Inappropriate Immune Activation Research Articles

An alternative spliced UPF2 transcript in pancreatic inflammatory myofibroblastic tumors

BackgroundInflammatory myofibroblastic tumors (IMTs) are characterized by myofibroblast proliferation and an inflammatory cell infiltrate. Our previous study on IMTs reveals that disrupt NMD pathway causes to lower the threshold for triggering the immune cell infiltration, thereby resulting in inappropriate immune activation. However, myofibroblast differentiation and proliferation is not yet known. MethodsRT-PCR, RT-qPCR, DNA sequence, western bolt, 5′race analysis and site-specific mutagenesis were used in this study. ResultsHere, an alternative spliced (ALS) UPF2 mRNA skipping exon 2 and 3 and corresponding to the truncated UPF2 protein were found in 2 pancreatic IMTs. We showed that the uORF present in the 5′UTR of UPF2 mRNA is responsible for the translation inhibition, whiles ALS UPF2 is more facilitated to be translated into the truncated UPF2 protein. Several mRNA targets of the NMD were upregulated in IMT samples, indicating that the truncated UPF2 function is strongly perturbed, resulted in disrupted NMD pathway in IMTs. These upregulated NMD targets included cdkn1a expression and the generation of high levels of p21 (waf1/cip1), which may contribute to triggering IMTs. ConclusionThe disrupt UPFs/NMD pathway may link to molecular alteration associated with differentiation and proliferation for IMTs.

Pathogen-driven CRISPR screens identify TREX1 as a regulator of DNA self-sensing during influenza virus infection

Host:pathogen interactions dictate the outcome of infection, yet the limitations of current approaches leave large regions of this interface unexplored. Here, we develop a novel fitness-based screen that queries factors important during the middle to late stages of infection. This is achieved by engineering influenza virus to direct the screen by programming dCas9 to modulate host gene expression. Our genome-wide screen for pro-viral factors identifies the cytoplasmic DNA exonuclease TREX1. TREX1 degrades cytoplasmic DNA to prevent inappropriate innate immune activation by self-DNA. We reveal that this same process aids influenza virus replication. Infection triggers release of mitochondrial DNA into the cytoplasm, activating antiviral signaling via cGAS and STING. TREX1 metabolizes the DNA, preventing its sensing. Collectively, these data show that self-DNA is deployed to amplify innate immunity, a process tempered by TREX1. Moreover, they demonstrate the power and generality of pathogen-driven fitness-based screens to pinpoint key host regulators of infection.

Unique ulcerative autoinflammatory disease mistaken for factitious disorder

Autoinflammatory diseases (AID) are disorders of inappropriate innate immune system activation. Twenty-four percent of patients with AID do not have a well-defined clinical picture or pathogenic mutation and are characterized as having undefined AID. Cutaneous ulcers have been described but not outside of distinct histologic and clinical disorders. We present a unique case of undefined adult-onset AID with ulcers mistaken for a factitious disorder.A 32 year-old female with borderline personality disorder, depression, and anxiety developed recurrent cutaneous MRSA abscesses and recurrent ulcers of the extremities and scalp associated with alopecia. The ulcers were minimally-responsive to IV antibiotics, isotretinoin, oral dapsone, intralesional triamcinolone, and adalimumab. Flares of the skin disease were associated with fevers and elevated inflammatory markers.Scalp ulcer biopsies revealed numerous pigmented hair casts with trichomalacia and perifollicular lymphocytic infiltrate. One hair follicle contained bacterial cocci associated with a perifollicular neutrophilic infiltrate. These findings along with the patient's psychiatric history led to a diagnosis of trichotillomania from multiple dermatology and psychiatry consultations. The patient denied that she was inducing the lesions and sought another psychiatric consultation, who felt this was not a factitious disease. She was referred to immunology for evaluation of a possible IEI. Laboratory evaluation revealed mild hypogammaglobulinemia with IgG of 663 (768–1632) mg/dL, normal antibody response to recall antigens, but absent response to neo-antigen (Salmonella typhi). Peripheral lymphocyte phenotyping was normal except for a relative decrease in the number of memory B-cells with CD27+IgD+% of 6.9 (13.4–21.4) and CD27+IgD-% of 2.5 (9.2–18.9). Neutrophil oxidative burst was normal. Whole exome sequencing did not identify variants in genes associated with her phenotype.The patient was partially responsive to IVIG but highly responsive to high-dose intravenous methylprednisolone. She was subsequently diagnosed with undefined AID based on Eurofever registry criteria matching her clinical course and had near complete resolution of skin lesions and alopecia with the addition of anakinra.Clinicians must be vigilant for atypical presentations of AID. Our patient had signs of undefined AID but had a delayed diagnosis due to her psychiatric disorders, to which her symptoms were attributed, and a previously undescribed presentation of AID.

