Publications by authors named "Chyi-Chia Richard Lee"

63 Publications

First Somatic Defect Associated With Mosaicism for Another Mutation in a Patient With Cushing Syndrome.

J Endocr Soc 2021 Apr 25;5(4):bvab007. Epub 2021 Jan 25.

Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.

Context: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome (CS) associated mostly with Carney complex (CNC), a rare autosomal dominant multiple neoplasia syndrome. More than two-thirds of familial cases and approximately one-third of sporadic cases of CNC harbor germline inactivating defects. Increasingly sensitive technologies for the detection of genetic defects such as next-generation sequencing (NGS) have further highlighted the importance of mosaicism in human disease.

Case Description: A 33-year-old woman was diagnosed with ACTH-independent CS with abdominal computed tomography showing bilateral micronodular adrenal hyperplasia with a left adrenal adenoma. She underwent left adrenalectomy with pathology demonstrating PPNAD with a 1.5-cm pigmented adenoma. DNA analysis by Sanger sequencing revealed 2 different variants in the adenoma that were absent from DNA extracted from blood and saliva: c.682C > T and c.974-2A > G. "Deep" NGS revealed that 0.31% of DNA copies extracted from blood and saliva did in fact carry the c.682C > T variant, suggesting low-level mosaicism for this defect.

Conclusions: We present a case of PPNAD due to low-level mosaicism for a defect which led to the formation of an adenoma due to a second, adrenal-specific, somatic mutation. The identification of mosaicism for , depending on the number and distribution of cells affected has implications for genetic counseling and tumor surveillance. This is the first recorded case of a patient with mosaicism, PPNAD, and an adenoma forming due to complete inactivation of in adrenal tissue from a second, somatic-only, coding sequence mutation.
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http://dx.doi.org/10.1210/jendso/bvab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885549PMC
April 2021

Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome.

J Clin Invest 2020 08;130(8):4167-4181

Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular Medicine Branch.

There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, also known as Job's syndrome) is caused by mutations in STAT3. These patients present with immunodeficiency accompanied by severe nonimmunological features, including skeletal, connective tissue, and vascular abnormalities, poor postinfection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here, we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin-wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3-controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia-inducible factor 1α (HIF-1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF-1α expression and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling using cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF-1α-stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and suggests potential treatment options for this rare disease.
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http://dx.doi.org/10.1172/JCI135490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410079PMC
August 2020

Identification of Small Molecule Enhancers of Immunotherapy for Melanoma.

Sci Rep 2020 03 30;10(1):5688. Epub 2020 Mar 30.

Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, Maryland, USA.

Small molecule based targeted therapies for the treatment of metastatic melanoma hold promise but responses are often not durable, and tumors frequently relapse. Response to adoptive cell transfer (ACT)-based immunotherapy in melanoma patients are durable but patients develop resistance primarily due to loss of antigen expression. The combination of small molecules that sustain T cell effector function with ACT could lead to long lasting responses. Here, we have developed a novel co-culture cell-based high throughput assay system to identify compounds that could potentially synergize or enhance ACT-based immunotherapy of melanoma. A BRAF mutant melanoma cell line, SB-3123 which is resistant to Pmel-1-directed ACT due to low gp100 expression levels was used to develop a homogenous time resolve fluorescence (HTRF), screening assay. This high throughput screening assay quantitates IFNγ released upon recognition of the SB-3123 melanoma cells by Pmel-1 CD8 T-cells. A focused collection of approximately 500 small molecules targeting a broad range of cellular mechanisms was screened, and four active compounds that increased melanoma antigen expression leading to enhanced IFNγ production were identified and their in vitro activity was validated. These four compounds may provide a basis for enhanced immune recognition and design of novel therapeutic approaches for patients with BRAF mutant melanoma resistant to ACT due to antigen downregulation.
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http://dx.doi.org/10.1038/s41598-020-62369-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105471PMC
March 2020

IL15 by Continuous Intravenous Infusion to Adult Patients with Solid Tumors in a Phase I Trial Induced Dramatic NK-Cell Subset Expansion.

Clin Cancer Res 2019 08 29;25(16):4945-4954. Epub 2019 May 29.

