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| Open AccessChronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release
Myotonic dystrophy type 2 is characterized by large CCUG repeats in the CNBP gene that result in myopathy. Here, the authors show that recognition of aberrant protein translation derived from these repeats leads to ER stress and mitochondrial DNA release, leading to cGAS/STING activation and type-I IFN responses.
- Sarah Rösing
- , Fabian Ullrich
- & Claudia Günther
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Article
| Open AccessSexual dimorphism in melanocyte stem cell behavior reveals combinational therapeutic strategies for cutaneous repigmentation
Vitiligo is an autoimmune condition that results in skin depigmentation due to melanocyte loss, but the root causes are not well understood. Here they identify sexual dimorphism in melanocyte stem cells behavior arising from distinct skin inflammatory responses, and propose Prostaglandin E2 as a potential therapy for depigmentation conditions.
- Luye An
- , Dahihm Kim
- & Andrew C. White
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Article
| Open AccessFunctional divergence of a bacterial enzyme promotes healthy or acneic skin
Cutibacterium acnes phylotypes can be catalogued based on their association with acneic or healthy skin. Here, Hajam et al show that the functional divergence of a hyaluronidase enzyme expressed by the phylotypes is a major determinant of acne severity.
- Irshad A. Hajam
- , Madhusudhanarao Katiki
- & George Y. Liu
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| Open AccessTh17-associated cytokines IL-17 and IL-23 in inflamed skin of Darier disease patients as potential therapeutic targets
The use of IL-17/IL-23 blocking therapy for rare inflammatory skin diseases needs proof of principle data for larger clinical trials. Here the authors show that patients with Darier disease have enhanced Th17 cells and, using IL-17/IL-23 blockers, they show that the immune gene signatures are altered in localised skin biopsies.
- Monika Ettinger
- , Teresa Burner
- & Wolfram Hoetzenecker
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Article
| Open AccessEuropean and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation
The genetic basis of atopic dermatitis is not fully understood. Here, the authors find 91 genetic loci associated with atopic dermatitis in a GWAS of >1million individuals, which highlight the importance of systemic immune regulation.
- Ashley Budu-Aggrey
- , Anna Kilanowski
- & Lavinia Paternoster
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Article
| Open AccessAnalysis of 72,469 UK Biobank exomes links rare variants to male-pattern hair loss
Here, the authors perform an association study on 72,469 exomes to identify significant associations between male-pattern hair loss and rare genetic variants in EDA2R, WNT10A, HEPH, CEPT1, and EIF3F, finding an enrichment of implicated genes in monogenic trichosis genes.
- Sabrina Katrin Henne
- , Rana Aldisi
- & Stefanie Heilmann-Heimbach
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Article
| Open AccessWhole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
Rosacea is a common, multi-factorial chronic inflammatory skin disorder. Here authors provide evidence of genetic predisposition by whole genome sequencing and whole exome sequencing of samples from familial cases, and by recapitulating a recurrent mutation in the LRRC4 gene in a mouse model, they find that neuron-derived vasoactive intestinal peptide is an important pathogenic factor for neurogenic inflammation in rosacea.’
- Zhili Deng
- , Mengting Chen
- & Ji Li
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Article
| Open AccessDifferentiation of IL-26+ TH17 intermediates into IL-17A producers via epithelial crosstalk in psoriasis
Interleukin 26 (IL-26) has been shown to have antimicrobial and pro-inflammatory effects. Here the authors establish a role for IL-26 in the generation of IL-17A producing Th17 CD4+ T cells and suggest it involves epithelial cross talk in skin lesions of psoriasis patients.
- Anissa Fries
- , Fanny Saidoune
- & Michel Gilliet
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Article
| Open AccessHydrogel dressing integrating FAK inhibition and ROS scavenging for mechano-chemical treatment of atopic dermatitis
Mechanical scratching and oxidative stress can aggravate atopic dermatitis symptoms, while treatment targeting scratching is often overlooked. Here, the authors find that enhanced phosphorylation of focal adhesion kinase is associated with scratch-exacerbated AD, then develop a hydrogel dressing that integrates oxidative stress modulation with FAK inhibition to synergistically treat AD.
