Debates in Allergy Medicine: Allergy skin testing cannot be replaced by molecular diagnosis in the near future

Percutaneous skin prick tests (SPT) have been considered the preferred method for confirming IgE-mediated sensitization. This reliable and minimally invasive technique correlates with in vivo challenges, has g...

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Debates in allergy medicine: Molecular allergy diagnosis with ISAC will replace screenings by skin prick test in the future

In today's clinical practice patients' skin is used as screening organ for diagnosing type 1 allergy. According to European guidelines skin prick testing with a panel of 18 allergen extracts is recommended, in...

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Pitted keratolysis – a study of various clinical manifestations

Abstract

Background

Pitted keratolysis (PK) is a common bacterial infection of skin characterized by noninflammatory superficial pits. Very few studies have focused on variations in clinical manifestations of PK. We conducted this study so that diagnosis of this treatable condition is not missed when it presents in an uncommonly perceived way.

Aims and objectives

Assessment of PK patients for various sites and morphologies.

Materials and methods

A total of 30 patients with PK were assessed for various sites and morphologies. Bacterial and fungal cultures along with histopathology were performed.

Results

Of 30 patients, 24 were females. Hyperhidrosis and malodour were the most common symptoms. Interdigital interface skin of the toes was the first site affected in most patients. Plantar skin was affected in all patients with involvement of interface skin of the toes in 29 patients. Other sites affected were palms, finger web spaces, nonglabrous skin, paronychium, and nail. Other than classical pits, scaly crusted inflammatory lesions with post-inflammatory hyperpigmentation (PIH) were noted. Associated keratoderma was also reported in some patients.

Discussion

The presence of hyperhidrosis, malodour, and plantar lesions is consistent with previous studies. Interface skin between toes as the first site affected, involvement of toe web spaces, and associated keratoderma have been reported rarely. However, female preponderance, involvement of finger web spaces, nonglabrous skin, paronychium, nail changes, the presence of inflammation with crusting, and PIH have never been reported previously.

Conclusion

PK can involve web spaces, nonglabrous skin, and paronychium, and can cause nail changes. The lesions can be inflammatory with crusting and PIH.

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Reply to “Transungual fibrokeratoma”

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Kimura's disease in the oral cavity: A rare manifestation of immunoglobulin G4-related disease

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Serum vascular endothelial growth factor A levels reflect itch severity in mycosis fungoides and Sézary syndrome

Abstract

Angiogenesis is an important step to support progression of malignancies, including mycosis fungoides (MF) and Sézary syndrome (SS). Vascular endothelial growth factor (VEGF)-A, a key player in angiogenesis, is secreted by tumor cells of MF/SS and its expression levels in lesional skin correlated with disease severity. In this study, we examined serum VEGF-A levels in MF/SS patients. Serum VEGF-A levels were elevated in patients with erythrodermic MF/SS and the levels decreased after treatment. Importantly, serum VEGF-A levels positively correlated with markers for pruritus. We also found that VEGF-A upregulated mRNA expression of thymic stromal lymphopoietin by keratinocytes. Taken together, our study suggests that VEGF-A can promote progression and pruritus in MF/SS. Inhibition of VEGF-A signaling can be a therapeutic strategy for patients with erythrodermic MF/SS.

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Autoimmune diseases involving skin and intestinal mucosa are more frequent in adolescents and young adults suffering from atopic dermatitis

Abstract

Evidence has emerged about the relationship between atopic dermatitis (AD) and autoimmune diseases, but the underlying mechanism of this association is complex and still unclear. Recent epidemiological data from the published work suggest a positive correlation. The aim of this review is to analyze the frequency of co-occurrence of AD and autoimmune diseases. Our systematic review included 22 articles from PubMed describing the reciprocal association between AD and autoimmune diseases. Although not all the studies achieved statistically significant results, patients suffering from autoimmune diseases involving skin and intestinal mucosa, such as vitiligo, alopecia areata, celiac disease and inflammatory bowel diseases, showed a higher risk to have AD as comorbidity. In contrast, patients with rheumatological autoimmune disorders did not show a significant correlation with AD. By analyzing the occurrence of autoimmune disorders in patients with AD, we confirmed a positive correlation between AD and autoimmune diseases involving skin and intestinal mucosa, but also with systemic lupus erythematosus, while the association between AD and type 1 diabetes, autoimmune thyroiditis and rheumatoid arthritis showed conflicting results. Further investigations are need to explain the mechanism underlying the observed comorbidity between AD and autoimmune diseases and to develop targeted prevention strategies and treatment.

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Lipofuscin deposition causes the pigmentation of apocrine hidrocystoma

Abstract

Apocrine hidrocystoma (AHC) is a benign cystic lesion arising from apocrine glands and frequently presents as a blue hae with a whitish gloss. It has been reported that the amount of lipofuscin and the degree of its oxidation determines the pigmentation of AHC. However, little is known about the correlation between clinical color and lipofuscin granules. In this study, we histopathologically investigated three cases of AHC and statistically analyzed the quantitative correlation between the clinical color tone and the amount of cytoplasmic lipofuscin deposits. The color tone was quantified as the mean gray value using Image J software. Statistical analysis showed a negative correlative tendency (P = 0.09) between the color tone and the amount of lipofuscin. Our study suggests that the color tone of AHC is associated with the amount of lipofuscin.

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Dermoscopy of linear dermatosis along Blaschko's line in childhood: Lichen striatus versus inflammatory linear verrucous epidermal nevus

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Adult-onset Still's disease presenting with shawl sign-like eruption

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Marital status as a predictor of survival in patients with human papilloma virus-positive oropharyngeal cancer

Determine whether marital status is a significant predictor of survival in human papillomavirus-positive oropharyngeal cancer.

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Comparison of radiation doses imparted during 128-multislice CT-scanners and cone beam computed tomography for intra- and perioperative cochlear implant assessment

To examine radiation-doses imparted during multislice (MSCT) and cone-beam computed-tomography (CBCT) for perioperative examination of cochlear-implant insertion.

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The folded postauricular flap: A novel approach to reconstruction of large full thickness defects of the conchal bowl

Extensive subtotal full-thickness auriculectomy defects pose a challenge for the reconstructive surgeon. The posterior island flap (PIF), based on the posterior auricular artery, has been described as a reconstructive option for auricular defects, with reports describing a "pull-through" or "revolving door" technique to reconstruct subtotal partial thickness and full thickness auricular defects. These techniques may result in posterior "pinning" of the auricle. This patient is an 87-year-old male who presented after Mohs excision of squamous cell carcinoma of the conchal bowl, which resulted in a 4x4cm subtotal auriculectomy defect.

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Serous retinal detachment after panretinal photocoagulation for proliferative diabetic retinopathy: a case report

Proliferative diabetic retinopathy is a major cause of visual impairment in working-age adults worldwide. Panretinal photocoagulation is a cornerstone in its management; however, it may include a range of side...

