Herpes zoster ophthalmicus is commonly used to describe viral reactivation from the trigeminal ganglia with ocular involvement. The ophthalmic branch is the most commonly involved, whereas the maxillary and mandibular dermatomes are less commonly affected. Neurotrophic ulcer may occur secondary to intentional or inadvertent damage to the trigeminal nucleus, root, ganglion, or any segment of the ophthalmic branch of this cranial nerve. We report a case of reactivated maxillary herpes zoster combined with neurotrophic keratitis due to percutaneous 2nd and 3rd branch of trigeminal nerve block with alcohol to treat trigeminal neuralgia. A 57-year-old female came to the ophthalmology department complaining of decreased visual acuity and skin vesicle over the right lower lid and cheek. She had undergone right trigeminal nerve block for treatment of trigeminal neuralgia. Clinical examination revealed neurotrophic keratitis and maxillary herpes zoster. She was treated with oral and topical antivirals and vigorous lubrication with eye drops. Her neurotrophic keratitis showed a slow recovery. Although a few cases of herpes zoster following nerve block have been described, it would appear that a case of simultaneous maxillary herpes zoster and neurotrophic keratitis following trigeminal block has not yet been documented. It is possible that trigeminal nerve block may cause reactivation of latent virus and refractory neurotrophic keratitis.
Case Rep Ophthalmol 2019;10:61–66
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Τετάρτη 6 Φεβρουαρίου 2019
Maxillary Zoster and Neurotrophic Keratitis following Trigeminal Block
Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice
Publication date: February 2019
Source: Journal of Allergy and Clinical Immunology, Volume 143, Issue 2
Author(s): Delphine Bouis, Peggy Kirstetter, Florent Arbogast, Delphine Lamon, Virginia Delgado, Sophie Jung, Claudine Ebel, Hugues Jacobs, Anne-Marie Knapp, Nadia Jeremiah, Alexandre Belot, Thierry Martin, Yanick J. Crow, Isabelle André-Schmutz, Anne-Sophie Korganow, Frédéric Rieux-Laucat, Pauline Soulas-Sprauel
Background
Autosomal dominant gain-of-function mutations in human stimulator of interferon genes (STING) lead to a severe autoinflammatory disease called STING-associated vasculopathy with onset in infancy that is associated with enhanced expression of interferon-stimulated gene transcripts.
Objective
The goal of this study was to analyze the phenotype of a new mouse model of STING hyperactivation and the role of type I interferons in this system.
Methods
We generated a knock-in model carrying an amino acid substitution (V154M) in mouse STING, corresponding to a recurrent mutation seen in human patients with STING-associated vasculopathy with onset in infancy. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. STING V154M/wild-type (WT) mice were crossed to IFN-α/β receptor (IFNAR) knockout mice to evaluate the type I interferon dependence of the mutant Sting phenotype recorded.
Results
In STING V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T, and natural killer cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B- and T-cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Although the V154M/WT mutant demonstrated increased expression of interferon-stimulated genes, the SCID phenotype was not reversed in STING V154M/WT IFNAR knockout mice. However, the antiproliferative defect in T cells was rescued partially by IFNAR deficiency.
Conclusions
STING gain-of-function mice developed an interferon-independent SCID phenotype with a T-cell, B-cell, and natural killer cell developmental defect and hypogammaglobulinemia that is associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was partially interferon dependent.
http://bit.ly/2Gccouf
Identification of galectin-3 as an autoantigen in patients with IgG4-related disease
Publication date: February 2019
Source: Journal of Allergy and Clinical Immunology, Volume 143, Issue 2
Author(s): Cory A. Perugino, Sultan B. AlSalem, Hamid Mattoo, Emanuel Della-Torre, Vinay Mahajan, Gayathri Ganesh, Hugues Allard-Chamard, Zachary Wallace, Sydney B. Montesi, Johannes Kreuzer, Wilhelm Haas, John H. Stone, Shiv Pillai
Background
The antigenic trigger that drives expansion of circulating plasmablasts and CD4+ cytotoxic T cells in patients with IgG4-related disease (IgG4-RD) is presently unknown.
Objective
We sought to sequence immunoglobulin genes from single-cell clones of dominantly expanded plasmablasts and generate recombinant human mAbs to identify relevant antigens in patients with IgG4-RD by using mass spectrometry.