A Case Report on Ibuprofen Induced Toxic Epidermal Necrolysis

Ibuprofen is a non steroidal anti-inflammatory drug that exhibits analgesic and antipyretic activities by inhibiting prostaglandin synthesis. Though available as an OTC drug, ibuprofen is potent enough to cause serious dermatologic adverse reactions like erythema multiforme, erythroderma, SJS (Stevens - Johnson syndrome), TEN (toxic epidermal necrolysis). TENis a potentially life threatening dermatologic disorder and a severe cutaneous ADR that involves skin and mucous membrane, characterized by widespread erythema, necrosis and bullous detachment, resulting in exfoliation & possible sepsis and/or death, which is most commonly drug induced. Toxic epidermal necrolysis is characterized by inappropriate immune activation in response to certain medications or their metabolites. The exact pathogenic mechanism of TEN is still uncertain. The exposure to drugs has increased with demographic shifts associated with a higher morbidity of the population. Along with this phenomenon, a rise in the incidence of adverse drug reactions (ADRs) has been observed. Hypersensitivity- syndrome associated with ibuprofen is a host-dependent idiosyncratic drug-reaction. Though ibuprofen is most widely used over the counter (OTC) medication, which is considered to be relatively safe, it is essential to understand its potential adverse effects. This rare case report addresses the fact that severe hypersensitivity reactions can occur with ibuprofen, which can be potentially dangerous and life threatening. This case report also adds a note on the diagnosis and management of Toxic Epidermal Necrolysis.

Reduced cutaneous CD200:CD200R1 signaling in psoriasis enhances neutrophil recruitment to skin.

IntroductionThe skin immune system is tightly regulated to prevent inappropriate inflammation in response to harmless environmental substances. This regulation is actively maintained by mechanisms including cytokines and cell surface receptors and its loss results in inflammatory disease. In the case of psoriasis, inappropriate immune activation leads to IL‐17‐driven chronic inflammation, but molecular mechanisms underlying this loss of regulation are not well understood. Immunoglobulin family member CD200 and its receptor, CD200R1, are important regulators of inflammation. Therefore, we determined if this pathway is dysregulated in psoriasis, and how this affects immune cell activity.MethodsHuman skin biopsies were examined by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. The role of CD200R1 in regulating psoriasis‐like skin inflammation was examined using CD200R1 blocking antibodies in mouse psoriasis models. CD200R1 blocking antibodies were also used in an in vivo neutrophil recruitment assay and in vitro assays to examine macrophage, innate lymphoid cell, γδ T cell, and neutrophil activity.ResultsWe reveal that CD200 and signaling via CD200R1 are reduced in non‐lesional psoriasis skin. In mouse models of psoriasis CD200R1 was shown to limit psoriasis‐like inflammation by enhancing acanthosis, CCL20 production and neutrophil recruitment, but surprisingly, macrophage function and IL‐17 production were not affected, and neutrophil reactive oxygen species production was reduced.ConclusionCollectively, these data show that CD200R1 affects neutrophil function and limits inflammatory responses in healthy skin by restricting neutrophil recruitment. However, the CD200 pathway is reduced in psoriasis, resulting in a loss of immune control, and increased neutrophil recruitment in mouse models. In conclusion, we highlight CD200R1:CD200 as a pathway that might be targeted to dampen inflammation in patients with psoriasis.