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Treatment outcomes of sialendoscopy for submandibular gland sialolithiasis: The minor axis of the sialolith is a regulative factor for the removal of sialoliths in the hilum of the submandibular gland using sialendoscopy alone

To assess the general guidelines for the removal of sialoliths for submandibular gland sialolithiasis using sialendoscopy alone.

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Alanine Aminotransferase and Total Bilirubin Are Synergistically Associated with Metabolic Syndrome Among Middle-Aged and Elderly Japanese Women

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.


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The Currency of Science

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.


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Immune regulation by histamine and histamine-secreting bacteria

Weronika Barcik | Marcin Wawrzyniak | Cezmi A Akdis | Liam O'Mahony

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Macrophage-Restricted Shp2 Tyrosine Phosphatase Acts as a Rheostat for MMP12 through TGF-{beta} Activation in the Prevention of Age-Related Emphysema in Mice [IMMUNE REGULATION]

Persistent activation of macrophages in lungs plays a critical role in the production of matrix metalloproteinases (MMPs) that contributes to the destruction of alveolar walls, a hallmark for pulmonary emphysema. Dysregulated TGF-β1 signaling has been an essential determinant in the elevation of MMPs during the development of emphysema. Nevertheless, the mechanism for this MMP-dependent pathogenesis has yet to be clearly investigated. Recently, we identified an important role for tyrosine phosphatase Src homology domain-containing protein tyrosine phosphatase 2 (Shp2) in regulating the activation of alveolar macrophages. Over a long-term observation period, mice with Shp2 deletion in macrophages (LysMCre:Shp2^fl/fl) develop spontaneous, progressive emphysema-like injury in the lungs, characterized by massive destruction of alveolar morphology, interstitial extracellular matrix degradation, and elevated levels of MMPs, particularly, significant increases of macrophage elastase (MMP12) in aged mice. Further analysis demonstrated that MMP12 suppression by TGF-β1 activation was apparently abrogated in LysMCre:Shp2^fl/fl mice, whereas the TGF-β1 concentration in the lungs was relatively the same. Mechanistically, we found that loss of Shp2 resulted in attenuated SMAD2/3 phosphorylation and nuclear translocation in response to TGF-β activation, thereby upregulating MMP12 expression in macrophages. Together, our findings define a novel physiological function of Shp2 in TGF-β1/MMP12-dependent emphysema, adding insights into potential etiologies for this chronic lung disorder.

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A Coronin 1-Dependent Decision Switch in Juvenile Mice Determines the Population of the Peripheral Naive T Cell Compartment [IMMUNE SYSTEM DEVELOPMENT]

Following thymic maturation, T cells egress as recent thymic emigrants to peripheral lymphoid organs where they undergo an additional maturation step to mature naive T cells that circulate through secondary lymphoid organs ready to be activated upon pathogenic challenges. Thymic maturation and peripheral T cell survival depend on several signaling cascades, but whether a dedicated mechanism exists that exclusively regulates homeostasis of mature naive T cells without affecting thymocytes and/or recent thymic emigrants remains unknown. In this article, we provide evidence for a specific and exclusive role of the WD repeat containing protein coronin 1 in the maintenance of naive T cells in peripheral lymphoid organs. We show that coronin 1 is dispensable for thymocyte survival and development, egress from the thymus, and survival of recent thymic emigrants. Importantly, coronin 1–deficient mice possessed comparable levels of peripheral T cells within the first 2 wk after birth but failed to populate the peripheral T cell compartment at later stages. Furthermore, dendritic cell– and IL-2/7–dependent T cell survival was found to be independent of coronin 1. Together, these results suggest the existence of a hitherto unrecognized coronin 1–dependent decision switch early during life that is responsible for peripheral naive T cell survival and homeostasis.

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IL-2 Shapes the Survival and Plasticity of IL-17-Producing {gamma}{delta} T Cells [IMMUNE REGULATION]

IL-17–producing T (T-17) cells have proved to be an important early source of IL-17 in many inflammatory settings and are emerging as an important participant in protumor immune responses. Considering that their peripheral activation depends largely on innate signals rather than TCR ligation, it is important to understand what mechanisms exist to curb unwanted activation. Expression of the high-affinity IL-2R on T-17 cells prompted us to investigate a role for this cytokine. We found T-17 cells to be enriched, not depleted, in IL-2–deficient mice. The absence of IL-2 also resulted in higher IL-17 production and the emergence of IL-17⁺IFN-⁺ double producers. Furthermore, the addition of IL-2 to in vitro cultures of sorted T-17 cells was able to moderate IL-17 and affect differentiation into polyfunctional cytokine-producing cells. Interestingly, the V6⁺ subset was more susceptible to the effects of IL-2 than V4⁺ T-17 cells. We also found that unlike other T cells, T-17 cells do not produce IL-2, but express Blimp-1, a known transcriptional repressor of IL-2. Although IL-2 was able to induce robust proliferation of T-17 cells, it did not sustain viability, negatively impacting their survival via downregulation of the IL-7R. Taken together, these data indicate that IL-2 can augment the T-17 response in favor of short-lived effectors with limited plasticity, particularly in the presence of IL-1β and IL-23. In this way, IL-2 may act to curtail the innate-like response of T-17 cells upon arrival of IL-2–producing adaptive immune cells at the site of inflammation.

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A Plant-Derived Nucleic Acid Reconciles Type I IFN and a Pyroptotic-like Event in Immunity against Respiratory Viruses [INNATE IMMUNITY AND INFLAMMATION]

Nucleic acids carrying pathogen-associated molecular patterns trigger innate immune responses and are used to activate host immunity. Although synthetic nucleic acids have been used for that purpose, they have shown limitations for in vivo and clinical applications. To address this issue, we tested a naturally occurring dsRNA extracted from rice bran (rb-dsRNA) and characterized it as a potent ligand of TLR3 and MDA5. In this study, intranasal administration of rb-dsRNA induced production of type I IFNs by alveolar macrophages and protected mice from morbidity and mortality resulting from respiratory virus infection, such as influenza A virus. This protection was completely absent in mice lacking both TRIF and MDA5, indicating the essential role of TLR3- and MDA5-dependent pathways. Interestingly, IFNAR1-deficient mice retained residual antiviral protection, which was abolished by pharmacological inhibition of caspase 1, but not IL-1β signaling. In fact, rb-dsRNA activated caspase 1 via TRIF, resulting in the release of IL-1β and LDH. In addition to the direct antiviral activity, rb-dsRNA modulated the immune cell population in the lungs by repopulating virus-depleted alveolar macrophages. Our data demonstrate that rb-dsRNA orchestrates IFN-dependent and -independent direct antiviral protection and that it is a potent immune stimulator modulating antiviral immunity in the lungs. These findings open doors to a range of precise immune-modulating studies and therapeutic options.

