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Immunomodulatory Functions of BTLA and HVEM Govern Induction of Extrathymic Regulatory T Cells and Tolerance by Dendritic Cells


Immunity, Volume 45, Issue 5, p1066–1077, 15 November 2016

Andrew Jones, Jessica Bourque, Lindsey Kuehm, Adeleye Opejin, Ryan M. Teague, Cindy Gross, Daniel Hawiger


• BTLA+ DCs govern peripheral Treg cell conversion

• Engagement of HVEM increases CD5 expression to promote Foxp3 expression

• BTLAneg DCs fail to induce pTreg cells and tolerance even in the steady state


Dendritic cells (DCs) initiate immunity and also antigen-specific tolerance mediated by extrathymic regulatory T (Treg) cells, yet it remains unclear how DCs regulate induction of such tolerance. Here, we report that efficient induction of Treg cells was instructed by BTLA+DEC205+CD8+CD11c+ DCs and the immunomodulatory functions of BTLA. In contrast, T cell activation in steady state by total CD11c+ DCs that include a majority of DCs that do not express BTLA did not induce Treg cells and had no lasting impact on subsequent immune responses. Engagement of HVEM, a receptor of BTLA, promoted Foxp3 expression in T cells through upregulation of CD5. In contrast, T cells activated in the absence of BTLA and HVEM-mediated functions remained CD5lo and therefore failed to resist the inhibition of Foxp3 expression in response to effector cell-differentiating cytokines. Thus, DCs require BTLA and CD5-dependent mechanisms to actively adjust tolerizing T cell responses under steady-state conditions.

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Hookworm recombinant protein promotes regulatory T cell responses that suppress experimental asthma


Science Translational Medicine 26 Oct 2016: Vol. 8, Issue 362, pp. 362ra143 DOI: 10.1126/scitranslmed.aaf8807

Severine Navarro, Darren A. Pickering, Ivana B. Ferreira, Linda Jones, Stephanie Ryan, Sally Troy, Andrew Leech, Peter J. Hotez, Bin Zhan, Thewarach Laha, Roger Prentice, Tim Sparwasser, John Croese, Christian R. Engwerda, John W. Upham, Valerie Julia, Paul R. Giacomin and Alex Loukas

One reason for allergy prevalence in the developed world may be a lack of exposure to parasites, which can influence immune development and function. Because administering live parasites to people might pose safety issues, Navarro et al. tested the ability of the hookworm protein AIP-2 to treat airway allergic sensitization. Administration of AIP-2 could prevent or treat asthma symptoms in a mouse model, in a mechanism that was dependent on dendritic cells and regulatory T cells. Encouragingly, AIP-2 also reduced activation of human dendritic cells and T cells, indicating that these findings may readily translate to the clinic.


In the developed world, declining prevalence of some parasitic infections correlates with increased incidence of allergic and autoimmune disorders. Moreover, experimental human infection with some parasitic worms confers protection against inflammatory diseases in phase 2 clinical trials. Parasitic worms manipulate the immune system by secreting immunoregulatory molecules that offer promise as a novel therapeutic modality for inflammatory diseases. We identify a protein secreted by hookworms, anti-inflammatory protein-2 (AIP-2), that suppressed airway inflammation in a mouse model of asthma, reduced expression of costimulatory markers on human dendritic cells (DCs), and suppressed proliferation ex vivo of T cells from human subjects with house dust mite allergy. In mice, AIP-2 was primarily captured by mesenteric CD103+ DCs and suppression of airway inflammation was dependent on both DCs and Foxp3+ regulatory T cells (Tregs) that originated in the mesenteric lymph nodes (MLNs) and accumulated in distant mucosal sites. Transplantation of MLNs from AIP-2–treated mice into naïve hosts revealed a lymphoid tissue conditioning that promoted Treg induction and long-term maintenance. Our findings indicate that recombinant AIP-2 could serve as a novel curative therapeutic for allergic asthma and potentially other inflammatory diseases.

Copyright © 2016, American Association for the Advancement of Science

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Mast Cells and KIT as Potential Therapeutic Targets in Severe Asthma


N Engl J Med 2017; 376:1983-1984May 18, 2017DOI: 10.1056/NEJMe1702653

Stephen J. Galli, M.D.