Methods
Paired heavy and light chain cDNAs from dominant plasmablast clones were expressed as mAbs and used to purify antigens by using immunoaffinity chromatography. Affinity-purified antigens were identified by using mass spectrometry and validated by means of ELISA. Plasma levels of the antigen of interest were also determined by using ELISA.
Results
mAbs expressed from the 2 dominant plasmablast clones of a patient with multiorgan IgG4-RD stained human pancreatic tissue sections. Galectin-3 was identified as the antigen specifically recognized by both mAbs. Anti–galectin-3 autoantibody responses were predominantly of the IgG4 isotype (28% of the IgG4-RD cohort, P = .0001) and IgE isotype (11% of the IgG4-RD cohort, P = .009). No significant responses were seen from the IgG1, IgG2, or IgG3 isotypes. IgG4 anti–galectin-3 autoantibodies correlated with increased plasma galectin-3 levels (P = .001), lymphadenopathy (P = .04), total IgG level increase (P = .05), and IgG4 level increase (P = .03).
Conclusion
Affinity chromatography using patient-derived mAbs identifies relevant autoantigens in patients with IgG4-RD. IgG4 galectin-3 autoantibodies are present in a subset of patients with IgG4-RD and correlate with galectin-3 plasma levels. The marked increases in levels of circulating IgG4 and IgE observed clinically are, at least in part, caused by the development of IgG4- and IgE-specific autoantibody responses.
http://bit.ly/2De2cxC
Eleven loci with new reproducible genetic associations with allergic disease risk
Publication date: February 2019
Source: Journal of Allergy and Clinical Immunology, Volume 143, Issue 2
Author(s): Manuel A.R. Ferreira, Judith M. Vonk, Hansjörg Baurecht, Ingo Marenholz, Chao Tian, Joshua D. Hoffman, Quinta Helmer, Annika Tillander, Vilhelmina Ullemar, Yi Lu, Franz Rüschendorf, 23andMe Research Team, SHARE study, David A. Hinds, Norbert Hübner, Stephan Weidinger, Patrik K.E. Magnusson, Eric Jorgenson, Young-Ae Lee, Dorret I. Boomsma, Robert Karlsson, Catarina Almqvist
Background
A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities.
Objective
We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects.
Methods
We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study.
Results
Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10−6. Of these, 20 were also significantly associated (P < .05/30 = .0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress TH2 responses.
Conclusion
Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.
http://bit.ly/2Gsieau
Profilin-mediated food-induced allergic reactions are associated with oral epithelial remodeling
Publication date: February 2019
Source: Journal of Allergy and Clinical Immunology, Volume 143, Issue 2
Author(s): Domenico Rosace, Cristina Gomez-Casado, Paloma Fernandez, Marina Perez-Gordo, María del Carmen Dominguez, Angel Vega, María Teresa Belver, Tania Ramos, Francisco Vega, Guadalupe Marco, Manuel de Pedro, Leticia Sanchez, María de las Mercedes Arnas, Marcela Santaolalla, Miguel Ángel Saez, Sara Benedé, Montserrat Fernandez-Rivas, Carlos Blanco, Maria Isabel Alvarado, María M. Escribese
Background
In areas of high exposure to grass pollen, allergic patients are frequently sensitized to profilin, and some experience severe profilin-mediated food-induced reactions. This specific population of patients is ideal to study the relationship between respiratory and food allergies.
Objective
We sought to determine the role of oral mucosal epithelial barrier integrity in profilin-mediated allergic reactions.
Methods
Thirty-eight patients with profilin allergy stratified into mild or severe according to their clinical history and response to a profilin challenge test and 6 nonallergic subjects were recruited. Oral mucosal biopsies were used for measurement of CD11c, CD3, CD4, tryptase, claudin-1, occludin, E-cadherin, and vascular endothelial growth factor A levels; Masson trichrome staining; and POSTN, IL33, TPSAB, TPSB, and CMA gene expression analysis by using quantitative RT-PCR. Blood samples were used for basophil activation tests.