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CXCL12-CXCR4 Axis Is Required for Contact-Mediated Human B Lymphoid and Plasmacytoid Dendritic Cell Differentiation but Not T Lymphoid Generation [IMMUNE REGULATION]

We investigated the involvement of CXCL12–CXCR4 interactions in human lymphohematopoiesis by coculture with telomerized human stromal cells. CXCR4 expression was low in CD34⁺CD38^–CD45RA^–CD10^–CD7^–CD19^– immature hematopoietic stem/precursor cells (HSPCs) but higher in CD34⁺CD38^–CD45RA⁺CD10⁺CD7^+/–CD19^– early lymphoid precursors and even higher in CD34⁺CD38⁺CD45RA⁺CD10⁺CD7^–CD19⁺ pro-B cells. Inhibition of the effect of stromal cell–produced CXCL12 by an anti-CXCR4–blocking Ab suppressed the generation of CD45RA⁺CD10^–CD7⁺CD19^– early T lymphoid precursors (ETPs) and CD45RA⁺CD10⁺CD7^–CD19^+/– B lymphoid precursors on stromal cells, but it did not affect the generation of ETPs in conditioned medium of stromal cell cultures. Replating assays showed that contact with stromal cells was critical for HSPC-derived CD45RA⁺CD10⁺CD7^–CD19^– B lineage–biased precursors to differentiate into CD19⁺ pro-B cells, which was suppressed by the anti-CXCR4 Ab. Conversely, HSPC-derived ETPs possessed T and B lymphoid and monocytic differentiation potential; stromal cell contact was not required for their growth but rather promoted B lymphoid differentiation. The anti-CXCR4 Ab did not affect the growth of ETPs in conditioned medium, but it suppressed their B lymphoid differentiation on stromal cells. CD14^–CD11c^–HLA-DR⁺CD123^highCD303⁺ plasmacytoid dendritic cells developed from HSPCs and ETPs exclusively in contact with stromal cells, which was suppressed by the anti-CXCR4 Ab. These data indicate that CXCL12 plays an essential role in stromal cell contact–mediated B lymphoid and plasmacytoid dendritic cell differentiation from immature hematopoietic and early T lymphoid precursors with a multilineage differentiation potential, but it does not participate in contact-independent generation of early T lymphoid precursors.

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Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity [IMMUNE REGULATION]

BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27⁺ memory and memory-like CD27^–IgD^– double-negative (DN) B cells, but not CD27^–IgD⁺ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27⁺ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines.

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Characterization of Mycobacterium tuberculosis-Specific Cells Using MHC Class II Tetramers Reveals Phenotypic Differences Related to HIV Infection and Tuberculosis Disease [INFECTIOUS DISEASE AND HOST RESPONSE]

A major challenge for the development of an effective vaccine against tuberculosis (TB) is that the attributes of protective CD4⁺ T cell responses are still elusive for human TB. Infection with HIV type 1 is a major risk factor for TB, and a better understanding of HIV-induced alterations of Mycobacterium tuberculosis–specific CD4⁺ T cells that leads to failed host resistance may provide insight into protective T cell immunity to TB. A total of 86 participants from a TB-endemic setting, either HIV-infected or uninfected and with latent or active TB (aTB), were screened using M. tuberculosis–specific MHC class II tetramers. We examined the phenotype as well as function of ex vivo M. tuberculosis–specific tetramer⁺CD4⁺ T cells using flow cytometry. The numbers of M. tuberculosis–specific tetramer⁺CD4⁺ T cells were relatively well maintained in HIV-infected persons with aTB, despite severe immunodeficiency. However, although HIV-uninfected persons with latent TB infection exhibited ex vivo M. tuberculosis–specific CD4⁺ T cells predominantly of a CXCR3⁺CCR6⁺CCR4^– (Th1*) phenotype, aTB or HIV infection was associated with a contraction of this subset. Nevertheless, in individuals with aTB and/or HIV infection, circulating ex vivo M. tuberculosis–specific CD4⁺ T cells did not display defects in exhaustion or polyfunctionality compared with healthy HIV-uninfected individuals with latent TB infection. Collectively, these data suggest that increased susceptibility to TB disease could be related to a loss of circulating Th1* CD4⁺ T cells rather than major changes in the number or function of circulating CD4⁺ T cells.

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Carbon Nanoparticles Inhibit the Antimicrobial Activities of the Human Cathelicidin LL-37 through Structural Alteration [INNATE IMMUNITY AND INFLAMMATION]

Host defense peptides, also known as antimicrobial peptides, are key elements of innate host defense. One host defense peptide with well-characterized antimicrobial activity is the human cathelicidin, LL-37. LL-37 has been shown to be upregulated at sites of infection and inflammation and is regarded as one of the primary innate defense molecules against bacterial and viral infection. Human exposure to combustion-derived or engineered nanoparticles is of increasing concern, and the implications of nanomaterial exposure on the human immune response is poorly understood. However, it is widely acknowledged that nanoparticles can interact strongly with several immune proteins of biological significance, with these interactions resulting in structural and functional changes of the proteins involved. This study investigated whether the potent antibacterial and antiviral functions of LL-37 were inhibited by exposure to, and interaction with, carbon nanoparticles, together with characterizing the nature of the interaction. LL-37 was exposed to carbon black nanoparticles in vitro, and the antibacterial and antiviral functions of the peptide were subsequently assessed. We demonstrate a substantial loss of antimicrobial function when the peptide was exposed to low concentrations of nanomaterials, and we further show that the nanomaterial-peptide interaction resulted in a significant change in the structure of the peptide. The human health implications of these findings are significant, as, to our knowledge, this is the first evidence that nanoparticles can alter host defense peptide structure and function, indicating a new role for nanoparticle exposure in increased disease susceptibility.

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IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-{kappa}B [IMMUNE REGULATION]

Group 3 innate lymphoid cells (ILC3s) are important regulators of the immune system, maintaining homeostasis in the presence of commensal bacteria, but activating immune defenses in response to microbial pathogens. ILC3s are a robust source of IL-22, a cytokine critical for stimulating the antimicrobial response. We sought to identify cytokines that can promote proliferation and induce or maintain IL-22 production by ILC3s and determine a molecular mechanism for this process. We identified IL-18 as a cytokine that cooperates with an ILC3 survival factor, IL-15, to induce proliferation of human ILC3s, as well as induce and maintain IL-22 production. To determine a mechanism of action, we examined the NF-B pathway, which is activated by IL-18 signaling. We found that the NF-B complex signaling component, p65, binds to the proximal region of the IL22 promoter and promotes transcriptional activity. Finally, we observed that CD11c⁺ dendritic cells expressing IL-18 are found in close proximity to ILC3s in human tonsils in situ. Therefore, we identify a new mechanism by which human ILC3s proliferate and produce IL-22, and identify NF-B as a potential therapeutic target to be considered in pathologic states characterized by overproduction of IL-18 and/or IL-22.

