A novel STAT3 mutation associated with hyper immunoglobulin E syndrome with a paucity of connective tissue signs

Abstract We recently demonstrated that immunoglobulin E (IgE), in the absence of cross-linking agents, activates signaling pathways in healthy murine bone marrow–derived mast cells (BMMCs) and that this activation enhances BMMC survival, at least in part, via secretion of autocrine-acting cytokines. We report herein that IgE alone also triggers the adhesion of both BMMCs and connective tissue mast cells (CTMCs) to the connective tissue component, fibronectin (FN). This adhesion occurs to the same extent as that triggered by optimal levels of Steel factor (SF) or IgE + antigen (IgE + Ag) and is mediated by an increased avidity of the integrin very late antigen 5 (VLA-5). Moreover, this IgE-induced adhesion, which is prolonged compared with that elicited by SF or IgE + Ag, requires phosphatidylinositol 3-kinase (PI3K), phospholipase C γ (PLCγ), and extracellular calcium but not extracellular-regulated kinase (Erk) or p38. Interestingly, we found, using the calcium channel blocker, 2-APB (2-aminoethoxydiphenyl borate) and Lyn–/– BMMCs that both IgE- and IgE + Ag-induced adhesion to FN require extracellular calcium entry, whereas SF does not. Furthermore, our data suggest that FN acts synergistically with IgE to prolong intracellular phosphorylation events and to enhance IgE-induced inflammatory cytokine production and BMMC survival.

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A STAT3 mutation in hyper-immunoglobulin E syndrome: A case report

Journal of Pediatric Genetics ◽

10.3233/pge-13053 ◽

2015 ◽

Vol 02 (02) ◽

pp. 091-096 ◽

Cited By ~ 1

Author(s):

Marielle Alders ◽

Elke Dierckx ◽

Paul Schil ◽

Veronique Demeulemeester ◽

Geert Mortier ◽

...

Keyword(s):

Case Report ◽

Immunoglobulin E ◽

Stat3 Mutation

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Hyper-IgE Syndrome with STAT3 Mutation: A Case Report in Mainland China

Clinical and Developmental Immunology ◽

10.1155/2010/289873 ◽

2010 ◽

Vol 2010 ◽

pp. 1-5 ◽

Cited By ~ 7

Author(s):

Lixin Xie ◽

Xiaoxiang Hu ◽

Yang Li ◽

Weihua Zhang ◽

Liang'an Chen

Keyword(s):

Autosomal Dominant ◽

Immunoglobulin E ◽

Mainland China ◽

High Serum ◽

Deciduous Teeth ◽

Autosomal Dominant Trait ◽

Hyper Ige Syndrome ◽

Stat3 Mutation ◽

Transcription 3 ◽

Human Signal

Hyper-immunoglobulin E syndromes (HIES) including compound primary immunodeficiency and nonimmunological abnormalities are characterized by extremely high serum IgE levels, eosinophilia, eczema, susceptibility to infections, distinctive facial appearance, retention of deciduous teeth, cyst-forming pneumonias, and skeletal abnormalities. Itis reported that some cases of familial HIES are relative to autosomal dominant or recessive inheritance, but most cases are sporadic, and result from mutations in the human signal transducer and activator of transcription 3 (STAT3) gene. In this paper, we firstly report a young man diagnosed of Hyper-IgE syndrome with STAT3 mutation in Mainland China, and investigate the autosomal dominant trait of his family members.

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Idiopathic Pancreatitis in a Patient with a STAT3 Mutation

Allergy & Rhinology ◽

10.2500/ar.2016.7.0148 ◽

2016 ◽

Vol 7 (1) ◽

pp. ar.2016.7.0148 ◽

Cited By ~ 1

Author(s):

Chelsea Michaud ◽

Brian Peppers ◽

John Frith ◽

Haig Tcheurekdjian ◽

Robert Hostoffer

Keyword(s):