S2758 A Case of Hemophagocytic Lymphohistiocytosis Presenting With Acute Liver Injury

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome with high rates of mortality marked by inappropriate immune activation of T-cells and macrophages that manifests with multi-organ dysfunction. HLH is primarily observed among pediatric patients and is exceedingly rare in adults. Here we present a case of acute liver injury with centrizonal hepatocellular necrosis on liver biopsy, secondary to HLH in an adult male. Case Description/Methods: Our patient is a 33-year-old white male resident of Guam with extensive binge drinking history who presented with two weeks of dry cough, generalized malaise, and fevers. Initial serologic workup was notable for anemia, leukopenia, elevated inflammatory markers, and elevated liver transaminases 400-500 U/L. Given his nonspecific symptoms and lab findings, there was moderate clinical concern for HLH. CT of the abdomen revealed hepatosplenomegaly with multifocal areas of nodular hyperenhancement of the liver. An MRI of the liver demonstrated multiple hypervascular nodules most consistent with a nonspecific inflammatory process. PET scan showed diffuse hypermetabolism throughout the liver consistent with inflammation. A liver biopsy demonstrated centrizonal hepatocellular necrosis. Despite biopsy results, clinical concern remained high for HLH and he was transferred to a higher level of care for further workup by a multidisciplinary team including Hepatology. Extensive rheumatologic and infectious workup, including hepatidities, were negative. At this time a clinical diagnosis of HLH was made based off HLH-2004 diagnostic criteria fever > 38.5°C, hypertriglyceridemia > 265 mg/dL, ferritin > 500ng/mL, elevated sCD25, and splenomegaly. Treatment was initiated with dexamethasone and IVIG with near resolution of his acute liver injury within two months of treatment onset. Discussion: HLH is an exceptionally rare syndrome among adults (one per 800,000 annually) that presents with many nonspecific signs and symptoms. This causes diagnostic difficulty making it crucial to maintain a broad differential to aid in proper diagnosis and to prevent the delay in potentially lifesaving treatment. Elevated liver transaminases are common among HLH patients, however the pattern of necrosis seen on biopsy in this patient is unique compared to current literature. This case represents the importance of maintaining a broad differential in patients with diffuse inflammatory symptoms in the setting of nonspecific liver inflammation, as seen in this exceedingly rare case of HLH.

Response to case report on myocarditis and pericarditis after COVID-19 vaccination.

We would like to comment on the publication “Myocarditis and pericarditis after vaccination for COVID-19.” Hudson et al reported on an interesting case study and concluded that, “Although the majority of reported cases are coming from the lay press as the number of reports increases there is growing concern for at least an association between COVID-19 vaccination and subsequent myocarditis.” 1 Hudson et al showed clinical data to support the existence of the cardiac problem. In the present case, a presumptive diagnosis of myocarditis is based on clinical history and laboratory findings. No cardiac imaging or pathological study is done. Based on the case report, the cardiac problem is confirmed, but the pathogenesis of the cardiac problem is not clear. Hudson et al discussed many potential mechanisms of the cardiac problem, including hypersensitivity, inflammatory process, or inappropriate immune activation.1 We agree that immunopathological processes might induce the problem. However, no laboratory evidence exists to confirm this. If there is a hypersensitivity problem, some basic laboratory findings, such as eosinophilia or basophilia, should be observed. For inflammatory process, there should be increased leukocyte count and elevated erythrocyte sedimentation rate. For inappropriate immune response, autoimmunity should be detected. Another possible explanation is hyperviscosity-induced cardiac problem.2 After vaccination, excessive increased blood viscosity might occur and it might cause further cardiac problems.3 The underlying mechanism of post COVID-19 vaccination hyperviscosity is a change of antibody level in plasma after vaccine stimulation. In the case of underlying high blood viscosity or previous COVID-19, the excessive increasing of antibody level might occur and can result in excessive blood viscosity and hyperviscosity.2, 3 Because hyperviscosity is a hypercoagulable state, there might be a clot and thrombosis of the heart and it can further result in acute myocarditis.4

Guillain–Barré Syndrome in COVID-19—The Potential Role of NCAM-1 and Immunotherapy