Lymphoid Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Purpose: The first-in-human clinical trial with human bolus intravenous infusion IL15 (rhIL15) was limited by treatment-associated toxicity. Here, we report toxicity, immunomodulation, and clinical activity of rhIL15 administered as a 10-day continuous intravenous infusion (CIV) to patients with cancers in a phase I trial.

Patients And Methods: Patients received treatment for 10 days with CIV rhIL15 in doses of 0.125, 0.25, 0.5, 1, 2, or 4 μg/kg/day. Correlative laboratory tests included IL15 pharmacokinetic (PK) analyses, and assessment of changes in lymphocyte subset numbers.

Results: Twenty-seven patients were treated with rhIL15; 2 μg/kg/day was identified as the MTD. There were eight serious adverse events including two bleeding events, papilledema, uveitis, pneumonitis, duodenal erosions, and two deaths (one due to likely drug-related gastrointestinal ischemia). Evidence of antitumor effects was observed in several patients, but stable disease was the best response noted. Patients in the 2 μg/kg/day group had a 5.8-fold increase in number of circulating CD8 T cells, 38-fold increase in total NK cells, and 358-fold increase in CD56 NK cells. Serum IL15 concentrations were markedly lower during the last 3 days of infusion.

Conclusions: This phase I trial identified the MTD for CIV rhIL15 and defined a treatment regimen that produced significant expansions of CD8 T and NK effector cells in circulation and tumor deposits. This regimen has identified several biological features, including dramatic increases in numbers of NK cells, supporting trials of IL15 with anticancer mAbs to increase antibody-dependent cell-mediated cytotoxicity and anticancer efficacy.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697593PMC
August 2019

Birt-Hogg-Dubé syndrome initially diagnosed as tuberous sclerosis complex.

JAAD Case Rep 2019 Apr 5;5(4):368-371. Epub 2019 Apr 5.

Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

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http://dx.doi.org/10.1016/j.jdcr.2019.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453834PMC
April 2019

Recurrent fevers, progressive lipodystrophy, and annular plaques in a child.

J Am Acad Dermatol 2019 Jan 8;80(1):291-295. Epub 2018 Sep 8.

Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland. Electronic address:

KEY TEACHING POINTS.
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http://dx.doi.org/10.1016/j.jaad.2018.08.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132105PMC
January 2019

Fibrous cephalic plaques in tuberous sclerosis complex.

J Am Acad Dermatol 2018 04 16;78(4):717-724. Epub 2017 Dec 16.

Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, Maryland. Electronic address:

Background: Fibrous cephalic plaques (FCPs) stereotypically develop on the forehead of patients with tuberous sclerosis complex (TSC). They constitute a major feature for TSC diagnosis and may present before other TSC-related cutaneous hamartomas.

Objective: To describe the clinical characteristics of FCPs in TSC.

Methods: A total of 113 patients with TSC were enrolled in an observational cohort study. Retrospective analysis of medical records and skin photography was performed. FCPs were categorized by anatomic location and size.

Results: FCPs were observed in 36% of patients (41 of 113). Of 62 total lesions, 58% were 1 to less than 5 cm, 13% were 5 cm or larger, and 29% were of unknown size mostly because of prior excision. The distribution of lesions was 39% on the forehead, 27% on the face (nonforehead), 3% on the neck, and 31% on the scalp. Fourteen patients had similar lesions less than 1 cm in diameter. Histopathologically, FCPs displayed dermal collagenosis, decreased elastic fibers, and features of angiofibromas or fibrofolliculomas.

Limitations: Men were under-represented because the cohort was enriched for patients with TSC with lymphangioleiomyomatosis, which occurs in adult women.

Conclusion: Two-fifths of FCPs presented on the forehead, with most of the remainder in other locations on the face and scalp. Better recognition of these lesions may lead to earlier diagnosis of TSC.
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http://dx.doi.org/10.1016/j.jaad.2017.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423974PMC
April 2018

Transcriptome Assessment of Erythema Migrans Skin Lesions in Patients With Early Lyme Disease Reveals Predominant Interferon Signaling.

J Infect Dis 2017 12;217(1):158-167

Department of Microbiology and Immunology, Valhalla.

