Abstract
Food allergies, and peanut allergy in particular, are leading causes of anaphylactic fatalities worldwide. The immune mechanisms that underlie food allergy remain ill-defined and controversial, in part because studies in humans typically focus on analysis of a limited number of prototypical Th1/Th2 cytokines. Here we determine the kinetics and prevalence of a broad panel of peanut-driven cytokine and chemokine responses in humans with current peanut allergy vs those with stable, naturally occurring clinical tolerance to peanut. Our primary focus is identification of novel indicators of immune dysregulation. Antigen-specific cytokine mRNA and protein responses were elicited in primary culture via peanut or irrelevant antigen (Leishmania extract, milk antigens) mediated stimulation of fresh peripheral blood cells from 40 individuals. Peanut extract exposure in vitro induced a broad panel of responses associated with Th2/Th9-like, Th1-like and Th17-like immunity. Peanut-dependent Type 2 cytokine responses were frequently found in both peanut allergic individuals and those who exhibit clinical tolerance to peanut ingestion. Among Th2/Th9-associated cytokines, IL-9 responses discriminated between allergic and clinically tolerant populations better than did commonly used IL-4, IL-5 or IL-13 responses. Comparison with responses evoked by unrelated control antigen-mediated stimulation showed that these differences are antigen-dependent and allergen-specific. Conversely, the intensity of IL-12, IL-17, IL-23 and IFN-γ production was indistinguishable in peanut allergic and peanut tolerant populations. In summary, the ability to generate and maintain cytokine responses to peanut is not inherently distinct between allergic and peanut tolerant humans. Quantitative differences in the intensity of cytokine production better reflects clinical phenotype, with optimally useful indicators being IL-9, IL-5, IL-13 and IL-4. Equivalent, and minimal, Ag-dependent pro-inflammatory cytokine levels in both healthy and peanut allergic volunteers argues against a key role for such cytokines in maintenance of clinical tolerance to food antigens in humans.
Highlights
Food allergies, and peanut allergy in particular, are leading causes of anaphylaxis
One key roadblock hindering development of improved prophylactic and therapeutic interventions is our limited understanding of which immune responses are differentially expressed in humans with food allergy vs those exhibited by individuals who maintain clinical tolerance to common foods
To identify optimal experimental conditions to elicit and quantify Ag-stimulated human cytokine mRNA responses for the range of cytokines being examined, freshly isolated peripheral blood mononuclear cells (PBMC) were cultured without stimulation and in the presence of a range of low endotoxin peanut antigen extract concentrations
Summary
Peanut allergy in particular, are leading causes of anaphylaxis. While their natural history, epidemiology and social consequences are increasingly well defined [1,2,3,4], validated gains in diagnosis, prevention or management are generally viewed as modest [5,6,7]. One key roadblock hindering development of improved prophylactic and therapeutic interventions is our limited understanding of which immune responses are differentially expressed in humans with food allergy vs those exhibited by individuals who maintain clinical tolerance to common foods. With a broad variety of innovative therapeutic approaches under consideration to modulate hypersensitivity [8,9,10,11,12], better understanding of characteristic human cytokine responses to common foods is key to progress. Murine models provide excellent tools, but with few exceptions [13,14], most require adjuvant and have other characteristics that may limit their ability to directly extrapolate their findings
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