Initiation of allergic immunity by parasites

-
Investigator: Richard M. Locksley, MD
Sponsor: NIH National Institute of Allergy and Infectious Disease

Location(s): United States

Description

We seek to understand the processes driving the increasing prevalence of allergic immune diseases in developing countries. This type of immunity, here termed type 2 immunity, commonly occurs during intestinal helminth infection, and likely underlies the evolution of this host response. We and others have noted the association of cellular constituents of allergic immunity, including eosinophils and alternatively activated macrophages, in mouse visceral adipose tissues, where these cells are required to sustain normal metabolic homeostasis. As shown here, these cell types are maintained in adipose tissues by constitutive activation of innate helper type 2 (ILC2) cells, a novel type of innate lymphoid cell simultaneously reported by this and two other laboratories. We seek to answer the hypothesis that ILC2 cells link mucosal integrity with metabolic homeostasis by attenuating lung and intestinal mucosal inflammation while sustaining systemic energy demands. To pursue this hypothesis in 3 Specific Aims: 1. To establish the role of ILC2 cells in immune and metabolic homeostasis associated with allergic inflammatory challenge; 2. To establish the role of ILC2 cells in immune and metabolic homeostasis in animals with genetic deficiencies associated with mucosal inflammation of the lung and intestinal mucosa; and 3. To assess the effects of intestinal parasitic infection on the microbiome and the role of type 2 cytokines in mediating these effects. The novel technical approach involves the use of unique lines of mice established in my laboratory with knockin fluorescent markers containing embedded Cre elements that facilitate cell function-marking, fate-mapping and cell-specific deletion based on function with a high degree of precision. Our approach will open up new lines of investigation in understanding the evolutionary role of ILC2 cells and possibly yield insights into the relationship of allergic immunity, mucosal integrity and systemic energy homeostasis. Allergic immunity is an increasing problem in developed countries, including the United States, but little is known regarding the basic mechanisms driving this process.We propose that a new type of innate lymphoid cell may link inflammation of the linings of the lung and intestines with how energy is utilized, and thus contribute to our understanding of factors that might be driving epidemics of allergy, inflammation and obesity.