Acute Pancreatitis ◽

Immunoglobulin E ◽

Necrotizing Pancreatitis ◽

Skin Infections ◽

Idiopathic Pancreatitis ◽

Genetic Ablation ◽

History Of ◽

Stat3 Mutation ◽

Stat3 Mutations ◽

Mammalian Protein

Background Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent skin infections with abscesses, recurrent pneumonias with pneumatoceles, and immunoglobulin E levels of >10 times the upper limit of normal. Case The patient described herein had a classic case of signal transducer and activator of transcription S (STAT3) deficiency associated with HIES diagnosed several years before this particular presentation. He demonstrated extraimmune manifestations of the disease as well, including characteristic facies and a history of skeletal fractures. In addition, the patient had several distinct episodes of idiopathic pancreatitis for which a full gastrointestinal workup had been performed. STAT3 mutation was confirmed by genotyping at the time of diagnosis of HIES. Conclusions STAT3, a mammalian protein that regulates cell growth, survival, and differentiation, has been linked to human pancreatic carcinogenesis as well as the above-mentioned immune deficiency. Mouse studies demonstrated that genetic ablation of STAT3 exacerbates the course of acute pancreatitis, whereas normal pancreatic STAT3 seems to have a protective effect against necrotizing pancreatitis. An association between STAT3 mutations and pancreatitis has not yet been revealed in humans. Here we describe a case of acute pancreatitis that presented in a patient with STAT3 mutation.

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Mast Cells in Liver Fibrogenesis

Cells ◽

10.3390/cells8111429 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1429 ◽

Cited By ~ 3

Author(s):

Ralf Weiskirchen ◽

Steffen K. Meurer ◽

Christian Liedtke ◽

Michael Huber

Keyword(s):

Mast Cells ◽

Connective Tissue ◽

Immunoglobulin E ◽

Calcium Influx ◽

Cell Types ◽

The Body ◽

Independent Manner ◽

Hematopoietic Stem ◽

Liver Fibrogenesis

Mast cells (MCs) are immune cells of the myeloid lineage that are present in the connective tissue throughout the body and in mucosa tissue. They originate from hematopoietic stem cells in the bone marrow and circulate as MC progenitors in the blood. After migration to various tissues, they differentiate into their mature form, which is characterized by a phenotype containing large granules enriched in a variety of bioactive compounds, including histamine and heparin. These cells can be activated in a receptor-dependent and -independent manner. Particularly, the activation of the high-affinity immunoglobulin E (IgE) receptor, also known as FcεRI, that is expressed on the surface of MCs provoke specific signaling cascades that leads to intracellular calcium influx, activation of different transcription factors, degranulation, and cytokine production. Therefore, MCs modulate many aspects in physiological and pathological conditions, including wound healing, defense against pathogens, immune tolerance, allergy, anaphylaxis, autoimmune defects, inflammation, and infectious and other disorders. In the liver, MCs are mainly associated with connective tissue located in the surrounding of the hepatic arteries, veins, and bile ducts. Recent work has demonstrated a significant increase in MC number during hepatic injury, suggesting an important role of these cells in liver disease and progression. In the present review, we summarize aspects of MC function and mediators in experimental liver injury, their interaction with other hepatic cell types, and their contribution to the pathogenesis of fibrosis.

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Induction and Differentiation of Dental Epithelium in Vivo and in Vitro

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053425 ◽

1982 ◽

Vol 40 ◽

pp. 142-145

Author(s):

E. J. Kollar

Keyword(s):

Connective Tissue ◽

Oral Mucosa ◽

Basal Lamina ◽

Functional Derivatives ◽

Specific Source ◽

Dental Epithelium ◽

Connective Tissue Stroma

The differentiation and maintenance of many specialized epithelial structures are dependent on the underlying connective tissue stroma and on an intact basal lamina. These requirements are especially stringent in the development and maintenance of the skin and oral mucosa. The keratinization patterns of thin or thick cornified layers as well as the appearance of specialized functional derivatives such as hair and teeth can be correlated with the specific source of stroma which supports these differentiated expressions.

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Ultrastructure of Liver in Lactosyl Ceramidosis

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100065602 ◽

1971 ◽

Vol 29 ◽

pp. 312-313

Author(s):

Z. Hruban ◽

J. R. Esterly ◽

G. Dawson ◽

A. O. Stein

Keyword(s):

Connective Tissue ◽

Liver Biopsy ◽

Osmium Tetroxide ◽

Close Contact ◽

Multivesicular Bodies ◽

Bile Canaliculi ◽

Dense Bodies ◽

Marginal Plates ◽

Membranous Material ◽

Perichromatin Granules

Samples of a surgical liver biopsy from a patient with lactosyl ceramidosis were fixed in paraformaldehyde and postfixed in osmium tetroxide. Hepatocytes (Figs. 1, 2) contained 0.4 to 2.1 μ inclusions (LCI) limited by a single membrane containing lucid matrix and short segments of curved, lamellated and circular membranous material (Fig. 3). Numerous LCI in large connective tissue cells were up to 11 μ in diameter (Fig. 2). Heterogeneous dense bodies (“lysosomes”) were few and irregularly distributed. Rough cisternae were dilated and contained smooth vesicles and surface invaginations. Close contact with mitochondria was rare. Stacks were small and rare. Vesicular rough reticulum and glycogen rosettes were abundant. Smooth vesicular reticulum was moderately abundant. Mitochondria were round with few cristae and rare matrical granules. Golgi complex was seen rarely (Fig. 1). Microbodies with marginal plates were usual. Multivesicular bodies were very rare. Neutral lipid was rare. Nucleoli were small and perichromatin granules were large. Small bile canaliculi had few microvilli (Fig. 1).