Background: The most common clinical manifestation of early Lyme disease is the erythema migrans (EM) skin lesion that develops at the tick bite site typically between 7 and 14 days after infection with Borreliella burgdorferi. The host-pathogen interactions that occur in the skin may have a critical role in determining outcome of infection.

Methods: Gene arrays were used to characterize the global transcriptional alterations in skin biopsy samples of EM lesions from untreated adult patients with Lyme disease in comparison to controls.

Results: The transcriptional pattern in EM biopsies consisted of 254 differentially regulated genes (180 induced and 74 repressed) characterized by the induction of chemokines, cytokines, Toll-like receptors, antimicrobial peptides, monocytoid cell activation markers, and numerous genes annotated as interferon (IFN)-inducible. The IFN-inducible genes included 3 transcripts involved in tryptophan catabolism (IDO1, KMO, KYNU) that play a pivotal role in immune evasion by certain other microbial pathogens by driving the differentiation of regulatory T cells.

Conclusions: This is the first study to globally assess the human skin transcriptional response during early Lyme disease. Borreliella burgdorferi elicits a predominant IFN signature in the EM lesion, suggesting a potential mechanism for spirochetal dissemination via IDO1-mediated localized immunosuppression.
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http://dx.doi.org/10.1093/infdis/jix563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853807PMC
December 2017

Recurrent scarring papulovesicular lesions on sun-exposed skin in a 22-year-old man.

J Am Acad Dermatol 2018 03 28;78(3):637-642. Epub 2017 Sep 28.

Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

KEY TEACHING POINTS.
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http://dx.doi.org/10.1016/j.jaad.2017.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815928PMC
March 2018

Clinical Characteristics of Connective Tissue Nevi in Tuberous Sclerosis Complex With Special Emphasis on Shagreen Patches.

JAMA Dermatol 2017 07;153(7):660-665

Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

Importance: Patients with tuberous sclerosis complex (TSC) frequently develop collagenous connective tissue nevi. The prototypical lesion is a large shagreen patch located on the lower back, but some patients only manifest small collagenomas or have lesions elsewhere on the body. The ability to recognize these variable presentations can be important for the diagnosis of TSC.

Objective: To describe the clinical characteristics of connective tissue nevi on the trunk and extremities of patients with tuberous sclerosis complex.

Design, Setting, And Participants: A retrospective analysis of patient medical records and skin photography was performed; 104 adult patients with TSC were enrolled in an observational cohort study that was enriched for those with pulmonary lymphangioleiomyomatosis, and was therefore composed mostly of women (99 women, 5 men). All patients included were examined at the National Institutes of Health (NIH) in Bethesda, Maryland, from 1998 to 2013. Connective tissue nevi were categorized per anatomic location and size. Lesions less than 1 cm in diameter were termed collagenomas. Shagreen patches were characterized as small (1 to <4 cm), medium (4 to <8 cm), and large (≥8 cm).

Main Outcome And Measures: Frequency, anatomic location, size, and histological appearance of connective tissue nevi in patients with TSC.

Results: Overall, 58 of 104 patients (median [range] age, 42 [19-70] years) with TSC (56%) had at least 1 connective tissue nevus on the trunk or thighs; of these, 28 of 58 patients (48%) had a solitary lesion, and 30 of 58 patients (52%) had 2 or more lesions. Overall, 120 lesions from 55 patients were classified by size; 46 lesions (38%) were collagenomas; 39 lesions (32%) were small shagreen patches; 21 lesions (18%), medium shagreen patches; and 14 lesions (12%), large shagreen patches. The distribution of lesions was 9% (n = 11), upper back; 29% (n = 35), middle back; 51% (n = 61), lower back; and 11% (n = 13), other locations. All 26 shagreen patches that were analyzed histopathologically had coarse collagen fibers and 24 of 26 stained with Miller elastic stain had decreased elastic fibers. On immunoblot analysis, fibroblasts grown from shagreen patches expressed higher levels of phosphorylated ribosomal protein S6 than paired fibroblasts from normal-appearing skin.

