostaglandin E2 stimulates adaptive IL-22 production and promotes allergic contact dermatitis.

BACKGROUND: Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are both forms of eczema and are common inflammatory skin diseases with a central role of T cell-derived IL-22 in their pathogenesis. Although prostaglandin (PG) E2 is known to promote inflammation, little is known about its role in processes related to AD and ACD development, including IL-22 upregulation. OBJECTIVES: We sought to investigate whether PGE2 has a role in IL-22 induction and development of ACD, which has increased prevalence in patients with AD. METHODS: T-cell cultures and in vivo sensitization of mice with haptens were used to assess the role of PGE2 in IL-22 production. The involvement of PGE2 receptors and their downstream signals was also examined. The effects of PGE2 were evaluated by using the oxazolone-induced ACD mouse model. The relationship of PGE2 and IL-22 signaling pathways in skin inflammation were also investigated by using genomic profiling in human lesional AD skin. RESULTS: PGE2 induces IL-22 from T cells through its receptors, E prostanoid receptor (EP) 2 and EP4, and involves cyclic AMP signaling. Selective deletion of EP4 in T cells prevents hapten-induced IL-22 production in vivo, and limits atopic-like skin inflammation in the oxazolone-induced ACD model. Moreover, both PGE2 and IL-22 pathway genes were coordinately upregulated in human AD lesional skin but were at less than significant detection levels after corticosteroid or UVB treatments. CONCLUSIONS: Our results define a crucial role for PGE2 in promoting ACD by facilitating IL-22 production from T cells.

TCR-stimulated changes in cell surface CD46 expression generate type 1 regulatory T cells.

A lack of regulatory T cell function is a critical factor in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). Ligation of the complement regulatory protein CD46 facilitates the differentiation of T helper 1 (TH1) effector cells into interleukin-10 (IL-10)-secreting type 1 regulatory T cells (Tr1 cells), and this pathway is defective in MS patients. Cleavage of the ectodomain of CD46, which contains three N-glycosylation sites and multiple O-glycosylation sites, enables CD46 to activate T cells. We found that stimulation of the T cell receptor (TCR)-CD3 complex was associated with a reduction in the apparent molecular mass of CD46 in a manner that depended on O-glycosylation. CD3-stimulated changes in CD46 O-glycosylation status reduced CD46 processing and subsequent T cell signaling. During T cell activation, CD46 was recruited to the immune synapse in a manner that required its serine-, threonine-, and proline-rich (STP) region, which is rich in O-glycosylation sites. Recruitment of CD46 to the immune synapse switched T cells from producing the inflammatory cytokine interferon-γ (IFN-γ) to producing IL-10. Furthermore, CD4+ T cells isolated from MS patients did not exhibit a CD3-stimulated reduction in the mass of CD46 and thus showed increased amounts of cell surface CD46. Together, these data suggest a possible mechanism underlying the regulatory function of CD46 on T cells. Our findings may explain why this pathway is defective in patients with MS and provide insights into MS pathogenesis that could help to design future immunotherapies.

NKT cells are important mediators of hepatic ischemia-reperfusion injury.

INTRODUCTION: IRI results from the interruption then reinstatement of an organ's blood supply, and this poses a significant problem in liver transplantation and resectional surgery. In this paper, we explore the role T cells play in the pathogenesis of this injury. MATERIALS & METHODS: We used an in vivo murine model of warm partial hepatic IRI, genetically-modified mice, in vivo antibody depletion, adoptive cell transfer and flow cytometry to determine which lymphocyte subsets contribute to pathology. Injury was assessed by measuring serum alanine aminotransfersase (ALT) and by histological examination of liver tissue sections. RESULTS: The absence of T cells (CD3εKO) is associated with significant protection from injury (p=0.010). Through a strategy of antibody depletion it appears that NKT cells (p=0.0025), rather than conventional T (CD4+ or CD8+) (p=0.11) cells that are the key mediators of injury. DISCUSSION: Our results indicate that tissue-resident NKT cells, but not other lymphocyte populations are responsible for the injury in hepatic IRI. Targeting the activation of NKT cells and/or their effector apparatus would be a novel approach in protecting the liver during transplantation and resection surgery; this may allow us to expand our current criteria for surgery.