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Ultrastructure of Lymphatic Capillaries in the Transport of Colloidal Particles

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100060945 ◽

1967 ◽

Vol 25 ◽

pp. 186-187

Author(s):

L. V. Leak ◽

J. F. Burke

Keyword(s):

Connective Tissue ◽

Colloidal Particles ◽

Ultrastructural Level ◽

Vital Role ◽

Time Intervals ◽

Thorium Dioxide ◽

Lymphatic Capillary ◽

Tissue Area ◽

Rapid Removal ◽

Tissue Fluids

The vital role played by the lymphatic capillaries in the transfer of tissue fluids and particulate materials from the connective tissue area can be demonstrated by the rapid removal of injected vital dyes into the tissue areas. In order to ascertain the mechanisms involved in the transfer of substances from the connective tissue area at the ultrastructural level, we have injected colloidal particles of varying sizes which range from 80 A up to 900-mμ. These colloidal particles (colloidal ferritin 80-100A, thorium dioxide 100-200 A, biological carbon 200-300 and latex spheres 900-mμ) are injected directly into the interstitial spaces of the connective tissue with glass micro-needles mounted in a modified Chambers micromanipulator. The progress of the particles from the interstitial space into the lymphatic capillary lumen is followed by observing tissues from animals (skin of the guinea pig ear) that were injected at various time intervals ranging from 5 minutes up to 6 months.

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Banded Structures in the Connective Tissue of Meningioma

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100091159 ◽

1976 ◽

Vol 34 ◽

pp. 234-235

Author(s):

C. N. Sun ◽

H. J. White

Keyword(s):

Connective Tissue ◽

Osmium Tetroxide ◽

Uranyl Acetate ◽

Collagen Fibrils ◽

Lead Citrate ◽

Connective Tissues ◽

Native Collagen ◽

Routine Procedures

Previously, we have reported on extracellular cross-striated banded structures in human connective tissues of a variety of organs (1). Since then, more material has been examined and other techniques applied. Recently, we studied a fibrocytic meningioma of the falx. After the specimen was fixed in 4% buffered glutaraldehyde and post-fixed in 1% buffered osmium tetroxide, other routine procedures were followed for embedding in Epon 812. Sections were stained with uranyl acetate and lead citrate. There were numerous cross striated banded structures in aggregated bundle forms found in the connecfive tissue of the tumor. The banded material has a periodicity of about 450 Å and where it assumes a filamentous arrangement, appears to be about 800 Å in diameter. In comparison with the vicinal native collagen fibrils, the banded material Is sometimes about twice the diameter of native collagen.

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Banded aggregates containing fibrillin are present in the cartilage matrix adjacent to chondrocytes in individuals affected with scoliosis

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100124860 ◽

1992 ◽

Vol 50 (1) ◽

pp. 892-893

Author(s):

Douglas R. Keene ◽

Magaret Fairhurst ◽

Catherine C. Ridgway ◽

Lynn Y. Sakai

Keyword(s):

Connective Tissue ◽

Marfan Syndrome ◽

Cross Section ◽

Immunoelectron Microscopy ◽

Cartilage Matrix ◽

Negative Stain ◽

Gene Coding ◽

Rotary Shadowing

Matrix microfibrils are present in the connective tissue matrices of all tissues. Following standard TEM processing, they appear in cross section as cylindrical fibrils 8-10 nm in diameter, often associated with amorphous elastin. They are also seen in the absence of amorphous elastin, for example in the shallow papillary layer of skin, and also in cartilage matrix (Figure 1). Negative stain and rotary shadowing studies suggest that microfibrils are composed of laterally associated globular structures connected by fine filamentous strands (“ beaded strings”), and that they are extendable. Immunoelectron microscopy has demonstrated that fibrillin, a 350 Kd glycoprotein, is distributed along all microfibrils with a relaxed periodicity of about 54 nm The gene coding for fibrillin has recently been identified and is defective in the Marfan syndrome.

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