- Yuanbo Jia
- , Jiahui Hu
- & Feng Xu
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Article
| Open AccessTopical phage therapy in a mouse model of Cutibacterium acnes-induced acne-like lesions
Bacteriophage therapy is evolving as a promising approach to tackling bacterial infection, even in the case of emerging antibiotic resistance. In this work, authors present the topical application of numerous Cutibacterium acnes phage in an in vivo mouse model of acne vulgaris.
- Amit Rimon
- , Chani Rakov
- & Ronen Hazan
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Article
| Open AccessApremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus
Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies which destabilize cell adhesion of keratinocytes. The phosphodiesterase 4 inhibitor apremilast prevents skin blistering by stabilizing the keratin filament anchorage of desmosomes.
- Anna M. Sigmund
- , Markus Winkler
- & Jens Waschke
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Article
| Open AccessTargeting the transcription factor HES1 by L-menthol restores protein phosphatase 6 in keratinocytes in models of psoriasis
Psoriasis is an inflammatory disease which has proven difficult to cure. Prof. Honglin Wang’s team describes L-menthol for treating models of psoriasis and uncovers the dysfunctional HES1- IGBP1-PP6 axis in psoriasis pathology by using L-menthol as a probe.
- Zhikai Wang
- , Yang Sun
- & Honglin Wang
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Article
| Open AccessCentromere defects, chromosome instability, and cGAS-STING activation in systemic sclerosis
Fibrosis of the skin plays an important role in scleroderma. Here the authors demonstrate genetic and epigenetic abnormalities at the centromere that affect the replication of the chromosomes, resulting in activation of pathways involved in inflammation and fibrosis
- Souren Paul
- , Mark H. Kaplan
- & Rafael Contreras-Galindo
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Article
| Open AccessShared genetic risk factors and causal association between psoriasis and coronary artery disease
Coronary artery disease (CAD) and psoriasis are established comorbidities, however their molecular relationship remains unclear. Here, the authors performed trans-disease meta-analysis, highlighting four genetic loci with evidence of colocalization, and prioritized genes based on multiomic data integration.
- Matthew T. Patrick
- , Qinmengge Li
- & Lam C. Tsoi
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Article
| Open AccessContext-dependent function of TSLP and IL-1β in skin allergic sensitization and atopic march
Allergic sensitisation in the skin can lead to allergic dermatitis and further to airway asthma in a process of atopic march. Here the authors examine the difference between superficial or deep skin sensitisation, characterise the immune cells generated and show differential TSLP and IL-1β involvement.
- Justine Segaud
- , Wenjin Yao
- & Mei Li
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Article
| Open AccessCalcium/calmodulin-dependent protein kinase IV promotes imiquimod-induced psoriatic inflammation via macrophages and keratinocytes in mice
Calcium/calmodulin-dependent protein kinase IV (CaMK4) has been shown to be involved in autoimmunity but it is not clear how it functions in psoriasis. Here the authors show that CaMK4 is increased in psoriasis and promotes inflammatory responses in mouse models of psoriasis mediated through macrophages and keratinocytes.
- Liang Yong
- , Yafen Yu
- & Liangdan Sun
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Article
| Open AccessSpatially resolved proteomic map shows that extracellular matrix regulates epidermal growth
Ling Leng et al. construct a hierarchical skin proteome map and identify an extracellular matrix glycoprotein TGFBI, which is located in basement membrane and could enhance the growth and function of epidermal stem cells and promote wound healing.
- Jun Li
- , Jie Ma
- & Ling Leng
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Article
| Open AccessGenome-wide association meta-analysis identifies 29 new acne susceptibility loci
Better understanding of the genetic basis of acne can pave the way to more effective treatments. Here, the authors perform a genome-wide association study meta-analysis of >20,000 cases and identify 29 new acne susceptibility loci, uncovering genetic links to Mendelian hair and skin disorders and other complex traits.
- Brittany L. Mitchell
- , Jake R. Saklatvala
- & Michael A. Simpson
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| Open AccessRare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4
Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.
