Allergic disease represents a spectrum of disorders including allergy, asthma, and parasitic helminth infections, which afflict more than 3 billion individuals worldwide. Current treatment options (steroids in the case of allergy and asthma; de-worming drugs for helminth infection) focus on treating the symptoms rather than prevention or the root cause of the underlying disease. Thus, the current standard of care in most cases is not curative, does not prevent secondary attacks or infections, and requires frequent treatments to control disease recurrence. Because most allergic disorders share many of the same underlying features and allergic hallmarks, there is great interest in identifying novel disease targets, whic are central to the development and maintenance of allergic inflammation, and therefore, when targeted, can provide long-term protection against a broad spectrum of allergic diseases. Preliminary data provided in the proposal has identified the AP-1 transcription factor BATF as one such candidate factor. BATF-deficient mice and novel reporter systems designed to explore allergic immunity in vivo have revealed that BATF is essential for the induction of allergic inflammation and immunity to the parasitic helminth Nippostrongylus brasiliensis. Furthermore, these initial studies indicate that BATF likely regulates the function and/or development of three essential cell types critical for the induction of allergic immunity to intestinal helminths. These cell types are T-helper type 2 (Th2) cells, follicular T cells (Tfh), and group 2 innate lymphoid cells (ILC2). The objective of this proposal is to identify the cellular and molecular mechanisms by which BATF regulates allergic immunity. Our central hypothesis is that BATF regulates Interleukin-4 (IL-4) and IL-13 production in Tfh, Th2, and ILC2 by modulating chromatin accessibility and long-range intrachromosomal interactions between the locus control region in the rad50 gene and the IL-4 and IL-13 promoters. IL-4 and IL-13 are two cytokines absolutely required for development of the allergic pathology. The central hypothesis will be tested in two specific aims: 1) Determine the role of BATF in anti-helminth immunity; 2) Define the molecular mechanism by which BATF regulates Type-2 cytokine production. The proposed project is innovative because it uses novel, in vivo reporter mouse strains and molecular and biochemical approaches to reveal the significance of a hitherto unknown molecular mechanism central to the control of allergic inflammation, and challenges the status quo that BATF has a limited role in Th2 and ILC2 cell function. This proposal is significant as it is expected to bridge a fundamental gap in our understanding of the underlying mechanisms inducing allergic disease. Bridging of this gap helps to integrate our current understanding of AP-1 transcription factors in allergic disease, and represents a major advancement for the development of therapies effective at ameliorating a spectrum of allergic disorders. This proposal also lays the foundation for exploring whether enhancement of BATF during vaccination is capable of providing more effective long-term immunity to helminth infection.

Public Health Relevance

The proposed research is relevant to public health because a more complete understanding of how allergic inflammation is induced will increase our overall understanding of the broad-spectrum of allergic diseases that in total afflict over 3 billion peopl worldwide. This proposal is relevant to the mission of NIH for providing important advancements in the realm of human health as allergic disease incidence continues to rise in the United States and parasitic helminth infection afflicts 1 in 4 people worldwide. As such allergic diseases represent a major health challenge over the next decade both in terms of patient care as well as the fiscal burden that care entails.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI119004-05
Application #
9394766
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Davidson, Wendy F
Project Start
2015-07-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Bao, Katherine; Carr, Tiffany; Wu, Jianxuan et al. (2016) BATF Modulates the Th2 Locus Control Region and Regulates CD4+ T Cell Fate during Antihelminth Immunity. J Immunol 197:4371-4381
O'Brien, T F; Bao, K; Dell'Aringa, M et al. (2016) Cytokine expression by invariant natural killer T cells is tightly regulated throughout development and settings of type-2 inflammation. Mucosal Immunol 9:597-609
Bao, Katherine; Reinhardt, R Lee (2015) The differential expression of IL-4 and IL-13 and its impact on type-2 immunity. Cytokine 75:25-37