Conclusions And Relevance: Tuberous sclerosis complex-related connective tissue nevi are not limited to the lower back, and occasionally present on the central or upper back, buttocks, or thighs. Elastic fibers are typically decreased. Recognition of these variable presentations can be important for TSC diagnosis.
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http://dx.doi.org/10.1001/jamadermatol.2017.0298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817464PMC
July 2017

A Pilot Trial of the Combination of Vemurafenib with Adoptive Cell Therapy in Patients with Metastatic Melanoma.

Clin Cancer Res 2017 Jan 7;23(2):351-362. Epub 2016 Oct 7.

Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Purpose: This pilot feasibility clinical trial evaluated the coadministration of vemurafenib, a small-molecule antagonist of BRAF mutations, and tumor-infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma.

Experimental Design: A metastatic tumor was resected for growth of TILs, and patients were treated with vemurafenib for 2 weeks, followed by resection of a second lesion. Patients then received a nonmyeloablative preconditioning regimen, infusion of autologous TILs, and high-dose interleukin-2 administration. Vemurafenib was restarted at the time of TIL infusion and was continued for 2 years or until disease progression. Clinical responses were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. Metastases resected prior to and after 2 weeks of vemurafenib were compared using TCRB deep sequencing, immunohistochemistry, proliferation, and recognition of autologous tumor.

Results: The treatment was well tolerated and had a safety profile similar to that of TIL or vemurafenib alone. Seven of 11 patients (64%) experienced an objective clinical response, and 2 patients (18%) had a complete response for 3 years (one response is ongoing at 46 months). Proliferation and viability of infusion bag TILs and peripheral blood T cells were inhibited in vitro by research-grade vemurafenib (PLX4032) when approaching the maximum serum concentration of vemurafenib. TCRB repertoire (clonotypes numbers, clonality, and frequency) did not significantly change between pre- and post-vemurafenib lesions. Recognition of autologous tumor by T cells was similar between TILs grown from pre- and post-vemurafenib metastases.

Conclusions: Coadministration of vemurafenib and TILs was safe and feasible and generated objective clinical responses in this small pilot clinical trial. Clin Cancer Res; 23(2); 351-62. ©2016 AACRSee related commentary by Cogdill et al., p. 327.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5245178PMC
January 2017

Dermatologic Manifestations of Monogenic Autoinflammatory Diseases.

Dermatol Clin 2017 Jan;35(1):21-38

Translational Autoinflammatory Disease Studies, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Building 10, Room 6D-47B, 10 Center Drive, Bethesda, MD 20892, USA. Electronic address:

Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever, rash, and disease-specific patterns of organ inflammation. Gain-of-function mutations in innate danger-sensing pathways, including the inflammasomes and the nucleic acid sensing pathways, play critical roles in the pathogenesis of IL-1 and Type-I IFN-mediated disorders and point to an important role of excessive proinflammatory cytokine signaling, including interleukin (IL)-1b , Type-I interferons, IL-18, TNF and others in causing the organ specific immune dysregulation. The article discusses the concept of targeting proinflammatory cytokines and their signaling pathways with cytokine blocking treatments that have been life changing for some patients.
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http://dx.doi.org/10.1016/j.det.2016.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147585PMC
January 2017

Diffuse atrophic papules and plaques, intermittent abdominal pain, paresthesias, and cardiac abnormalities in a 55-year-old woman.

J Am Acad Dermatol 2016 Dec 4;75(6):1274-1277. Epub 2016 Oct 4.

Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

KEY TEACHING POINTS.
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http://dx.doi.org/10.1016/j.jaad.2016.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112129PMC
December 2016

Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

JCI Insight 2016 Aug;1(13)

Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common mutation was c.967_979del13. All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4 T cells and CD21CD38 B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications.
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http://dx.doi.org/10.1172/jci.insight.88782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004733PMC
August 2016

Batf3-dependent CD103(+) dendritic cell accumulation is dispensable for mucosal and systemic antifungal host defense.

Virulence 2016 10 18;7(7):826-35. Epub 2016 May 18.

a Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda , MD , USA.