Coronavirus disease 2019 (COVID-19) interacts with the nervous system directly and indirectly by affecting the activation of the immune system. Guillain–Barré syndrome (GBS) is triggered by an inappropriate immune system activation that overlaps with the neurotoxic mechanism of an invading pathogen. Here, we discuss the complexity of an abnormal immune system response leading to the generation of autoimmunity in the setting of acute viral infection. A 67-year-old male patient with COVID-19 developed a sensory motor acute polyneuropathy with respiratory failure. Several serum inflammatory and neurodegeneration markers were collected during hospital days 1, 3, 8, and 67 and compared to healthy individuals. Neural cell adhesion molecule 1 (NCAM-1) and neurofilament light chain (NfL) values were highly variable when compared to healthy individuals, but not to the reference COVID-19 group. We focused our attention on NCAM-1 as a possible target for antibodies directed at COVID-19 in silico.

Divergence of neuroimmune circuits activated by afferent and efferent vagal nerve stimulation in the regulation of inflammation.

It has previously been shown that afferent and efferent vagal nerve stimulation potently inhibits lipopolysaccharide (LPS)-induced inflammation Our data show inhibition of inflammation by efferent but not afferent vagal nerve stimulation requires T-cell derived acetylcholine We show that afferent and efferent neuroimmune circuits require β2 -adrenergic receptor signalling ABSTRACT: Chronic inflammation due to inappropriate immune cell activation can have significant effects on a variety of organ systems, reducing lifespan and quality of life. As such, highly targeted control of immune cell activation is a major therapeutic goal. Vagus nerve stimulation (VNS) has emerged as a therapeutic modality that exploits neuroimmune communication to reduce immune cell activation and consequently inflammation. Although vagal efferent fibres were originally identified as the primary driver of anti-inflammatory actions, the vagus nerve in most species of animals predominantly comprises afferent fibres. Stimulation of vagal afferent fibres can also reduce inflammation; it is, however, uncertain how these two neuroimmune circuits diverge. Here we show that afferent VNS induces a mechanism distinct from efferent VNS, ameliorating lipopolysaccharide (LPS)-induced inflammation independently of T-cell derived acetylcholine (ACh) which is required by efferent VNS. Using a β2 -adrenergic receptor antagonist (β2 -AR), we find that immune regulation induced by intact, afferent, or efferent VNS occurs in a β2- AR-dependent manner. Together, our findings indicate that intact VNS activates at least two distinct neuroimmune circuits each with unique mechanisms of action. Selective targeting of either the vagal efferent or afferent fibres may provide more personalized, robust and effective control over inappropriate immune responses.

Evolution of Biochemical, Hematological, Inflammatory and Immunological Markers among Person Living with HIV-1 on ART in Burkina Faso

In Human immunodeficiency virus infected (HIV+) patients, deregulation of regulatory T (Treg) cells can be deleterious for the development of an efficient anti-HIV specific immune response with an inappropriate immune activation despite anti-retroviral therapy (ART). In addition, infection and ART have the potential to cause hematological and biochemical abnormalities that can lead to the discontinuation of ART. The aim of this study was to assess hematological, biochemical and immunological abnormalities in HIV+ patients’ naïve to ART and 6 months after ART initiation. In a cross-sectional study, 11 HIV+ patients and 09 healthy individuals (control group) were voluntarily recruited. At inclusion, blood samples were taken before administration of ART. All hematological, biochemical, immunological parameters and viral load were measured and assessed at inclusion (M0) and three and/or six months later (M3, M6). Higher level of white blood cells and CD4+ T lymphocytes (p = 0.032, 0.038 respectively) were observed in HIV+ patients. ART also had significantly effect on the level of red blood cells (p = 0.04) and Hb (p = 0.015). The inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) that were significantly increased by HIV infection, tended to decrease for ESR and revert to levels similar to those of control for CRP. Analysis of CD4+CD25+ cells and CD4+Foxp3+CD25+ showed significantly elevated levels of activated form of all CD4+ cells and Treg cells. Interestingly, six months after initiation of ART, the average percentage of CD4+CD25+ was not significantly different from control group (p = 0.382). Our study provides information about the evolution of the activated form of all CD4 cells and Treg cells and points out the necessity to monitor hematological and biochemical parameters in order to detect and prevent toxicity, improve the quality of life and reduce the risk of mortality.

