Genetic restriction of antigen-presentation dictates allergic sensitization and disease in humanized mice.

Abstract

BACKGROUND:

Immunoglobulin(Ig)E-associated allergies result from misguided immune responses against innocuous antigens. CD4+ T lymphocytes are critical for initiating and perpetuating that process, yet the crucial factors determining whether an individual becomes sensitized towards a given allergen remain largely unknown.

OBJECTIVE:

To determine the key factors for sensitization and allergy towards a given allergen.

METHODS:

We here created a novel human T cell receptor(TCR) and human leucocyte antigen (HLA)-DR1 (TCR-DR1) transgenic mouse model of asthma, based on the human-relevant major mugwort (Artemisia vulgaris) pollen allergen Art v 1 to examine the critical factors for sensitization and allergy upon natural allergen exposure via the airways in the absence of systemic priming and adjuvants.

RESULTS:

Acute allergen exposure led to IgE-independent airway hyperreactivity (AHR) and T helper(Th)2-prone lung inflammation in TCR-DR1, but not DR1, TCR or wildtype (WT) control mice, that was alleviated by prophylactic interleukin(IL)-2-αIL-2 mAb complex-induced expansion of Tregs. Chronic allergen exposure sensitized one third of single DR1 transgenic mice, however, without impacting on lung function. Similar treatment led to AHR and Th2-driven lung pathology in >90% of TCR-DR1 mice. Prophylactic and therapeutic expansion of Tregs with IL-2-αIL-2 mAb complexes blocked the generation and boosting of allergen-specific IgE associated with chronic allergen exposure.

CONCLUSIONS:

We identify genetic restriction of allergen presentation as primary factor dictating allergic sensitization and disease against the major pollen allergen from the weed mugwort, which frequently causes sensitization and disease in humans. Furthermore, we demonstrate the importance of the balance between allergen-specific T effector and Treg cells for modulating allergic immune responses.

• Authors: Alina Neunkirchner, Bernhard Kratzer, Cordula Köhler, Ursula Smole, Lukas F Mager, Klaus G Schmetterer, Doris Trapin, Victoria Leb-Reichl, Edward Rosloniec, Ronald Naumann, Lukas Kenner, Beatrice Jahn-Schmid, Barbara Bohle, Rudolf Valenta, Winfried F Pickl
• Journal: EBioMedicine (EBioMedicine) Vol. 31 Pg. 66-78 (May 2018) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 29678672 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antigens, Plant
• Art v 1 protein, mugwort
• Plant Proteins
• Receptors, Antigen
• Immunoglobulin E

Topics

• Animals
• Antigen Presentation (genetics)
• Antigens, Plant (toxicity)
• Humans
• Hypersensitivity (genetics, immunology, pathology)
• Immunoglobulin E (genetics, immunology)
• Mice
• Mice, Transgenic
• Plant Proteins (toxicity)
• Receptors, Antigen (genetics, immunology)
• Th2 Cells (immunology, pathology)