Dendritic cells (DCs) are critical for defense against a variety of pathogens and the formation of adaptive immune responses. The transcription factor Batf3 is critical for the development of CD103(+)CD11b(-) DCs, which promote IL-12-dependent protective immunity during viral and parasitic infections, dampen Th2 immunity during helminthic infection, and exert detrimental effects during bacterial infection. Whether CD103(+) DCs modulate immunity during systemic or mucosal fungal disease remains unknown. Herein, we report that Batf3 is critical for accumulation of CD103(+) DCs in the kidney and tongue at steady state, for their expansion during systemic and oropharyngeal candidiasis, and for tissue-specific production of IL-12 in kidney but not tongue during systemic and oropharyngeal candidiasis, respectively. Importantly, deficiency of CD103(+) DCs does not impair survival or fungal clearance during systemic or oropharyngeal candidiasis, indicating that Batf3-dependent CD103(+) DC accumulation mediates pathogen- and tissue-specific immune effects.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029292PMC
http://dx.doi.org/10.1080/21505594.2016.1186324DOI Listing
October 2016

Nipple Angiofibromas with Loss of TSC2 Are Associated with Tuberous Sclerosis Complex.

J Invest Dermatol 2016 Feb 10;136(2):535-538. Epub 2015 Dec 10.

Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2015.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733881PMC
February 2016

CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival.

Sci Transl Med 2016 Jan;8(322):322ra10

Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892, USA.

Systemic Candida albicans infection causes high morbidity and mortality and is now the leading cause of nosocomial bloodstream infection in the United States. Neutropenia is a major risk factor for poor outcome in infected patients; however, the molecular factors that mediate neutrophil trafficking and effector function during infection are poorly defined. Using a mouse model of systemic candidiasis, we found that the neutrophil-selective CXC chemokine receptor Cxcr1 and its ligand, Cxcl5, are highly induced in the Candida-infected kidney, the target organ in the model. To investigate the role of Cxcr1 in antifungal host defense in vivo, we generated Cxcr1(-/-) mice and analyzed their immune response to Candida. Mice lacking Cxcr1 exhibited decreased survival with enhanced Candida growth in the kidney and renal failure. Increased susceptibility of Cxcr1(-/-) mice to systemic candidiasis was not due to impaired neutrophil trafficking from the blood into the infected kidney but was the result of defective killing of the fungus by neutrophils that exhibited a cell-intrinsic decrease in degranulation. In humans, the mutant CXCR1 allele CXCR1-T276 results in impaired neutrophil degranulation and fungal killing and was associated with increased risk of disseminated candidiasis in infected patients. Together, our data demonstrate a biological function for mouse Cxcr1 in vivo and indicate that CXCR1-dependent neutrophil effector function is a critical innate protective mechanism of fungal clearance and host survival in systemic candidiasis.
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http://dx.doi.org/10.1126/scitranslmed.aac7718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938152PMC
January 2016

Expression of MAGE-A and NY-ESO-1 in Primary and Metastatic Cancers.

J Immunother 2016 Jan;39(1):1-7

*Surgery Branch †Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Melanoma-associated antigen-A (MAGE-A) and New York esophageal squamous cell cancer-1 (NY-ESO-1) are 2 cancer testis antigens (CTA) demonstrating potential for use in targeted immunotherapy. Clinical trials in melanoma and synovial sarcomas targeting these antigens in immune-based therapies have demonstrated durable tumor regression. Although protein expression of NY-ESO-1 has been assessed in a variety of cancer types, the expression of MAGE-A has not been studied in depth. In this study we analyzed MAGE-A and NY-ESO-1 expression in 314 melanoma specimens from 301 melanoma patients, 38 patients with squamous cell cancers and 111 patients with adenocarcinomas. Our results demonstrated higher expression of MAGE-A compared with NY-ESO-1 in melanomas (32% vs. 13%) and squamous cell carcinomas (45% vs. 7.9%), and higher expression of both CTAs in metastatic versus primary tumors. CTA expression in adenocarcinomas was low (MAGE-A: 10%, NY-ESO-1: 0.9%). In addition, we looked at concordance of expression among metastatic melanoma lesions within the same patient and found concordant expression in 38 of 47 patients for MAGE-A and 43 of 47 patients for NY-ESO-1. Our study demonstrated that the MAGE-A family may be of greater utility than NY-ESO-1 for targeted immunotherapy in a variety of cancer histologies, in particular metastatic melanomas and squamous cell carcinomas.
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http://dx.doi.org/10.1097/CJI.0000000000000101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453128PMC
January 2016

Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production.