- Sarah Grosche
- , Ingo Marenholz
- & Young-Ae Lee
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Article
| Open AccessAgrin-Matrix Metalloproteinase-12 axis confers a mechanically competent microenvironment in skin wound healing
Replenishing key extracellular matrix (ECM) proteins facilitate wound healing through unclear mechanisms. Here the authors report that injury-triggered Agrin, an ECM proteoglycan, tunes a mechanocompetent niche by engaging MMP-12, thereby enforcing efficient skin wound healing.
- Sayan Chakraborty
- , Divyaleka Sampath
- & Wanjin Hong
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Article
| Open AccessThe serine proteases dipeptidyl-peptidase 4 and urokinase are key molecules in human and mouse scar formation
Mechanisms triggering hypertrophic scar formation remain poorly understood. Here the authors perform scRNA-seq on mature human hypertrophic scars and developing scars in mice to identify the serine proteases dipeptidyl-peptidase 4 and urokinase as key molecules in this process.
- Vera Vorstandlechner
- , Maria Laggner
- & Michael Mildner
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Article
| Open Access3-hydroxy-L-kynurenamine is an immunomodulatory biogenic amine
3-hydroxy-L-kynurenamine (3-HKA) is a metabolite deriving from a lateral pathway of tryptophan catabolism. Here the authors identify 3-HKA as a biogenic amine and show it has anti-inflammatory properties that can protect mice against psoriasis and nephrotoxic nephritis.
- Cristina C. Clement
- , Angelo D’Alessandro
- & Laura Santambrogio
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Article
| Open AccessA small molecule HIF-1α stabilizer that accelerates diabetic wound healing
Impaired wound healing is a serious complication in diabetic patients, and is associated with reduced HIF1α stability. Here, the authors design a small molecule that stabilizes HIF1α by blocking its interaction with VHL and show that it promotes wound healing in mouse models of diabetes.
- Guodong Li
- , Chung-Nga Ko
- & Chung-Hang Leung
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Article
| Open AccessSymmetry breaking of tissue mechanics in wound induced hair follicle regeneration of laboratory and spiny mice
How hair follicle regeneration arises readily in some species ie. spiny rather than laboratory mice, is unclear. Here, authors compare them, showing an optimal stiffness is needed for placode formation and the difference in hair follicle regenerative behaviour after wounding is linked to Twist1.
- Hans I-Chen Harn
- , Sheng-Pei Wang
- & Cheng-Ming Chuong
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Article
| Open AccessA pulsatile release platform based on photo-induced imine-crosslinking hydrogel promotes scarless wound healing
Dysfunctional and disfiguring scars can result from aberrant wound repair. Here, the authors develop a wound dressing material based on an integrated photo-crosslinking strategy and a microcapsule platform with pulsatile release of TGF-β inhibitor to achieve spatiotemporal specificity for scarless wound repair.
- Jian Zhang
- , Yongjun Zheng
- & Xiaoyang Wu
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Article
| Open AccessVirus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis
Checkpoint blocking therapies are used to treat metastatic melanoma, but can have adverse immune-mediated effects, including liver pathology. Here the authors identify an expanded pool of CD4+ effector memory T cells resulting from prior CMV exposure as a risk factor for this adverse effect in these patients.
- James A. Hutchinson
- , Katharina Kronenberg
- & Sebastian Haferkamp
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Article
| Open AccessGranzyme B inhibition reduces disease severity in autoimmune blistering diseases
Pemphigoid diseases involve autoimmune mediated blistering and immunopathology of the upper dermis. Here, the authors implicate granzyme B in the immunopathology in multiple in vivo models of pemphigoid diseases and utilise a topical granzyme B inhibitor that attenuates disease phenotypes in vivo.
- Sho Hiroyasu
- , Matthew R. Zeglinski
- & David J. Granville
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| Open AccessContribution of GATA6 to homeostasis of the human upper pilosebaceous unit and acne pathogenesis
Although acne vulgaris is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here the authors show that GATA6 is involved in maintaining homeostasis of the upper pilosebaceous unit of human skin and may contribute to acne pathogenesis.