Results
Distinct features of the group with severe allergy included the following: (1) impaired epithelial integrity with reduced expression of claudin-1, occludin, and E-cadherin and decreased numbers of epithelial cells, which is indicative of acanthosis, higher collagen deposition, and angiogenesis; (2) inflammatory immune response in the mucosa, with an increased number of CD11c+ and CD4+ infiltrates and increased expression of the cytokine genes POSTN and IL33; and (3) a 10-fold increased sensitivity of basophils to profilin.
Conclusions
Patients with profilin allergy present with significant damage to the oral mucosal epithelial barrier, which might allow profilin penetration into the oral mucosa and induction of local inflammation. Additionally, severely allergic patients presented with increased sensitivity of effector cells.
Graphical abstract
http://bit.ly/2Sy2vNl
Novel peptide nanoparticle–biased antagonist of CCR3 blocks eosinophil recruitment and airway hyperresponsiveness
Publication date: February 2019
Source: Journal of Allergy and Clinical Immunology, Volume 143, Issue 2
Author(s): Milica Grozdanovic, Kimberly G. Laffey, Hazem Abdelkarim, Ben Hitchinson, Anantha Harijith, Hyung-Geon Moon, Gye Young Park, Lee K. Rousslang, Joanne C. Masterson, Glenn T. Furuta, Nadya I. Tarasova, Vadim Gaponenko, Steven J. Ackerman
Background
Chemokine signaling through CCR3 is a key regulatory pathway for eosinophil recruitment into tissues associated with allergic inflammation and asthma. To date, none of the CCR3 antagonists have shown efficacy in clinical trials. One reason might be their unbiased mode of inhibition that prevents receptor internalization, leading to drug tolerance.
Objective
We sought to develop a novel peptide nanoparticle CCR3 inhibitor (R321) with a biased mode of inhibition that would block G protein signaling but enable or promote receptor internalization.
Methods
Self-assembly of R321 peptide into nanoparticles and peptide binding to CCR3 were analyzed by means of dynamic light scattering and nuclear magnetic resonance. Inhibitory activity on CCR3 signaling was assessed in vitro by using flow cytometry, confocal microscopy, and Western blot analysis in a CCR3+ eosinophil cell line and blood eosinophils. In vivo effects of R321 were assessed by using a triple-allergen mouse asthma model.
Results
R321 self-assembles into nanoparticles and binds directly to CCR3, altering receptor function. Half-maximal inhibitory concentration values for eotaxin-induced chemotaxis of blood eosinophils are in the low nanomolar range. R321 inhibits only the early phase of extracellular signal-regulated kinase 1/2 activation and not the late phase generally associated with β-arrestin recruitment and receptor endocytosis, promoting CCR3 internalization and degradation. In vivo R321 effectively blocks eosinophil recruitment into the blood, lungs, and airways and prevents airway hyperresponsiveness in a mouse eosinophilic asthma model.
Conclusions
R321 is a potent and selective antagonist of the CCR3 signaling cascade. Inhibition through a biased mode of antagonism might hold significant therapeutic promise by eluding the formation of drug tolerance.
Graphical abstract
http://bit.ly/2Gopi7O
Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature
Publication date: February 2019
Source: Journal of Allergy and Clinical Immunology, Volume 143, Issue 2
Author(s): Kunal Malik, Helen He, Thy Nhat Huynh, Gary Tran, Kelly Mueller, Kristina Doytcheva, Yael Renert-Yuval, Tali Czarnowicki, Shai Magidi, Margaret Chou, Yeriel D. Estrada, Huei-Chi Wen, Xiangyu Peng, Hui Xu, Xiuzhong Zheng, James G. Krueger, Amy S. Paller, Emma Guttman-Yassky
Background
Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much-needed pathogenesis-based therapy.
Objective
We sought to profile the molecular fingerprint of the most common orphan ichthyoses.
Methods
Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age-matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16).
Results
Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL-17 and TNF-α–coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity-related manner, patients with Netherton syndrome showed the greatest T-cell activation (inducible costimulator [ICOS]) and a broader immune phenotype with TH1/IFN-γ, OASL, and TH2/IL-4 receptor/IL-5 skewing, although less than seen in patients with AD (all P < .05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL-17–regulated gene expression (IL17F and IL36A/IL36B/IL36G).
Conclusion
Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis-like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL-17/IL-36–targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis.
http://bit.ly/2SvMUOi