J Clin Invest 2015 Nov 20;125(11):4196-211. Epub 2015 Oct 20.

Autosomal recessive mutations in proteasome subunit β 8 (PSMB8), which encodes the inducible proteasome subunit β5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes α7), PSMB4 (encodes β7), PSMB9 (encodes β1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production.
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http://dx.doi.org/10.1172/JCI81260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639987PMC
November 2015

Histologic and Immunohistochemical Features of the Skin Lesions in CANDLE Syndrome.

Am J Dermatopathol 2015 Jul;37(7):517-22

*Department of Dermatology, Hospital del Niño Jesús, Madrid, Spain; †Paediatric Histopathology Department, Birmingham Children's Hospital, Birmingham, United Kingdom; ‡Department of Dermatology, Fundación Jiménez Díaz, Madrid, Spain; §Department of Dermatology, Northwestern University, Chicago, IL; ¶Department of Dermatology and the Center for Genetic Diseases of the Skin and Hair, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; ‖Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, MD; **Department of Dermatology, Hospital Carlos Haya, Málaga, Spain; ††Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, MD; and ‡‡Dermatohistopathologisches Gemeinschaftslabor, Friedrichshafen, Germany.

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a newly characterized autoinflammatory disorder, caused by mutations in PSMB8. It is characterized by early-onset fevers, accompanied by a widespread, violaceous, and often annular cutaneous eruption. Although the exact pathogenesis of this syndrome is still obscure, it is postulated that the inflammatory disease manifestations stem from excess secretion of interferons. Based on preliminary blood cytokine and gene expression studies, the signature seems to come mostly from type I interferons, which are proposed to lead to the recruitment of immature myeloid cells into the dermis and subcutis. In this study, we systematically analyzed skin biopsies from 6 patients with CANDLE syndrome by routine histopathology and immunohistochemistry methods. Skin lesions showed the presence of extensive mixed dermal and subcutaneous inflammatory infiltrate, composed of mononuclear cells, atypical myeloid cells, neutrophils, eosinophils, and some mature lymphocytes. Positive LEDER and myeloperoxidase staining supported the presence of myeloid cells. Positive CD68/PMG1 and CD163 staining confirmed the existence of histiocytes and monocytic macrophages in the inflammatory infiltrate. CD123 staining was positive, demonstrating the presence of plasmacytoid dendritic cells. Uncovering the unique histopathological and immunohistochemical features of CANDLE syndrome provides tools for rapid and specific diagnosis of this disorder and further insight into the pathogenesis of this severe life-threatening condition.
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http://dx.doi.org/10.1097/DAD.0000000000000340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476069PMC
July 2015

Distinct Cutaneous Manifestations and Cold-Induced Leukocyte Activation Associated With PLCG2 Mutations.

JAMA Dermatol 2015 Jun;151(6):627-34

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

Importance: PLCG2-associated antibody deficiency and immune dysregulation (PLAID) is a newly characterized immunodeficiency syndrome associated with distinct cutaneous features. Awareness of the cutaneous skin findings associated with PLAID may facilitate diagnosis and improve patient care.

Objectives: To characterize the cutaneous manifestations of PLAID and identify potential cellular mechanisms of the disease.

Design, Setting, And Participants: In this retrospective analysis of patients with PLAID and PLAID-like disease evaluated at the National Institutes of Health from January 1, 2005, through December 31, 2014, patients with deletions in PLCG2 leading to PLAID and patients with PLAID-like disease for whom a PLAID mutation was not identified were studied.

Main Outcomes And Measures: Characterization of cutaneous manifestations of PLAID and PLAID-like disease and analysis of PLAID immune cell activation.

Results: Among 36 patients with PLAID and PLAID-like phenotypes, all of whom had evaporative cold urticaria, 8 patients had a history of unique neonatal-onset ulcerative and cutaneous lesions in cold-sensitive regions of the body. Granulomatous skin lesions sparing warm regions (eg, flexural surfaces and skinfolds) were identified in 4 patients. Neutrophils and monocytes from patients with PLAID exhibited enhanced baseline activation in vitro, which was potentiated by ambient temperature exposure.