Mast cells and many of their secreted products have long been thought to contribute to the pathologic processes underlying asthma, but no clinical studies have assessed whether specifically targeting mast-cell survival or development would have therapeutic benefit in the treatment of this disorder. In this issue of the Journal, Cahill and colleagues report the results of a randomized, double-blind, placebo-controlled, phase 2, 24-week, proof-of-principle trial in which patients with severe, poorly controlled asthma were treated with the tyrosine kinase inhibitor imatinib, which can inhibit KIT, the major survival and growth factor for mast cells. The total number of patients . . .

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Hypoxic brain injury with motor apraxia following an anaphylactic reaction to hymenoptera venom.


Brain Inj. 1998 Mar;12(3):239-44.

Speach DP, Wong TM, Cattarin JA, Livecchi MA (Department of Physical Medicine and Rehabilitation, University of Rochester, New York, USA)


Hypoxic brain injury can be a complication following several well known situations or disorders. The neurological and neuropsychological characteristics of patients who suffer hypoxic brain injury depend on the mechanism of injury and the structures of the brain that are particularly vulnerable to hypoxia. Injury to the hippocampus with resultant memory impairment is a well described clinical feature. Motor apraxia has not been described as a common feature following hypoxic injury. This paper describes an unusual case of hypoxic brain injury that resulted from an anaphylactic reaction to hymenoptera venom. The patient presented with severe ideomotor apraxia as he emerged from coma after cardiorespiratory arrest. Surprisingly, the patients memory was relatively preserved in relation to other cognitive impairments. A brief discussion of the pathophysiology of hypoxic brain injury and the patient’s rehabilitation outcome is presented.

Also of interest:


Pediatric Syncope: Is Detailed Medical History the Key Point for Differential Diagnosis?

Ikiz, Mehmet Alper MD; Çetin, Ibrahim Ilker MD; Ekici, Filiz MD; Güven, Alev MD; Değerliyurt, Aydan MD; Köse, Gülşen MD


Physiological Effects of Chronic Hypoxia

John B. West, M.D., Ph.D.

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Anaphylaxis epidemic: Fact or fiction?


The Journal of Allergy and Clinical Immunology, December 2008, Volume 122, Issue 6, Pages 1166–1168

F. Estelle R. Simons, MD, FAAAAI, Hugh A. Sampson, MD, FAAAAI

Article Outline

Anaphylaxis definition and clinical criteria for diagnosis

Role of laboratory tests in diagnosis

Is anaphylaxis overdiagnosed?

Is anaphylaxis underdiagnosed?

Issues with ICD-9 and ICD-10 coding for anaphylaxis



Epidemiologic studies have confirmed a steady increase in the rate of occurrence of asthma, allergic rhinitis, and eczema in recent decades.1, 2 The magnitude of this increase is so great that the term “epidemic” is correctly used to describe it. The rate of occurrence of anaphylaxis has also reportedly increased during this time, but the magnitude of this increase is more difficult to ascertain with certainty, and it might or might not warrant the designation “epidemic.”1, 2, 3, 4, 5, 6

Until the mid 20th century, anaphylaxis was reported rarely and sporadically. In the 1950s and 1960s, the first small case series of individuals with anaphylaxis from medications, diagnostic agents, insect venoms, and foods was published, followed in the 1970s by the first case series of individuals with idiopathic anaphylaxis. The first case series of individuals with exercise-induced anaphylaxis and the first case series of those with natural rubber latex–induced anaphylaxis were not reported until the 1980s.7

In this issue of the Journal, in a retrospective population-based study, Decker et al8 report the incidence of anaphylaxis from 1990 to 2000 in Olmstead County, Minnesota, as 49.8/100,000 person-years. They note that during this decade, the incidence varied from year to year, with a low of 20 per 100,000 person-years in 1993 to a high of 70 per 100,000 person-years in 1998, and that although there was no steady increase, the incidence of 49.8 per 100,000 person-years is more than double the incidence reported from 1983 to 1987 in Olmstead County by Yocum et al.9 Both of these studies used the resources of the Rochester Epidemiology Project.8, 9 Recent publications from other areas of the United States and from around the world also suggest an increase in the rate of occurrence of anaphylaxis1, 2, 3, 4, 5, 6; for example, in the United Kingdom hospitalization for anaphylaxis has recently increased by 700%.2, 3