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A20 Restrains Thymic Regulatory T Cell Development [IMMUNE REGULATION]

Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (T_reg) cells in the thymus. Activation of NF-B transcription factors is critically required for T_reg cell development, partly via initiating Foxp3 expression. NF-B activation is controlled by a negative feedback regulation through the ubiquitin editing enzyme A20, which reduces proinflammatory signaling in myeloid cells and B cells. In naive CD4⁺ T cells, A20 prevents kinase RIPK3-dependent necroptosis. Using mice deficient for A20 in T lineage cells, we show that thymic and peripheral T_reg cell compartments are quantitatively enlarged because of a cell-intrinsic developmental advantage of A20-deficient thymic T_reg differentiation. A20-deficient thymic T_reg cells exhibit reduced dependence on IL-2 but unchanged rates of proliferation and apoptosis. Activation of the NF-B transcription factor RelA was enhanced, whereas nuclear translocation of c-Rel was decreased in A20-deficient thymic T_reg cells. Furthermore, we found that the increase in T_reg cells in T cell–specific A20-deficient mice was already observed in CD4⁺ single-positive CD25⁺ GITR⁺ Foxp3^– thymic T_reg cell progenitors. T_reg cell precursors expressed high levels of the tumor necrosis factor receptor superfamily molecule GITR, whose stimulation is closely linked to thymic T_reg cell development. A20-deficient T_reg cells efficiently suppressed effector T cell–mediated graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, suggesting normal suppressive function. Holding thymic production of natural T_reg cells in check, A20 thus integrates T_reg cell activity and increased effector T cell survival into an efficient CD4⁺ T cell response.

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Ectopic Expression of Self-Antigen Drives Regulatory T Cell Development and Not Deletion of Autoimmune T Cells [AUTOIMMUNITY]

Type 1 diabetes is a T cell–mediated autoimmune disease that is characterized by Ag-specific targeting and destruction of insulin-producing β cells. Although multiple studies have characterized the pathogenic potential of β cell–specific T cells, we have limited mechanistic insight into self-reactive autoimmune T cell development and their escape from negative selection in the thymus. In this study, we demonstrate that ectopic expression of insulin epitope B:9–23 (InsB_9–23) by thymic APCs is insufficient to induce deletion of high- or low-affinity InsB_9–23–reactive CD4⁺ T cells; however, we observe an increase in the proportion and number of thymic and peripheral Foxp3⁺ regulatory T cells. In contrast, the MHC stable insulin mimetope (InsB_9–23 R22E) efficiently deletes insulin-specific T cells and prevents escape of high-affinity thymocytes. Collectively, these results suggest that Ag dose and peptide–MHC complex stability can lead to multiple fates of insulin-reactive CD4⁺ T cell development and autoimmune disease outcome.

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Anti-Cancer Drug HMBA Acts as an Adjuvant during Intracellular Bacterial Infections by Inducing Type I IFN through STING [INNATE IMMUNITY AND INFLAMMATION]

The anti-proliferative agent hexamethylene bisacetamide (HMBA) belongs to a class of hybrid bipolar compounds developed more than 30 y ago for their ability to induce terminal differentiation of transformed cells. Recently, HMBA has also been shown to trigger HIV transcription from latently infected cells, via a CDK9/HMBA inducible protein-1 dependent process. However, the effect of HMBA on the immune response has not been explored. We observed that pretreatment of human peripheral blood mononuclear cells with HMBA led to a markedly increased production of IL-12 and IFN-, but not of TNF-α, IL-6, and IL-8 upon subsequent infection with Burkholderia pseudomallei and Salmonella enterica. HMBA treatment was also associated with better intracellular bacterial control. HMBA significantly improved IL-12p70 production from CD14⁺ monocytes during infection partly via the induction of type I IFN in these cells, which primed an increased transcription of the p35 subunit of IL-12p70 during infection. HMBA also increased early type I IFN transcription in human monocytic and epithelial cell lines, but this was surprisingly independent of its previously reported effects on positive transcription elongation factor b and HMBA inducible protein-1. Instead, the effect of HMBA was downstream of a calcium influx, and required the pattern recognition receptor and adaptor STING but not cGAS. Our work therefore links the STING-IRF3 axis to enhanced IL-12 production and intracellular bacterial control in primary monocytes. This raises the possibility that HMBA or related small molecules may be explored as therapeutic adjuvants to improve disease outcomes during intracellular bacterial infections.

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Klhl6 Deficiency Impairs Transitional B Cell Survival and Differentiation [IMMUNE SYSTEM DEVELOPMENT]

Klhl6 belongs to the KLHL gene family, which is composed of an N-terminal BTB-POZ domain and four to six Kelch motifs in tandem. Several of these proteins function as adaptors of the Cullin3 E3 ubiquitin ligase complex. In this article, we report that Klhl6 deficiency induces, as previously described, a 2-fold reduction in mature B cells. However, we find that this deficit is centered on the inability of transitional type 1 B cells to survive and to progress toward the transitional type 2 B cell stage, whereas cells that have passed this step generate normal germinal centers (GCs) upon a T-dependent immune challenge. Klhl6-deficient type 1 B cells showed a 2-fold overexpression of genes linked with cell proliferation, including most targets of the anaphase-promoting complex/cyclosome complex, a set of genes whose expression is precisely downmodulated upon culture of splenic transitional B cells in the presence of BAFF. These results thus suggest a delay in the differentiation process of Klhl6-deficient B cells between the immature and transitional stage. We further show, in the BL2 Burkitt's lymphoma cell line, that KLHL6 interacts with Cullin3, but also that it binds to HBXIP/Lamtor5, a protein involved in cell-cycle regulation and cytokinesis. Finally, we report that KLHL6, which is recurrently mutated in B cell lymphomas, is an off-target of the normal somatic hypermutation process taking place in GC B cells in both mice and humans, thus leaving open whether, despite the lack of impact of Klhl6 deficiency on GC B cell expansion, mutants could contribute to the oncogenic process.