- Bénédicte Oulès
- , Christina Philippeos
- & Fiona M. Watt
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Article
| Open AccessDeregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing
Diabetic foot ulcers (DFU) represent a complex disease with limited treatment options. Here, the authors compare human RNASeq patient data from DFU, oral mucosa and skin acute wounds, identifying FOXM1 as a mediator of macrophage and neutrophil recruitment, which contributes to disease pathogenesis and is dysregulated in patients.
- Andrew P. Sawaya
- , Rivka C. Stone
- & Marjana Tomic-Canic
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Article
| Open AccessDisease-associated KIF3A variants alter gene methylation and expression impacting skin barrier and atopic dermatitis risk
Genetic variants in KIF3A are associated with atopic dermatitis (AD). Here, the authors identify two AD-risk alleles that show high methylation resulting in lower KIF3A expression. Mice with epidermis-specific loss of Kif3a show disrupted skin barrier homeostasis and increased AD susceptibility.
- Mariana L. Stevens
- , Zhonghua Zhang
- & Gurjit K. Khurana Hershey
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Article
| Open AccessActivin-mediated alterations of the fibroblast transcriptome and matrisome control the biomechanical properties of skin wounds
The relationship between histopathology, gene expression, and biochemical and mechanical properties of wounds is largely unknown. Here, the authors show that activin A alters wound healing at multiple levels by promoting pro-fibrotic gene expression and matrix deposition, thereby affecting biomechanical properties of skin wounds.
- Mateusz S. Wietecha
- , Marco Pensalfini
- & Sabine Werner
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Article
| Open AccessNeutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis
Antimicrobial peptide LL37 can bind nucleic acids and potentiate their sensing by endosomal TLRs. Here the authors show that LL37 binds to RNA from neutrophil extracellular traps (NETs), which amplifies inflammation and production of more LL37 and NETs via TLR8/13, suggesting that LL37 contribution to psoriasis may be fueled by NET-associated RNA.
- Franziska Herster
- , Zsofia Bittner
- & Alexander N. R. Weber
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Article
| Open AccessAbl family tyrosine kinases govern IgG extravasation in the skin in a murine pemphigus model
How antibody reaches tissues from circulation is critical for understanding antibody-mediated immunity. Here the authors show that IgG extravasation in the skin is mediated by endothelial caveolin transport independently of FcR, and is targetable by imatinib, which reduces IgG-dependent pathology in a mouse model of pemphigus.
- Sachiko Ono
- , Gyohei Egawa
- & Kenji Kabashima
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Article
| Open AccessInnate lymphocyte-induced CXCR3B-mediated melanocyte apoptosis is a potential initiator of T-cell autoreactivity in vitiligo
Tissue signals that prime autoreactive T cells at the onset of autoimmunity remain enigmatic. Here the authors show NK and ILC1 cells are increased in vitiligo patients, and induce melanocyte apoptosis via CXCR3B, which in turn leads to increased priming of T cell responses in cell culture.
- Meri K. Tulic
- , Elisa Cavazza
- & Thierry Passeron
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Article
| Open AccessGenome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02
Frontal fibrosing alopecia (FFA) features lichenoid cutaneous inflammation and scarring hair loss. Here, Tziotzios et al. identify four genetic loci associated with FFA by GWAS followed by Bayesian fine-mapping, co-localisation and HLA imputation which highlights HLA-B*07:02 as a risk factor.
- Christos Tziotzios
- , Christos Petridis
- & John A. McGrath
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Article
| Open AccessEarly-onset autoimmune vitiligo associated with an enhancer variant haplotype that upregulates class II HLA expression
GWAS have led to the identification of 49 genetic loci associated with vitiligo. Here, the authors observe a bimodal distribution of age-of-onset and find a novel genetic locus specifically associated with early-onset vitiligo, located in a regulatory element in the MHC class II region.
- Ying Jin
- , Genevieve H. L. Roberts
- & Richard A. Spritz
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Article
| Open AccessGenome-wide meta-analysis implicates mediators of hair follicle development and morphogenesis in risk for severe acne
Acne vulgaris is a chronic inflammation of the skin, the genetic basis of which is incompletely understood. Here, Petridis et al. perform GWAS and meta-analysis for acne in 26,722 individuals and identify 12 novel risk loci that implicate structure and maintenance of the skin in severe acne risk.