Chlamydia trachomatis infection of human endometrial stromal cells induces defective decidualisation and chemokine release.

Miscarriage affects ~20% of pregnancies and maternal infections account for ~15% of early miscarriages. Chlamydia trachomatis (Ct) has been associated with miscarriage but the underlying mechanisms are unknown. Successful implantation requires endometrial stromal cell (ESC) decidualisation. Maintenance of pregnancy requires angiogenesis, establishment of the correct cellular milieu and trophoblast invasion, all of which involve the action of chemokines. Our objective was to determine whether Ct infection impacts upon ESC decidualisation and chemokine secretion. Human primary ESC were decidualised in-vitro, infected with Ct serovar E, and changes in expression of genes of interest were measured using RT-PCR, proteomic array and ELISA. We demonstrate for the first time that Ct can infect and proliferate in ESC. Expression of the decidualisation marker prolactin was decreased in Ct-infected ESC at both mRNA and protein levels. Ct infection altered the chemokine profile of decidualised ESC as shown by proteomic array. Chemokines CXCL12 and CXCL16, important for trophoblast invasion, were analysed further and expression was reduced in infected decidualised cells at mRNA and protein levels. Our data indicate that Ct infection of ESC impairs decidualisation and alters chemokine release. These findings at least partially explain how Ct infection could result in adverse pregnancy outcomes.

Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells.

BACKGROUND: Mutations in the gene encoding filaggrin (FLG), an epidermal structural protein, are the strongest risk factor identified for the development of atopic dermatitis (AD). Up to 50% of patients with moderate-to-severe AD in European populations have FLG-null alleles compared with a general population frequency of 7% to 10%. OBJECTIVE: This study aimed to investigate the relationship between FLG-null mutations and epidermal antigen-presenting cell (APC) maturation in subjects with and without AD. Additionally, we investigated whether the cis isomer of urocanic acid (UCA), a filaggrin breakdown product, exerts immunomodulatory effects on dendritic cells. METHODS: Epidermal APCs from nonlesional skin were assessed by using flow cytometry (n = 27) and confocal microscopy (n = 16). Monocyte-derived dendritic cells from healthy volunteers were used to assess the effects of cis- and trans-UCA on dendritic cell phenotype by using flow cytometry (n = 11). RESULTS: Epidermal APCs from FLG-null subjects had increased CD11c expression. Confocal microscopy confirmed this and additionally revealed an increased number of epidermal CD83(+) Langerhans cells in FLG-null subjects. In vitro differentiation in the presence of cis-UCA significantly reduced costimulatory molecule expression on monocyte-derived dendritic cells from healthy volunteers and increased their ability to induce a regulatory T-cell phenotype in mixed lymphocyte reactions. CONCLUSIONS: We show that subjects with FLG-null mutations have more mature Langerhans cells in nonlesional skin irrespective of whether they have AD. We also demonstrate that cis-UCA reduces maturation of dendritic cells and increases their capacity to induce regulatory T cells, suggesting a novel link between filaggrin deficiency and immune dysregulation.

Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell-IL-22 axis.

Systemic inflammation, which results from the massive release of proinflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are not fully understood. We observed that prostaglandin E2 (PGE2), through its receptor EP4, is down-regulated in human systemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treatment with EP4 agonists. Mechanistically, we demonstrate that PGE2-EP4 signaling acts directly on type 3 innate lymphoid cells (ILCs), promoting their homeostasis and driving them to produce interleukin-22 (IL-22). Disruption of the ILC-IL-22 axis impairs PGE2-mediated inhibition of systemic inflammation. Hence, the ILC-IL-22 axis is essential in protecting against gut barrier dysfunction, enabling PGE2-EP4 signaling to impede systemic inflammation.

Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis.

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.

The role of infection in miscarriage.

BACKGROUND: Miscarriage is the spontaneous loss of a pregnancy before 12 weeks (early miscarriage) or from 12 to 24 weeks (late miscarriage) of gestation. Miscarriage occurs in one in five pregnancies and can have considerable physiological and psychological implications for the patient. It is also associated with significant health care costs. There is evidence that potentially preventable infections may account for up to 15% of early miscarriages and up to 66% of late miscarriages. However, the provision of associated screening and management algorithms is inconsistent for newly pregnant women. Here, we review recent population-based studies on infections that have been shown to be associated with miscarriage. METHODS: Our aim was to examine where the current scientific focus lies with regards to the role of infection in miscarriage. Papers dating from June 2009 with key words 'miscarriage' and 'infection' or 'infections' were identified in PubMed (292 and 327 papers, respectively, on 2 June 2014). Relevant human studies (meta-analyses, case-control studies, cohort studies or case series) were included. Single case reports were excluded. The studies were scored based on the Newcastle - Ottawa Quality Assessment Scale. RESULTS: The association of systemic infections with malaria, brucellosis, cytomegalovirus and human immunodeficiency virus, dengue fever, influenza virus and of vaginal infection with bacterial vaginosis, with increased risk of miscarriage has been demonstrated. Q fever, adeno-associated virus, Bocavirus, Hepatitis C and Mycoplasma genitalium infections do not appear to affect pregnancy outcome. The effects of Chlamydia trachomatis, Toxoplasma gondii, human papillomavirus, herpes simplex virus, parvovirus B19, Hepatitis B and polyomavirus BK infections remain controversial, as some studies indicate increased miscarriage risk and others show no increased risk. The latest data on rubella and syphilis indicate increased antenatal screening worldwide and a decrease in the frequency of their reported associations with pregnancy failure. Though various pathogens have been associated with miscarriage, the mechanism(s) of infection-induced miscarriage are not yet fully elucidated. CONCLUSIONS: Further research is required to clarify whether certain infections do increase miscarriage risk and whether screening of newly pregnant women for treatable infections would improve reproductive outcomes.

Acute Liver Injury Is Independent of B Cells or Immunoglobulin M.

BACKGROUND & AIMS: Acute liver injury is a clinically important pathology and results in the release of Danger Associated Molecular Patterns, which initiate an immune response. Withdrawal of the injurious agent and curtailing any pathogenic secondary immune response may allow spontaneous resolution of injury. The role B cells and Immunoglobulin M (IgM) play in acute liver injury is largely unknown and it was proposed that B cells and/or IgM would play a significant role in its pathogenesis. METHODS: Tissue from 3 models of experimental liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury) and patients transplanted following paracetamol overdose were stained for evidence of IgM deposition. Mice deficient in B cells (and IgM) were used to dissect out the role B cells and/or IgM played in the development or resolution of injury. Serum transfer into mice lacking IgM was used to establish the role IgM plays in injury. RESULTS: Significant deposition of IgM was seen in the explanted livers of patients transplanted following paracetamol overdose as well as in 3 experimental models of acute liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury). Serum transfer into IgM-deficient mice failed to reconstitute injury (p = 0.66), despite successful engraftment of IgM. Mice deficient in both T and B cells (RAG1-/-) mice (p<0.001), but not B cell deficient (µMT) mice (p = 0.93), were significantly protected from injury. Further interrogation with T cell deficient (CD3εKO) mice confirmed that the T cell component is a key mediator of sterile liver injury. Mice deficient in B cells and IgM mice did not have a significant delay in resolution following acute liver injury. DISCUSSION: IgM deposition appears to be common feature of both human and murine sterile liver injury. However, neither IgM nor B cells, play a significant role in the development of or resolution from acute liver injury. T cells appear to be key mediators of injury. In conclusion, the therapeutic targeting of IgM or B cells (e.g. with Rituximab) would have limited benefit in protecting patients from acute liver injury.