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In This Issue [IN THIS ISSUE]

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TIM-4 Identifies IFN-{gamma}-Expressing Proinflammatory B Effector 1 Cells That Promote Tumor and Allograft Rejection [TRANSPLANTATION]

B cells give rise to polarized subsets, including B effector 1 (Be1) cells and regulatory B cells, which can promote or inhibit immune responses through expression of IFN- and IL-10, respectively. Such subsets likely explain why B cell depletion can either ameliorate or exacerbate inflammatory diseases; however, these cells remain poorly understood because of the absence of specific markers. Although T cell Ig and mucin domain-containing molecule (TIM)-1 broadly identifies IL-10⁺ regulatory B cells, no similar markers for Be1 cells have been described. We now show that TIM-4 is expressed by a subset of B cells distinct from those expressing TIM-1. Although TIM-1⁺ B cells are enriched for IL-10, TIM-4⁺ B cells are enriched for IFN-. TIM-1⁺ B cells enhanced the growth of B16-F10 melanoma. In contrast, TIM-4⁺ B cells decreased B16-F10 metastasis and s.c. tumor growth, and this was IFN- dependent. TIM-1⁺ B cells prolonged islet allograft survival in B-deficient mice, whereas TIM-4⁺ B cells accelerated rejection in an IFN-–dependent manner. Moreover, TIM-4⁺ B cells promoted proinflammatory Th differentiation in vivo, increasing IFN- while decreasing IL-4, IL-10, and Foxp3 expression by CD4⁺ T cells—effects that are opposite from those of TIM-1⁺ B cells. Importantly, a monoclonal anti–TIM-4 Ab promoted allograft tolerance, and this was dependent on B cell expression of TIM-4. Anti–TIM-4 downregulated T-bet and IFN- expression by TIM-4⁺ B cells and indirectly increased IL-10 expression by TIM-1⁺ B cells. Thus, TIM-4⁺ B cells are enriched for IFN-–producing proinflammatory Be1 cells that enhance immune responsiveness and can be specifically targeted with anti–TIM-4.

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M1 Means Kill; M2 Means Heal [PILLARS OF IMMUNOLOGY]

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Chemokine Receptor-Dependent Control of Skin Tissue-Resident Memory T Cell Formation [INFECTIOUS DISEASE AND HOST RESPONSE]

Infection or inflammation of the skin recruits effector CD8⁺ T cells that enter the epidermis and form populations of long-lived tissue-resident memory T (T_RM) cells. These skin T_RM cells migrate within the constrained epidermal environment by extending multiple dynamic dendritic projections and squeezing between keratinocytes to survey the tissue for pathogens. In this study, we examined the signals required for this distinctive mode of T cell migration by inhibiting key cytoskeletal components and performing intravital two-photon microscopy to visualize T_RM cell behavior. We found that T_RM cell motility and dendrite formation required an intact actomyosin cytoskeleton and the Rho-associated coiled-coil containing kinases. We also identified an essential role for microtubules for maintaining skin T_RM cell shape and cellular integrity. We reveal a role for pertussis toxin–sensitive signaling for T_RM cell dendritic morphology and migration that is independent of CXCR3 or CXCR6, or the skin-selective chemokine receptors CCR10 and CCR8. However, we found that CXCR6 and CCR10 expression by CD8⁺ T cells was required for the optimal formation of memory T cell populations, in particular T_RM cell populations in the skin.

http://ift.tt/2xbCeXZ

Pillars Article: M-1/M-2 Macrophages and the Th1/Th2 Paradigm. J. Immunol. 2000. 164: 6166-6173 [PILLARS OF IMMUNOLOGY]

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IL-15 Complexes Induce Migration of Resting Memory CD8 T Cells into Mucosal Tissues [MUCOSAL IMMUNOLOGY]

IL-15 is an essential cytokine known to promote T cell survival and activate the effector function of memory phenotype CD8 T cells. Blocking IL-15 signals also significantly impacts tissue-specific effector and memory CD8 T cell formation. In this study, we demonstrate that IL-15 influences the generation of memory CD8 T cells by first promoting their accumulation into mucosal tissues and second by sustaining expression of Bcl-6 and T-bet. We show that the mechanism for this recruitment is largely dependent on mammalian target of rapamycin and its subsequent inactivation of FoxO1. Last, we show that IL-15 complexes delivered locally to mucosal tissues without reinfection is an effective strategy to enhance establishment of tissue resident memory CD8 T cells within mucosal tissues. This study provides mechanistic insight into how IL-15 controls the generation of memory CD8 T cells and influences their trafficking and ability to take up residence within peripheral tissues.

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Emerging Concepts in TCR Specificity: Rationalizing and (Maybe) Predicting Outcomes [BRIEF REVIEWS]

T cell specificity emerges from a myriad of processes, ranging from the biological pathways that control T cell signaling to the structural and physical mechanisms that influence how TCRs bind peptides and MHC proteins. Of these processes, the binding specificity of the TCR is a key component. However, TCR specificity is enigmatic: TCRs are at once specific but also cross-reactive. Although long appreciated, this duality continues to puzzle immunologists and has implications for the development of TCR-based therapeutics. In this review, we discuss TCR specificity, emphasizing results that have emerged from structural and physical studies of TCR binding. We show how the TCR specificity/cross-reactivity duality can be rationalized from structural and biophysical principles. There is excellent agreement between predictions from these principles and classic predictions about the scope of TCR cross-reactivity. We demonstrate how these same principles can also explain amino acid preferences in immunogenic epitopes and highlight opportunities for structural considerations in predictive immunology.

http://ift.tt/2xcCQwL

Integrated STAT3 and Ikaros Zinc Finger Transcription Factor Activities Regulate Bcl-6 Expression in CD4+ Th Cells [IMMUNE REGULATION]

B cell lymphoma-6 (Bcl-6) is a transcriptional repressor that is required for the differentiation of T follicular helper (T_FH) cell populations. Currently, the molecular mechanisms underlying the transcriptional regulation of Bcl-6 expression are unclear. In this study, we have identified the Ikaros zinc finger transcription factors Aiolos and Ikaros as novel regulators of Bcl-6. We found that increased expression of Bcl-6 in CD4⁺ Th cell populations correlated with enhanced enrichment of Aiolos and Ikaros at the Bcl6 promoter. Furthermore, overexpression of Aiolos or Ikaros, but not the related family member Eos, was sufficient to induce Bcl6 promoter activity. Intriguingly, STAT3, a known Bcl-6 transcriptional regulator, physically interacted with Aiolos to form a transcription factor complex capable of inducing the expression of Bcl6 and the T_FH-associated cytokine receptor Il6ra. Importantly, in vivo studies revealed that the expression of Aiolos was elevated in Ag-specific T_FH cells compared with that observed in non-T_FH effector Th cells generated in response to influenza infection. Collectively, these data describe a novel regulatory mechanism through which STAT3 and the Ikaros zinc finger transcription factors Aiolos and Ikaros cooperate to regulate Bcl-6 expression.

http://ift.tt/2xdEeza

Rhinovirus Infection of ORMDL3 Transgenic Mice Is Associated with Reduced Rhinovirus Viral Load and Airway Inflammation [ALLERGY AND OTHER HYPERSENSITIVITIES]

