Exploiting CD22 on Antigen-Specific B-Cells to Prevent Allergy to the Major Peanut Allergen Ara h 2

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Kelly A. Orgel, Shiteng Duan, Benjamin L. Wright, Soheila J. Maleki, John C. Wolf, Brian P. Vickery, A. Wesley Burks, James C. Paulson, Mike D. Kulis, Matthew S. Macauley

Teaser

Methods for inducing antigen-specific immune tolerance are needed for the treatment and prevention of food allergies. We demonstrate that mice can be tolerized to the major peanut allergen through engaging CD22, an inhibitory B-cell co-receptor.


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An IL-17-dominant immune profile is shared across the major orphan forms of ichthyosis

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Amy S. Paller, Yael Renert-Yuval, Maria Suprun, Hitokazu Esaki, Margeaux Oliva, Thy Nhat Huynh, Benjamin Ungar, Norma Kunjravia, Rivka Friedland, Xiangyu Peng, Xiuzhong Zheng, Yeriel D. Estrada, James G. Krueger, Keith A. Choate, Mayte Suárez-Fariñas, Emma Guttman-Yassky
BackgroundThe ichthyoses are rare genetic disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis-based therapy is largely lacking, since the underlying molecular basis is poorly understood.ObjectiveTo characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics.MethodsWe analyzed biopsies from 21 genotyped ichthyosis patients (congenital ichthyosiform erythroderma (n=6), lamellar ichthyosis (n=7), epidermolytic ichthyosis, (n=5) and Netherton syndrome (n=3)) by immunohistochemistry and RT-PCR and compared them with healthy controls, and atopic dermatitis (AD) and psoriasis patients. Clinical measures included an ichthyosis severity score (IASI) which integrates erythema (IASI-E) and scaling (IASI-S), transepidermal water loss (TEWL), and pruritus.ResultsIchthyosis samples showed increased epidermal hyperplasia (increased thickness and K16 expression) and T-cell and dendritic-cell infiltrates. Increases of general inflammatory (IL-2), innate (IL-1β), and some Th1/IFN (IFNγ) markers in ichthyosis were comparable to psoriasis or AD. TNFα levels in ichthyosis were elevated only in Netherton syndrome, but were much lower than in psoriasis and AD. Expression of Th2 cytokines (IL-13, IL-31) was similar to controls. The striking induction of IL-17-related genes or markers synergistically induced by IL-17 and TNFα (IL-17A/C, IL-19, CXCL1, PI3, CCL20, IL36G; p<0.05) in ichthyosis was similar to psoriasis. IASI and IASI-E strongly correlated with IL-17A (r=0.74, p<0.001) and IL-17/TNF-synergistic/additive genes. These markers also significantly correlated with TEWL, suggesting a link between the barrier defect and inflammation in ichthyosis.ConclusionOur data associates a shared Th17/IL-23 immune fingerprint with the major orphan forms of ichthyosis and raises the possibility of IL-17-targeting strategies.Clinical ImplicationsThe link between increased expression of Th17 pathway cytokines and clinical disease severity raises the possibility of a new therapeutic paradigm of targeted IL-17/IL-23 intervention for ichthyosis patients.

Teaser

CIE, LI, EI and NS subtypes of ichthyosis are Th17-skewed. IL-17/TNF-synergistic/additive genes are predominantly increased and significantly correlated with disease severity scores and functional barrier abnormalities (TEWL).