Renal Function: Guardian of Immune Homeostasis

Microbial cell components from the intestinal microbiota spread systemically in a healthy host, posing the threat of inappropriate immune activation. In this issue of Immunity, Troha etal. identify a key role for renal function in the clearance of circulating Lys-type peptidoglycan, revealing a mechanism that keeps these inflammatory triggers in check to maintain systemic immune homeostasis.

Commensal polysaccharide-induced T cell communication and peripheral immune regulation

Abstract The increasing prevalence of inflammatory and autoimmune diseases across the world has been attributed in part to a shift in microbial exposure both in the exogenous environment and the endogenous microbiome. Here we identify and adopt a strategy used by a common commensal gut microbe, Bacteroides fragilis, to suppress inappropriate immune activation. Bacteroides fragilis produces a protective capsule containing polysaccharide A (PSA), which has been shown to suppress a host of inflammatory diseases in an IL-10-dependent manner. We have discovered that PSA is endocytosed, processed, and presented by APCs through MHCII and αβTCR engagement, and clonally expands CD4+FoxP3−CD25−CD45Rblo cells of an effector memory subset (RbloTEM). RbloTEM are capable of suppressing peripheral inflammation in way dependent on IL-10, however, they themselves do not produce the IL-10 necessary for suppression of disease. We show here that RbloTEM cells communicate directly with FoxP3+ Regulatory T cells, resulting in enhanced IL-10 production. Using novel FoxP3RFP/IL-10GFP dual reporter mice, we further demonstrate that this communication induces synergistic IL-10 expression specifically in Tregs, enhances Treg proliferation, and drives Treg-mediated immune inhibition by preferentially favoring the expansion of IL-10+ Tregs. Through promoting a robust and rapid Treg response, we show that the cytokine signature of PSA-responding RbloTEM cells and coordinating FoxP3+ Tregs can suppress mouse models of inflammatory disease, including HDM-induced asthma and EAE.

Cellular and Molecular Therapeutic Targets in Inflammatory Bowel Disease-Focusing on Intestinal Barrier Function.

The human gut relies on several cellular and molecular mechanisms to allow for an intact and dynamical intestinal barrier. Normally, only small amounts of luminal content pass the mucosa, however, if the control is broken it can lead to enhanced passage, which might damage the mucosa, leading to pathological conditions, such as inflammatory bowel disease (IBD). It is well established that genetic, environmental, and immunological factors all contribute in the pathogenesis of IBD, and a disturbed intestinal barrier function has become a hallmark of the disease. Genetical studies support the involvement of intestinal barrier as several susceptibility genes for IBD encode proteins with key functions in gut barrier and homeostasis. IBD patients are associated with loss in bacterial diversity and shifts in the microbiota, with a possible link to local inflammation. Furthermore, alterations of immune cells and several neuro-immune signaling pathways in the lamina propria have been demonstrated. An inappropriate immune activation might lead to mucosal inflammation, with elevated secretion of pro-inflammatory cytokines that can affect the epithelium and promote a leakier barrier. This review will focus on the main cells and molecular mechanisms in IBD and how these can be targeted in order to improve intestinal barrier function and reduce inflammation.

Epithelial-derived TGF-\u03b21 acts as a pro-viral factor in the lung during influenza A infection

Mucosal surfaces are under constant bombardment from potentially antigenic particles and so must maintain a balance between homeostasis and inappropriate immune activation and consequent pathology. Epithelial cells have a vital role orchestrating pulmonary homeostasis and defense against pathogens. TGF-β regulates an array of immune responses—both inflammatory and regulatory—however, its function is highly location- and context-dependent. We demonstrate that epithelial-derived TGF-β acts as a pro-viral factor suppressing early immune responses during influenza A infection. Mice specifically lacking bronchial epithelial TGF-β1 (epTGFβKO) displayed marked protection from influenza-induced weight loss, airway inflammation, and pathology. However, protection from influenza-induced pathology was not associated with a heightened lymphocytic immune response. In contrast, the kinetics of interferon beta (IFNβ) release into the airways was significantly enhanced in epTGFβKO mice compared with control mice, with elevated IFNβ on day 1 in epTGFβKO compared with control mice. This induced a heighted antiviral state resulting in impaired viral replication in epTGFβKO mice. Thus, epithelial-derived TGF-β acts to suppress early IFNβ responses leading to increased viral burden and pathology. This study demonstrates the importance of the local epithelial microenvironmental niche in shaping initial immune responses to viral infection and controlling host disease.