Conclusions And Relevance: Collectively, these findings suggest that early identification of neonatal lesions may help in the diagnosis of PLAID and that leukocyte hyperactivation may underlie cutaneous lesions in patients with PLAID. Further characterization of mechanisms underlying leukocyte hyperactivation may contribute to the fundamental understanding of granuloma formation.
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http://dx.doi.org/10.1001/jamadermatol.2014.5641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664155PMC
June 2015

CX3CR1 is dispensable for control of mucosal Candida albicans infections in mice and humans.

Infect Immun 2015 Mar 29;83(3):958-65. Epub 2014 Dec 29.

Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA

Candida albicans is part of the normal commensal microbiota of mucosal surfaces in a large percentage of the human population. However, perturbations of the host's immune response or bacterial microbiota have been shown to predispose individuals to the development of opportunistic Candida infections. It was recently discovered that a defect in the chemokine receptor CX3CR1 increases susceptibility of mice and humans to systemic candidiasis. However, whether CX3CR1 confers protection against mucosal C. albicans infection has not been investigated. Using two different mouse models, we found that Cx3cr1 is dispensable for the induction of interleukin 17A (IL-17A), IL-22, and IL-23 in the tongue after infection, as well as for the clearance of mucosal candidiasis from the tongue or lower gastrointestinal (GI) tract colonization. Furthermore, the dysfunctional human CX3CR1 allele CX3CR1-M280 was not associated with development of recurrent vulvovaginal candidiasis (RVVC) in women. Taken together, these data indicate that CX3CR1 is not essential for protection of the host against mucosal candidiasis, underscoring the dependence on different mammalian immune factors for control of mucosal versus systemic Candida infections.
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http://dx.doi.org/10.1128/IAI.02604-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333470PMC
March 2015

Episodic angioedema with eosinophilia (Gleich syndrome) is a multilineage cell cycling disorder.

Haematologica 2015 Mar 19;100(3):300-7. Epub 2014 Dec 19.

Laboratory of Parasitic Diseases, NIAID, National Institutes of Health, Bethesda, MD.

Episodic angioedema with eosinophilia (Gleich syndrome) is a rare disorder characterized by episodes of angioedema and eosinophilia that occur at monthly intervals and resolve spontaneously without therapy. Despite the striking periodicity of this disorder, its similarity to other cyclic hematopoietic disorders with multilineage involvement has not been assessed. To characterize the involvement of cell lineages in the etiology and pathogenesis of episodic angioedema with eosinophilia, four subjects were evaluated by blood counts and other analyses over the course of 1-2 months. Surface marker expression was assessed on T cells by flow cytometry and clonality by polymerase chain reaction. Intracellular cytokine evaluation, bone marrow and skin biopsies were performed during different parts of the cycle. Cycling of multiple cell lineages, including neutrophils, lymphocytes and eosinophils, was observed in the four subjects with the disorder with a periodicity of 25-35 days. An aberrant CD3(-)CD4(+) T-cell population was detected in all four subjects, and T-cell receptor rearrangement studies showed a clonal pattern in three subjects. A peak of type II cytokines was detected in the serum of subjects prior to the onset of symptoms and eosinophil cycling and corresponded to ex-vivo type II cytokines detected intracellularly in CD3(+)CD4(+)CD154(+) T cells. Although the etiology of episodic angioedema with eosinophilia is not yet known, multiple lineages, including lymphocytes, neutrophils and mast cells, are involved and may be related to disease pathogenesis. Whether these cells act directly or promote eosinophilia and eosinophil activation remains to be elucidated. All subjects gave informed consent and were evaluated under an Institutional Review Board-approved protocol (NCT00001406).
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http://dx.doi.org/10.3324/haematol.2013.091264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349267PMC
March 2015

A case of severe hyperaldosteronism caused by a de novo mutation affecting a critical salt bridge Kir3.4 residue.