Orosomucoid like 3 (ORMDL3), a gene localized to chromosome 17q21, has been linked in epidemiologic studies to childhood asthma and rhinovirus (RV) infections. As the single nucleotide polymorphisms linking ORMDL3 to asthma are associated with increased expression of ORMDL3, we have used hORMDL3^zp3-Cre mice (which have universal increased expression of human ORMDL3) to determine whether infection of these transgenic mice with RV influences levels of airway inflammation or RV viral load. RV infection of hORMDL3^zp3-Cre mice resulted in reduced RV viral load assessed by quantitative real-time PCR (lung and airway epithelium), as well as reduced airway inflammation (total bronchoalveolar lavage cells, neutrophils, macrophages, and lymphocytes) compared with RV-infected wild-type mice. Levels of the antiviral pathways including IFNs (IFN-α, IFN-β, IFN-) and RNAse L were significantly increased in the lungs of RV-infected hORMDL3^zp3-Cre mice. Levels of the antiviral mouse oligoadenylate synthetase (mOas)1g pathway and RNAse L were upregulated in the lungs of unchallenged hORMDL3^zp3-Cre mice. In addition, levels of mOas2, but not mOas1 (mOas1a, mOas1b, mOas1g), or mOas3 pathways were significantly more upregulated by IFNs (IFN-α, IFN-β, IFN-) in epithelial cells from hORMDL3^zp3-Cre mice compared with RV-infected wild-type mouse epithelial cells. RNAse L–deficient mice infected with RV had increased RV viral load. Overall, these studies suggest that increased levels of ORMDL3 contribute to antiviral defense to RV infection in mice through pathways that may include IFNs (IFN-α, IFN-β, IFN-), OAS, and RNAse L.

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Single Nucleotide Polymorphisms of the High Affinity IgG Receptor Fc{gamma}RI Reduce Immune Complex Binding and Downstream Effector Functions [IMMUNOGENETICS]

Binding of IgG Abs to FcRs on immune cells induces FcR cross-linking that leads to cellular effector functions, such as phagocytosis, Ab-dependent cellular cytotoxicity, and cytokine release. However, polymorphisms in low affinity FcRs have been associated with altered avidity toward IgG, thereby substantially impacting clinical outcomes of multimodular therapy when targeting cancer or autoimmune diseases with mAbs as well as the frequency and severity of autoimmune diseases. In this context, we investigated the consequences of three nonsynonymous single nucleotide polymorphisms (SNPs) for the high affinity receptor for IgG, FcRI. Only SNP V39I, located in the extracellular domain of FcRI, reduces immune-complex binding of FcRI whereas monomeric IgG binding is unaffected. This leads to reduced FcRI effector functions, including Fc receptor -chain signaling and intracellular calcium mobilization. SNPs I301M and I338T, located in the transmembrane or intracellular domain, respectively, have no influence on monomeric IgG or immune complex binding, but FcR signaling is decreased for both SNPs, especially for I338T. We also found that the frequency of these SNPs in a cohort of healthy Dutch individuals is very low within the population. To our knowledge, this study addresses for the first time the biological consequences of SNPs in the high affinity FcR, and reveals reduction in several FcRI functions, which have the potential to alter efficacy of therapeutic Abs.

http://ift.tt/2xbCiqH

Role of Lymphocyte Subsets in the Immune Response to Primary B Cell-Derived Exosomes [ANTIGEN RECOGNITION AND RESPONSES]

Exosomes are lipid nanovesicles released after fusion of the endosomal limiting membrane with the plasma membrane. In this study, we investigated the requirement for CD4 T cells, B cells, and NK cells to provide help for CD8 T cell–mediated response to B cell–derived exosomes. CTL responses to Ag-loaded exosomes were dependent on host MHC class I, with a critical role for splenic langerin⁺ CD8α⁺ dendritic cells (DCs) in exosomal Ag cross-presentation. In addition, there was an absolute dependence on the presence of CD4 T cells, CD8 T cells, and NK cells, where the loss of any one of these subsets led to a complete loss of CTL response. Interestingly, NK cell depletion experiments demonstrated a critical cutoff point for depletion efficacy, with low-level residual NK cells providing sufficient help to allow optimal CD8 T cell proliferative responses to exosomal protein. Despite the potential role for B cells in the response to B cell–derived exosomal proteins, B cell depletion did not alter the exosome-induced CTL response. Similarly, a possible role for the BCR or circulating Ab in mediating CTL responses to B cell–derived exosomes was ruled out using D_HLMP2A mice, which lack secreted and membrane-bound Ab, yet harbor marginal zone and follicular B cells. In contrast, CTL responses to DC-derived exosomes were significantly inhibited within Ab-deficient D_HLMP2A mice compared with wild-type mice. However, this response was not restored upon serum transfer, implicating a role for the BCR, but not circulating Ab, in DC-derived exosome responses.

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Ku70 Senses HTLV-1 DNA and Modulates HTLV-1 Replication [INNATE IMMUNITY AND INFLAMMATION]

Human T lymphotropic virus type 1 (HTLV-1) belongs to the deltaretrovirus family and has been linked to multiple diseases. However, the innate host defense against HTLV-1 is unclear. In this study, we report that the expression of Ku70, a known DNA sensor against DNA viruses, could be induced by HTLV-1 infection in HeLa, PMA-differentiated THP1 cells, primary human monocytes, and human monocyte-derived macrophages. In these cells, the overexpression of Ku70 inhibited the HTLV-1 protein expression, whereas the knockdown of Ku70 promoted the HTLV-1 protein expression. Furthermore, the overexpression of Ku70 enhanced the cellular response to HTLV-1 infection, whereas Ku70 knockdown yielded the opposite effect. Additionally, Ku70 was found to interact with HTLV-1 reverse transcription intermediate ssDNA90. ssDNA90 stimulation induced Ku70 expression and Ku70 promoted ssDNA90-triggered innate immune responses. Finally, HTLV-1 infection enhanced the association between Ku70 and stimulator of IFN genes, suggesting that stimulator of IFN genes was involved in Ku70-mediated host defenses against HTLV-1 infection. Taken together, our findings suggest a new sensor that detects HTLV-1 reverse transcription intermediate and controls HTLV-1 replication. These findings may provide new angles to understand host defenses against HTLV-1 infection and HTLV-1–associated diseases.

http://ift.tt/2xdE76I

IL-4/IL-13 Heteroreceptor Influences Th17 Cell Conversion and Sensitivity to Regulatory T Cell Suppression To Restrain Experimental Allergic Encephalomyelitis [AUTOIMMUNITY]