Red Blood Cells Homeostatically Bind Mitochondrial DNA through TLR9 to Maintain Quiescence and to Prevent Lung Injury.

Potentially hazardous CpG-containing cell-free mitochondrial DNA (cf-mtDNA) is routinely released into the circulation and is associated with morbidity and mortality in critically ill patients. How the body avoids inappropriate innate immune activation by cf-mtDNA remains unknown. Because red blood cells (RBCs) modulate innate immune responses by scavenging chemokines, we hypothesized that RBCs may attenuate CpG-induced lung inflammation through direct scavenging of CpG-containing DNA. To determine the mechanisms of CpG-DNA binding to RBCs and the effects of RBC-mediated DNA scavenging on lung inflammation. mtDNA on murine RBCs was measured under basal conditions and after systemic inflammation. mtDNA content on human RBCs from healthy control subjects and trauma patients was measured. Toll-like receptor 9 (TLR9) expression on RBCs and TLR9-dependent binding of CpG-DNA to RBCs were determined. A murine model of RBC transfusion after CpG-DNA-induced lung injury was used to investigate the role of RBC-mediated DNA scavenging in mitigating lung injury in vivo. Under basal conditions, RBCs bind CpG-DNA. The plasma-to-RBC mtDNA ratio is low in naive mice and in healthy volunteers but increases after systemic inflammation, demonstrating that the majority of cf-mtDNA is RBC-bound under homeostatic conditions and that the unbound fraction increases during inflammation. RBCs express TLR9 and bind CpG-DNA through TLR9. Loss of TLR9-dependent RBC-mediated CpG-DNA scavenging increased lung injury in vivo. RBCs homeostatically bind mtDNA, and RBC-mediated DNA scavenging is essential in mitigating lung injury after CpG-DNA. Our data suggest a role for RBCs in regulating lung inflammation during disease states where cf-mtDNA is elevated, such as sepsis and trauma.

The Type I Interferonopathies.

Type I interferons (IFNs) play a central role in the immune defense against viral infections. Type I IFN activation is induced by pattern-recognition receptors of the innate immune system that sense pathogen-derived nucleic acids. Cellular responses to type I IFN signaling are orchestrated by a complex network of regulatory pathways that involve both the innate and adaptive immune system. The genetic and molecular dissection of rare Mendelian disorders associated with constitutive overproduction of type I IFN has provided unique insight into cell-intrinsic disease mechanisms that initiate and sustain autoinflammation and autoimmunity and that are caused by disturbances in the intracellular nucleic acid metabolism or in cytosolic nucleic acid-sensing pathways. Collectively, these findings have greatly advanced our understanding of mechanisms that protect the organism against inappropriate immune activation triggered by self nucleic acids while maintaining a prompt and efficient immune response to foreign nucleic acids derived from invading pathogens.

The Transcriptional Repressor Polycomb Group Factor 6, PCGF6, Negatively Regulates Dendritic Cell Activation and Promotes Quiescence

Pro-inflammatory signals provided by the microenvironment are critical to activate dendritic cells (DCs), components of the innate immune system that shape both innate and adaptive immunity. However, to prevent inappropriate immune activation, mechanisms must be in place to restrain DC activation to ensure DCs are activated only once sufficient stimuli have been received. Here, we report that DC activation and immunogenicity are regulated by the transcriptional repressor Polycomb group factor 6 (PCGF6). Pcgf6 is rapidly downregulated upon stimulation, and this downregulation is necessary to permit fullDC activation. Silencing PCGF6 expression enhanced both spontaneous and stimulated DC activation. We show that PCGF6 associates with the H3K4me3 demethylase JARID1c, and together, they negatively regulate H3K4me3 levels in DCs. Our results identify two key regulators, PCGF6 and JARID1c that temper DC activation and implicate active transcriptional silencing via histone demethylation as a previously unappreciated mechanism for regulating DC activation and quiescence.