It is difficult to determine whether there truly is an anaphylaxis epidemic. The presentation of anaphylaxis is often enigmatic, with variable target organ involvement and expression of symptoms. The clinical diagnosis can sometimes be difficult to make because many of the symptoms are subjective and many of the signs are nonspecific. Both overdiagnosis and underdiagnosis occur and have the potential to affect diagnostic coding and epidemiologic studies. It is therefore possible that the dramatic increase in the rate of occurrence of anaphylaxis reported recently is, at least in part, an artifact attributable either to diagnostic issues, including the recently broadened definition of anaphylaxis, or to coding issues.10, 11 We will examine each of these possibilities in turn.

Key word: Anaphylaxis

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Anaphylaxis Treatment Guidelines


Emergency treatment of anaphylactic reactions – guidelines. Slide set. This slide set describes the incidence, recognition and treatment of anaphylactic reactions.


Clinical Practice Guidelines : Anaphylaxis

RCH: Consider Criteria Led Discharge Acute Management Anaphylaxis action plans. See also: Emergency drug and fluid calculator Resuscitation guidelines


World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis … treatment of anaphylaxis was documented.


Anaphylaxis Guidelines – World Allergy Organization

Anaphylaxis Guidelines. In February 2011, the World Allergy Organization Anaphylaxis Guidelines were published concurrently in the WAO Journal and The …


Anaphylaxis Treatment & Management: Approach …

Feb 22, 2017 · Disposition of patients with anaphylaxis depends on the severity of the initial reaction and the response to treatment. Patients with non–life …


World Allergy Organization Guidelines for the assessment and management of anaphylaxis


AAP Releases Guidelines on Treatment of Anaphylaxis


ASCIA Guidelines Acute Management of Anaphylaxis 2016 300.04


Anaphylaxis treatment: An evidence-based guideline for EMS


An overview of anaphylaxis symptoms, diagnosis, treatment and management written and reviewed by the leading experts in allergy, asthma and immunology.


Food Allergy | NIH: National Institute of Allergy and …

Treatment for Living with Food Allergy.


Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology


World Allergy Organization Guidelines for Anaphylaxis


Guideline Anaphylactic Reaction – AST

Adopted BOD October 2005 Updated BOD January 2013 Guideline Statement for Treatment of Anaphylactic Reaction in the Surgical Patient Introduction


EAACI food allergy and anaphylaxis guidelines


Anaphylaxis : MedlinePlus Medical Encyclopedia


Anaphylaxis: Emergency treatment – UpToDate


Anaphylaxis: Acute diagnosis – uptodate.com


Customizing Anaphylaxis Guidelines for Emergency Medicine


Practice Parameters and Guidelines | AAAAI

Emergency department diagnosis and treatment of anaphylaxis: a practice parameter (2014)


Anaphylaxis Treatment – Mayo Clinic


VIRGINIA SCHOOL HEALTH GUIDELINES – Recognition and Treatment of Anaphylaxis in the School Setting


Anaphylaxis – Home | Auckland District Health Board


Anaphylaxis – Resuscitation Council (UK)


Guidelines – Anaphylaxis Campaign


About Anaphylaxis – Food Allergy Research & Education


Anaphylaxis NICE clinical guideline 134


Two new anaphylaxis guidelines – Resus ME


Anaphylaxis and Emergency Treatment | Articles | Pediatrics


World Allergy Organization Guidelines

The illustrated World Allergy Organization (WAO) Anaphylaxis Guidelines were created in response to absence of global guidelines for anaphylaxis.


Anaphylaxis Symptoms and Treatment – Verywell


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New ACAAI/AAAAI GUIDELINES – Quick-Reference Tools


Summarized versions of ACAAI/AAAAI full text guideline recommendations in a brief, algorithmic format. Perfect for quick-reference, educating and use at point of care. Hard copy, online and mobile (iOS and Android) forms are offered.

Topics covered include:

SLIT Guidelines

Sublingual Immunotherapy


Urticaria Guidelines

Acute and Chronic Urticaria

EIB Guidelines

Primary Immunodeficiency


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