J Clin Endocrinol Metab 2015 Jan;100(1):E114-8

Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences (S.M., P.M., T.A.W.), University of Torino, Torino 10124 Italy; Medical Cell Biology (S.B., J.S.), University of Regensburg, 93053 Regensburg, Germany; Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, and Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (M.Z., C.A.S.), and Laboratory of Pathology (M.A., C.-C.R.L.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892; and Department of Inherited Endocrine Disorders (I.D., A.T.), Endocrinology Research Centre, Moscow 117036, Russia.

Context: Familial hyperaldosteronism type III (FH-III) is a rare and clinically heterogeneous condition, that can display mild as well as severe phenotypes. Point mutations in the KCNJ5 gene, affecting the ion selectivity of the inward rectifier K(+) channel 4 (Kir3.4), underlie the molecular basis of FH-III.

Objective: The objective of the study was to investigate the effects of a de novo germline KCNJ5 mutation.

Patients And Methods: We describe the case of a girl who came to medical attention at the age of 2 years because of polydipsia, polyuria, and failure to thrive. The patient, affected by hypertension and hypokalemia, was diagnosed with primary aldosteronism on the basis of extremely high aldosterone levels and suppressed plasma renin activity. Genomic DNA was isolated and KCNJ5 sequenced. Human adrenocortical cells were used as an in vitro model for the functional characterization of the mutant channel.

Results: KCNJ5 sequencing in the index case and her parents revealed a de novo p.Glu145Gln germline mutation. The substitution resulted in Na(+)-dependent depolarization of adrenal cells and increased intracellular calcium concentration, which activated the transcription of NR4A2 and, in turn, CYP11B2. Pharmacological studies revealed that the mutant channel was insensitive to tertiapin-Q and calcium-channel blocker verapamil.

Conclusions: Herein we report the identification of a novel KCNJ5 germline mutation responsible for severe hyperaldosteronism that presented in infancy with symptoms of diabetes insipidus. The findings of this study further elucidate the etiology of FH-III and expand our knowledge of this rare condition.
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http://dx.doi.org/10.1210/jc.2014-3636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283020PMC
January 2015

Malignant melanoma masquerading as an angiofibroma in a patient with MEN-1.

JAMA Dermatol 2015 Jan;151(1):105-6

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jamadermatol.2014.2186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747011PMC
January 2015

Palmoplantar pustules and osteoarticular pain in a 42-year-old woman.

J Am Acad Dermatol 2015 Mar 12;72(3):550-3. Epub 2014 Aug 12.

Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Key teaching points • Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome is characterized by distinctive osteoarticular manifestations and a spectrum of neutrophilic dermatoses. • The most common dermatologic manifestations include palmoplantar pustulosis, acne conglobata, and acne fulminans. • SAPHO syndrome should be considered in patients presenting osteoarticular pain, particularly involving the anterior chest wall and/or spine, and neutrophilic skin lesions.
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http://dx.doi.org/10.1016/j.jaad.2014.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326625PMC
March 2015

New facial papules in a 66-year-old woman with bladder cancer.

J Am Acad Dermatol 2014 Dec 7;71(6):1250-5. Epub 2014 Aug 7.

Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2014.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253599PMC
December 2014

Adult T-cell leukemia-lymphoma associated with follicular mucinosis.

Am J Dermatopathol 2014 Nov;36(11):901-3

*Laboratory of Pathology, and †Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Follicular mucinosis is frequently associated with follicular mycosis fungoides, but its association with adult T-cell leukemia-lymphoma (ATLL) is extremely rare. We report a case of a 50-year-old female patient with a history of ATLL, after multiple treatments, with residual/recurrent skin tumors in the forehead and legs. Biopsy of a skin tumor from the forehead revealed a perifollicular and intrafollicular atypical lymphoid infiltrate with abundant mucin deposition. Immunohistochemical stains showed that the atypical cells were positive for CD3, CD4, and CD25. Reverse transcription polymerase chain reaction performed on the tissue sections confirmed the presence of human T-cell leukemia virus in the biopsies of skin tumors. To our knowledge, this is only the third reported case of a follicular mucinosis in the setting of ATLL.
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http://dx.doi.org/10.1097/DAD.0000000000000082DOI Listing
November 2014
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