IL-4 and IL-13 have been defined as anti-inflammatory cytokines that can counter myelin-reactive T cells and modulate experimental allergic encephalomyelitis. However, it is not known whether endogenous IL-4 and IL-13 contribute to the maintenance of peripheral tolerance and whether their function is coordinated with T regulatory cells (Tregs). In this study, we used mice in which the common cytokine receptor for IL-4 and IL-13, namely the IL-4Rα/IL-13Rα1 (13R) heteroreceptor (HR), is compromised and determined whether the lack of signaling by endogenous IL-4 and IL-13 through the HR influences the function of effector Th1 and Th17 cells in a Treg-dependent fashion. The findings indicate that mice-deficient for the HR (13R^–/–) are more susceptible to experimental allergic encephalomyelitis than mice sufficient for the HR (13R^+/+) and develop early onset and more severe disease. Moreover, Th17 cells from 13R^–/– mice had reduced ability to convert to Th1 cells and displayed reduced sensitivity to suppression by Tregs relative to Th17 effectors from 13R^+/+ mice. These observations suggest that IL-4 and IL-13 likely operate through the HR and influence Th17 cells to convert to Th1 cells and to acquire increased sensitivity to suppression, leading to control of immune-mediated CNS inflammation. These previously unrecognized findings shed light on the intricacies underlying the contribution of cytokines to peripheral tolerance and control of autoimmunity.

http://ift.tt/2y9SCb0

Dual-Specificity Phosphatase 3 Deletion Protects Female, but Not Male, Mice from Endotoxemia-Induced and Polymicrobial-Induced Septic Shock [INNATE IMMUNITY AND INFLAMMATION]

Dual-specificity phosphatase 3 (DUSP3) is a small phosphatase with poorly known physiological functions and for which only a few substrates are known. Using knockout mice, we recently reported that DUSP3 deficiency confers resistance to endotoxin- and polymicrobial-induced septic shock. We showed that this protection was macrophage dependent. In this study, we further investigated the role of DUSP3 in sepsis tolerance and showed that the resistance is sex dependent. Using adoptive-transfer experiments and ovariectomized mice, we highlighted the role of female sex hormones in the phenotype. Indeed, in ovariectomized females and in male mice, the dominance of M2-like macrophages observed in DUSP3^–/– female mice was reduced, suggesting a role for this cell subset in sepsis tolerance. At the molecular level, DUSP3 deletion was associated with estrogen-dependent decreased phosphorylation of ERK1/2 and Akt in peritoneal macrophages stimulated ex vivo by LPS. Our results demonstrate that estrogens may modulate M2-like responses during endotoxemia in a DUSP3-dependent manner.

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The Autoimmune Risk Variant PTPN22 C1858T Alters B Cell Tolerance at Discrete Checkpoints and Differentially Shapes the Naive Repertoire [AUTOIMMUNITY]

A common genetic variant in the gene encoding the protein tyrosine phosphatase nonreceptor type 22 (PTPN22 C1858T) has been linked to a wide range of autoimmune disorders. Although a B cell–intrinsic role in promoting disease has been reported, the mechanism(s) through which this variant functions to alter the preimmune B cell repertoire remains unknown. Using a series of polyclonal and transgenic self-reactive models harboring the analogous mutation in murine Ptpn22, we show evidence for enhanced BCR, B cell–activating factor receptor, and CD40 coreceptor programs, leading to broadly enhanced positive selection of B cells at two discrete checkpoints in the bone marrow and spleen. We further identified a bias for selection of B cells into the follicular mature versus marginal zone B cell compartment. Using a biomarker to track a self-reactive H chain in peripheral blood, we found evidence of similarly enhanced positive selection in human carriers of the PTPN22 C1858T variant. Our combined data support a model whereby the risk variant augments the BCR and coreceptor programs throughout B cell development, promoting enrichment of self-reactive specificities into the follicular mature compartment and thereby likely increasing the risk for seeding of autoimmune B cell responses.

http://ift.tt/2xc2bqB

CXCR3 Signaling Is Required for Restricted Homing of Parenteral Tuberculosis Vaccine-Induced T Cells to Both the Lung Parenchyma and Airway [MUCOSAL IMMUNOLOGY]

Although most novel tuberculosis (TB) vaccines are designed for delivery via the muscle or skin for enhanced protection in the lung, it has remained poorly understood whether systemic vaccine-induced memory T cells can readily home to the lung mucosa prior to and shortly after pathogen exposure. We have investigated this issue by using a model of parenteral TB immunization and intravascular immunostaining. We find that systemically induced memory T cells are restricted to the blood vessels in the lung, unable to populate either the lung parenchymal tissue or the airway under homeostatic conditions. We further find that after pulmonary TB infection, it still takes many days before such T cells can enter the lung parenchymal tissue and airway. We have identified the acquisition of CXCR3 expression by circulating T cells to be critical for their entry to these lung mucosal compartments. Our findings offer new insights into mucosal T cell biology and have important implications in vaccine strategies against pulmonary TB and other intracellular infections in the lung.

http://ift.tt/2xdDTfS

Lack of Trex1 Causes Systemic Autoimmunity despite the Presence of Antiretroviral Drugs [AUTOIMMUNITY]

Biallelic mutations of three prime repair exonuclease 1 (TREX1) cause the lupus-like disease Aicardi–Goutières syndrome in which accumulation of a yet unknown endogenous DNA substrate of TREX1 triggers a cyclic GMP–AMP synthase-dependent type I IFN response and systemic autoimmunity. Products of reverse transcription originating from endogenous retroelements have been suggested to be a major substrate for TREX1, and reverse transcriptase inhibitors (RTIs) were proposed as a therapeutic option in autoimmunity ensuing from defects of TREX1. In this study, we treated Trex1^–/– mice with RTIs. The serum RTI levels reached were sufficient to block retrotransposition of endogenous retroelements. However, the treatment did not reduce the spontaneous type I IFN response and did not ameliorate lethal inflammation. Furthermore, long interspersed nuclear elements 1 retrotransposition was not enhanced in the absence of Trex1. Our data do not support the concept of retroelement-derived cDNA as key triggers of systemic autoimmunity in Trex1-deficient humans and mice and motivate the continuing search for the pathogenic IFN-inducing Trex1 substrate.

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From the Thymus to the Mucosa: A Three-Decade Journey [PRESIDENT'S ADDRESS]

http://ift.tt/2xc2bH7

Evaluating real-time effects of topical 1:1000 epinephrine in endoscopic sinus and skull-base surgery on hemodynamic parameters through intraoperative arterial line monitoring

Background

Administration of topical 1:1000 epinephrine is commonly used in practice to achieve vasoconstriction during endoscopic sinus surgery and skull-base surgery; however, real-time effects on cardiovascular changes from systemic absorption have not been well studied.

Methods

Twenty-six patients undergoing endoscopic transsphenoidal resection of a pituitary lesion at a single institution were included into the study. Following arterial line placement by anesthesiology, 6 cottonoid pledgets soaked in 1:1000 epinephrine were placed into the bilateral nasal passages. Hemodynamic parameters including heart rate, blood pressure, and mean arterial pressure were collected at baseline, 30 seconds, and increments in minutes up to 10 minutes. Additional potentially confounding factors such as use of antihypertensives, stress dose steroids, and positioning with head pins were all performed following termination of data collection.

