Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness.
BACKGROUND
In humans, immune responses to inhaled aeroallergens develop in the lung and draining lymph nodes. Many animal models of asthma bypass this route and instead use intraperitoneal injections of allergen using aluminum hydroxide as an adjuvant.


OBJECTIVE
We investigated whether allergic sensitization through the airway elicits immune responses qualitatively different than those arising in the peritoneum.


METHODS
Mice were sensitized to allergen through the airway using low-dose LPS as an adjuvant, or through the peritoneum using aluminum hydroxide as an adjuvant. After a single allergen challenge, ELISA and flow cytometry were used to measure cytokines and leukocyte subsets. Invasive measurements of airway resistance were used to measure allergen-induced airway hyperreactivity (AHR).


RESULTS
Sensitization through the peritoneum primed strong Th2 responses and eosinophilia, but not AHR, after a single allergen challenge. By contrast, allergic sensitization through the airway primed only modest Th2 responses, but strong Th17 responses. Th17 cells homed to the lung and released IL-17 into the airway on subsequent encounter with inhaled allergen. As a result, these mice developed IL-17-dependent airway neutrophilia and AHR. This AHR was neutrophil-dependent because it was abrogated in CXCR2-deficient mice and also in wild-type mice receiving a neutrophil-depleting antibody. Individually, neither IL-17 nor ongoing Th2 responses were sufficient to confer AHR, but together they acted synergistically to promote neutrophil recruitment, eosinophil recruitment and AHR.


CONCLUSIONS
Allergic sensitization through the airway primes modest Th2 responses but strong Th17 responses that promote airway neutrophilia and acute AHR. These findings support a causal role for neutrophils in severe asthma.
Wilson
Rhonda H
RH
Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA.
Whitehead
Gregory S
GS
Nakano
Hideki
H
Free
Meghan E
ME
Kolls
Jay K
JK
Cook
Donald N
DN
D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D004195:Disease Models, Animal; D007114:Immunization; D020381:Interleukin-17 / Q000276:immunology*; D007964:Leukocytosis; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D020381:Interleukin-17; D008070:Lipopolysaccharides