Pulmonary Epithelial Cell-Derived Cytokine TGF-β1 Is a Critical Cofactor for Enhanced Innate Lymphoid Cell Function

SummaryEpithelial cells orchestrate pulmonary homeostasis and pathogen defense and play a crucial role in the initiation of allergic immune responses. Maintaining the balance between homeostasis and inappropriate immune activation and associated pathology is particularly complex at mucosal sites that are exposed to billions of potentially antigenic particles daily. We demonstrated that epithelial cell-derived cytokine TGF-β had a central role in the generation of the pulmonary immune response. Mice that specifically lacked epithelial cell-derived TGF-β1 displayed a reduction in type 2 innate lymphoid cells (ILCs), resulting in suppression of interleukin-13 and hallmark features of the allergic response including airway hyperreactivity. ILCs in the airway lumen were primed to respond to TGF-β by expressing the receptor TGF-βRII and ILC chemoactivity was enhanced by TGF-β. These data demonstrate that resident epithelial cells instruct immune cells, highlighting the central role of the local environmental niche in defining the nature and magnitude of immune reactions.

Ubiquitin‐dependent regulation of Foxp3 and Treg function

Regulatory T (Treg) cells are crucial enforcers of immune homeostasis. Their characteristic suppressive function largely arises from an equally unique pattern of gene expression. A complex network of factors and processes contribute to this 'signature' Treg gene expression landscape. Many of these alter the level and activity of the Treg-defining transcription factor Foxp3. As stable expression of Foxp3 is important for the ability of Treg cells to successfully prevent excessive or inappropriate immune activation, uncovering the mechanisms regulating Foxp3 level is required for the understanding and therapeutic exploitation of Tregs. While transcriptional regulation of the Foxp3 gene has been studied in depth, additional regulatory layers exist controlling the expression and activity of this key transcription factor. These include less-defined mechanisms active at the post-translational level. These pathways are just beginning to be elucidated. Here, we summarize emerging evidence for distinct, post-translationally active, ubiquitin-dependent pathways capable of controlling the activation and expression of Foxp3 and the function of Tregs. These pathways offer untapped opportunities for therapeutic fine-tuning of Tregs and their all-important restraint of the immune system.

Attenuation of Colitis by Serum-Derived Bovine Immunoglobulin/Protein Isolate in a Defined Microbiota Mouse Model.

BackgroundThe pathogenesis of inflammatory bowel disease (IBD) is complex and multifaceted including genetic predisposition, environmental components, microbial dysbiosis, and inappropriate immune activation to microbial components. Pathogenic bacterial provocateurs like adherent and invasive E. coli have been reported to increase susceptibility to Crohn’s disease. Serum-derived bovine immunoglobulin/protein isolate (SBI) is comprised primarily of immunoglobulins (Igs) that bind to conserved microbial components and neutralize exotoxins.AimTo demonstrate that oral administration of SBI may modulate mucosal inflammation following colonization with E. coli, LF82, and exposure to dextran sodium sulfate (DSS).MethodsDefined microbiota mice harboring the altered Schaedler flora (ASF) were administered SBI or hydrolyzed collagen twice daily starting 7 days prior to challenge with E. coli LF82 and continuing for the remainder of the experiment. Mice were treated with DSS for 7 days and then evaluated for evidence of local and peripheral inflammation.ResultsIgs within SBI bound multiple antigens from all eight members of the ASF and E. coli LF82 by western blot analysis. Multiple parameters of LF82/DSS-induced colitis were reduced following administration of SBI, including histological lesion scores, secretion of cytokines and chemokines from cecal biopsies, intestinal fatty acid binding protein (I-FABP) and serum amyloid A from plasma.ConclusionsOral administration of SBI attenuated clinical signs of LF82/DSS-induced colitis in mice. The data are consistent with the hypothesis that SBI immunoglobulin binding of bacterial antigens in the intestinal lumen may inhibit the inflammatory cascades that contribute to IBD, thus attenuating DSS-induced colitis.Electronic supplementary materialThe online version of this article (doi:10.1007/s10620-015-3726-5) contains supplementary material, which is available to authorized users.