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Human CD40L deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Otavio Cabral-Marques, Rodrigo Nalio Ramos, Lena F. Schimke, Taj Ali Khan, Eduardo Pinheiro Amaral, Caio César Barbosa Bomfim, Osvaldo Reis Junior, Tabata Takahashi França, Christina Arslanian, Joanna Darck Carola Correia Lima, Cristina Worm Weber, Janaíra Fernandes Ferreira, Fabiola Scancetti Tavares, Jing Sun, Maria Regina D´Imperio Lima, Marília Seelaender, Vera Lucia Garcia Calich, José Alexandre Marzagão Barbuto, Beatriz Tavares Costa-Carvalho, Gabriela Riemekasten, Gisela Seminario, Liliana Bezrodnik, Luigi Notarangelo, Troy R. Torgerson, Hans D. Ochs, Antonio Condino-Neto
BackgroundCD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T-, B-, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated.ObjectivesTo determine the impact of CD40L absence on monocytes-derived macrophage (MDMs) responses.MethodsAfter observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed killing activity, oxidative burst, cytokine production, and in vitro effects that rhIFN-γ and soluble CD40L (sCD40L) treatment had on macrophages. In addition, the impact of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied.ResultsMacrophages from CD40L-deficient patient exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of M. tuberculosis proliferation by patient macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors such as TLR1 and TLR2, dectin 1 and DC-SIGN in both controls' and patients' macrophages.ConclusionAbsence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.Clinical ImplicationsThe absence of CD40L impairs macrophage differentiation and function, and its lack contributes to increased susceptibility of CD40L-deficient patients to life threatening infections. Furthermore, rhIFN-γ improves the function of macrophages from CD40L-deficient patients, indicating this cytokine as a potential new adjuvant therapy.

Teaser

Human CD40L deficiency dysregulates the macrophage transcriptome causing functional defects, including defective microbicidal activity, reduced oxidative burst, and impaired production of inflammatory cytokines that are improved by exogenous IFN-γ.


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Allergy-Related Disease in Relation to Early Life Exposures – The Aladdin Birth Cohort

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Helena Marell Hesla, Fredrik Stenius, Hans Järnbert-Pettersson, Johan Alm

Teaser

An anthroposophic lifestyle is associated with reduced risk of parent-reported food hypersensitivity and recurrent wheeze up to two years of age. Mediating factors for the risk reduction appear to be different for the two outcomes.


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Antibody Drug Conjugates (ADCs): Changing the Treatment Landscape of Lymphoma

Opinion statement

While strides advancing cancer treatment have made it possible to cure some malignancies, the effort to strike an intricate balance between attaining higher efficacy and lower toxicity has been difficult to accomplish, especially with conventional chemotherapy agents. Introduction of antibody drug conjugates (ADCs) has brought us a step closer to this goal and made it possible to target the cancer cells and to minimize effects on normal tissue. Continued efforts have led to approval of two ADCs for cancer therapy, while many others are in various stages of clinical development. The design of ADCs allows them to be internalized into the cancer cells where the drug payload is released and leads to cell death. The key is to identify targets that are exclusively expressed on malignant cells with minimal or no expression on normal cells, which allows for selective killing of tumor cells. Development and approval of more potent ADCs could change the landscape of cancer therapy and possibly eliminate traditional chemotherapy agents from treatment algorithms. In this review, we discuss the ADCs that are being investigated in early and late stage clinical trials for the treatment of B cell non-Hodgkin lymphoma (NHL).

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The health capability paradigm and the right to health care in the United States

Abstract

Against a backdrop of non-ideal political and legal conditions, this article examines the health capability paradigm and how its principles can help determine what aspects of health care might legitimately constitute positive health care rights—and if indeed human rights are even the best approach to equitable health care provision. This article addresses the long American preoccupation with negative rights rather than positive rights in health care. Positive health care rights are an exception to the overall moral range and general thrust of U.S. legal doctrine. Some positive rights to health care have arisen from U.S. Constitutional Eighth Amendment cases and federal and state laws like Medicare, Medicaid, the State Children's Health Insurance Program, the Emergency Medical Treatment and Active Labor Act, and the Patient Protection and Affordable Care Act. Finally, this article discusses some of the difficulties inherent in implementing a positive right to health care in the U.S.

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Surgical strategy for aortic prosthetic graft infection with 18 F-fluorodeoxyglucose positron emission tomography/computed tomography

Abstract

A 30-year-old man with Marfan syndrome who underwent Crawford type II extension aneurysm repair about 9 years ago was referred to our hospital with persistent fever. Computed tomography (CT) showed air around the mid-descending aortic prosthetic graft. Because the air did not disappear in spite of intravenous antibiotics, ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) was performed. FDG-PET/CT revealed four high-uptake lesions. After dissecting the aortic graft particularly focusing on the high-uptake lesions, this patient underwent in situ graft re-replacement of descending aortic graft with a rifampicin-bonded gelatin-impregnated Dacron graft and omentopexy. The patient remains well without recurrent infection at 3 months after surgery.

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