- Christos Petridis
- , Alexander A. Navarini
- & Michael A. Simpson
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Article
| Open AccessJunB defines functional and structural integrity of the epidermo-pilosebaceous unit in the skin
Epidermal homeostasis is maintained by the activity of stem cells. Here, the authors show that deficiency of the transcription factor JunB leads to altered Notch signaling in stem cells, resulting in a cell fate switch and de novo formation of aberrant sebaceous glands, altered epidermal differentiation and impaired barrier function.
- Karmveer Singh
- , Emanuela Camera
- & Karin Scharffetter-Kochanek
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Article
| Open AccessCD4+ T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema
CD4+ T cells are critical for the development of lymphedema. Here the authors show how these cells contribute to lymphedema and identify that the sphingosine-1-phosphate receptor modulator FTY720 can prevent lymphedema in a mouse tail injury model by blocking the release of CD4+ T cells from the lymph nodes to the skin.
- Gabriela D. García Nores
- , Catherine L. Ly
- & Babak J. Mehrara
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Article
| Open AccessEpigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation
Although IL-23 is expressed by psoriatic keratinocytes as well as immune cells, only the immune cell derived IL-23 is thought to be important for the development of psoriasis. Here the authors provide evidence that keratinocyte-produced IL-23 is sufficient to cause a chronic skin inflammation.
- Hui Li
- , Qi Yao
- & Cord Brakebusch
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Article
| Open Accessp63 is a key regulator of iRHOM2 signalling in the keratinocyte stress response
Mutations in the gene encoding iRHOM2 are associated with hyperproliferative epidermal disorders. Here, the authors show that iRHOM2 is a target gene of p63, that together they regulate inflammation, cell survival and response to oxidative stress, and inhibition of p63-iRHOM2 signalling with an antioxidant reduces epidermal inflammation.
- Paola Arcidiacono
- , Catherine M. Webb
- & Anissa Chikh
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Article
| Open AccessLarge scale meta-analysis characterizes genetic architecture for common psoriasis associated variants
Psoriasis is an immune-mediated skin disease with a complex genetic architecture. Here, Elder and colleagues identify 16 novel psoriasis susceptibility loci using GWAS meta-analysis with a combined effective sample size of over 39,000 individuals.
- Lam C. Tsoi
- , Philip E. Stuart
- & James T Elder
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Article
| Open AccessPNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide
Loss-of-function mutations in an enzyme of unknown function, PNPLA1, cause dry and scaling skin in humans. Here Ohnoet al. show that PNPLA1 is a transacylase that acts in the final step of acylceramide production- esterification between ω-hydroxyceramide and linoleic acid acylceramide, yielding a lipid essential for skin barrier function.
- Yusuke Ohno
- , Nozomi Kamiyama
- & Akio Kihara
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Article
| Open AccessPNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis
Loss-of-function mutations inPNPLA1, a gene encoding an enzyme with unknown function, cause dry and scaling skin in humans. Using mouse models with PNPLA1 deficiency, the authors show that PNPLA1 participates in the biosynthesis of acylceramide, a lipid component essential for skin barrier function.
- Tetsuya Hirabayashi
- , Tatsuki Anjo
- & Makoto Murakami
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Article
| Open AccessA large-scale genome-wide association and meta-analysis identified four novel susceptibility loci for leprosy
Previous studies have shown genetic associations between leprosy and 18 different genes/loci. Here, Wang and colleagues perform genome-wide association study in Han Chinese leprosy patients and describe four novel loci to be associated to the disease.
- Zhenzhen Wang
- , Yonghu Sun
- & Furen Zhang
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Article
| Open AccessThe Nedd4-2/Ndfip1 axis is a negative regulator of IgE-mediated mast cell activation
Aberrant activation of the IgE receptor on mast cells leads to allergic responses. Here, the authors identify an E3 ligase and adaptor protein that can reduce IgE signalling by targeting phosphorylated-Syk for degradation.
- Kwok Ho Yip
- , Natasha Kolesnikoff
- & Michele A. Grimbaldeston