Results

The majority of patients (20/26, 77%) showed no significant change in any parameter following placement of epinephrine soaked cottonoids. Six patients, however, had transient increases in blood pressure following administration of topical epinephrine, with a few requiring vasodilatory interventions. Return to baseline cardiovascular values were noted after an average of 7 minutes. There was no correlative preoperative characteristic that predicted sensitivity to placement of epinephrine. There were no lasting or permanent effects.

Conclusion

Although intranasal topical 1:1000 epinephrine use showed no substantial hemodynamic changes in the majority of patients, in a subset of patients it can cause significant transient elevations in blood pressure to a degree necessitating intervention. Topical epinephrine should be used judiciously in endoscopic sinus surgery.

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Adrenal Insufficiency in Pediatric Eosinophilic Esophagitis Patients Treated with Swallowed Topical Steroids

Pediatric Allergy, Immunology, and Pulmonology Sep 2017, Vol. 30, No. 3: 135-140.


http://ift.tt/2w3Ej78

Outcomes for Umbilical Cord Blood Transplantation in Severe Combined Immunodeficiency Disorders: Ten-Year Experience

Pediatric Allergy, Immunology, and Pulmonology Sep 2017, Vol. 30, No. 3: 171-180.


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Inhaling Essential Oils: Purported Benefits and Harms

Pediatric Allergy, Immunology, and Pulmonology Sep 2017, Vol. 30, No. 3: 186-188.


http://ift.tt/2w3cwn3

A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN

Abstract

Dowling-Degos disease, featuring reticulate pigmentation, and familial hidradenitis suppurativa share many clinical features including autosomal dominant inheritance, flexural location and follicular defects. The co-existence of the two disorders was recently found to result from mutations in PSENEN, encoding protein presenilin enhancer gamma-secretase subunit. Here we report 4 additional families of Jewish Ashkenazi origin who presented with clinical features characteristic of both disorders. All patients were found to carry the same, heterozygous mutation in PSENEN (c.168T>G, p.Y56X). Haplotype analysis revealed that the mutation originated from a common ancestor. Dowling-Degos disease- as well as hidradenitis suppurativa-associated genes have been shown to encode important regulators of Notch signaling. Accordingly, using a reporter assay, we demonstrated decreased Notch activity in patient's keratinocytes. The present data confirm the genetic basis of the combined Dowling-Degos disease-hidradenitis suppurativa phenotype and suggest that Notch signaling may play a central role in the pathogenesis of this rare condition.

This article is protected by copyright. All rights reserved.

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Stereotactic Radiotherapy of the Resection Cavity of Brain Metastases vs. Post-operative Whole-brain Radiotherapy

Condition:   Brain Metastases, Adult
Interventions:   Radiation: post-operative stereotactic radiosurgery (SRS);   Radiation: Whole brain radiotherapy (WBRT)
Sponsors:   Juergen Debus;   Heidelberg University
Not yet recruiting - verified September 2017

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An Exploratory Clinical Study of Apatinib for the 2nd Treatment of Esophageal Cancer or Esophageal and Gastric

Conditions:   Esophagus Cancer, Stage III;   Esophageal Gastric Cardia Type Metaplasia;   Esophagus Cancer, Stage IV
Intervention:   Drug: Apatinib
Sponsor:   Tianjin Medical University Cancer Institute and Hospital
Recruiting - verified July 2017

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Dactylitis in sarcoidosis

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Atenolol treatment for severe Infantile Hemangiomas: a single-centre prospective study

Abstract

Infantile hemangiomas (IHs) are common benign vascular tumors of infancy with an incidence of 4-5% ¹. The majority of IHs are self-limited, though in approximately 10% of patients, when their lesions compromise vital and sensory functions or cause disfigurement, medical treatment is warranted ^2,3. Τhe most exciting development in the treatment for IHs over the last decade has been the discovery of propranolol's effects during the proliferative phase of the hemangioma cycle ⁴.

This article is protected by copyright. All rights reserved.

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Exome sequencing identifies a TCF4 mutation in a Chinese pedigree with symmetrical acral keratoderma

Abstract

Background

Symmetrical acral keratoderma (SAK) is a rare skin disorder and its pathogenesis and inheritability are unknown.

Objectives

To investigate the inheritance and pathogenesis of SAK.

Methods

Four SAK cases occurred in a four-generation Chinese family. Exome sequencing identified SNPs with potential SAK related mutations, and a potentially responsible gene (Transcription factor 4, TCF4) was identified. TCF4 was then sequenced in all 11 family members and pedigree analysis was performed. Histopathology and immunohistochemistry evaluated TCF4 expression in skin lesions. The gene mutation was investigated in human keratinocytes for keratin related protein expression.

Results

A novel heterozygous missense mutation, c.85C>A (p.Pro29Thr) was found in TCF4. The mutation showed autosomal dominant inheritance and perfectly cosegregated with the SAK phenotype in all family members. In skin lesions TCF4 was present in the cytoplasm and membranes of the basal layer, the stratum spinosum, and the stratum granulosum of the epidermis. The mutant TCF4 induced overexpression of differentiation markers including KRT1, KRT14, loricrin and involucrin.

Conclusions

A SAK related gene mutation in TCF4 may function through transcriptional regulation of keratin.

This article is protected by copyright. All rights reserved.

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Tonsillectomy-Comparative Study of Various Techniques and Changing Trend

Abstract

Tonsillectomy is a major surgical procedure in terms of volume in the general otolaryngological practice. It is a 3000-year-old surgical operation, referred in Hindu medicine. There has been a conceptual change in the indications and surgical technique in the last 40 years. A comparative study between the various methods of tonsillectomy was done. The study was carried out in the single institutional set up by the same surgeon but using different techniques. The study aimed at comparing the intra-operative factors (blood loss, time taken for surgery), postoperative results (pain, bleeding, dehydration, time taken for complete healing), and other complications like vomiting and hospitalization time between different groups of surgical methods. This study was done in 2500 patients undergoing tonsillectomy with or without adenoid removal in a period of 35 years (1979–2013). The majority of the patients (approximately 41%) in the first half of this period underwent cold steel tonsillectomy whereas 39% underwent microdebrider assisted tonsillectomy. Microdebrider assisted tonsil surgery was done as day care procedure in 90%. In 21% of the patients, other methods viz coblation, radio frequency and laser were used. Microdebrider intracapsular tonsillectomy is associated with lower mortality and morbidity as compared to cold steel, coblation, electrodissection, laser and radio frequency.

http://ift.tt/2fe0qEA