Nasal Sensitization with Ragweed Pollen Induces Local-Allergic-Rhinitis-Like Symptoms in Mice

<div><p>Recently, the concept of local allergic rhinitis (LAR) was established, namely rhinitis symptoms with local IgE production and negative serum antigen-specific IgE. However, the natural course of LAR development and the disease pathogenesis is poorly understood. This study investigated the pathophysiology of mice with allergic rhinitis that initially sensitized with ragweed pollen through the nasal route. Mice were nasally administrated ragweed pollen over consecutive days without prior systemic immunization of the allergen. Serial nasal sensitization of ragweed pollen induced an allergen-specific increase in sneezing, eosinophilic infiltration, and the production of local IgE by day 7, but serum antigen-specific IgE was not detected. Th2 cells accumulated in nose and cervical lymph nodes as early as day 3. These symptoms are characteristic of human LAR. Continual nasal exposure of ragweed pollen for 3 weeks resulted in the onset of classical AR with systemic atopy and adversely affected lung inflammation when the allergen was instilled into the lung. <i>Fcer1a</i>^−/− mice were defective in sneezing but developed normal eosinophilic infiltration. Contrary, <i>Rag2</i>^−/− mice were defective in both sneezing and eosinophilic infiltration, suggesting that T cells play a central role in the pathogenesis of the disease. These observations demonstrate nasal allergen sensitization to non-atopic individuals can induce LAR. Because local Th2 cell accumulation is the first sign and Th2 cells have a central role in the disease, a T-cell-based approach may aid the diagnosis and treatment of LAR.</p></div

Repeated nasal ragweed sensitization induces systemic atopy.

<p>Nasal, ragweed (RW)-sensitized mice were analyzed 1 day after final sensitization. (A) Experimental schema. (B) Serum immunoglobulin levels. (C) Production of cytokines in cLN cells. (D–F) Histological examinations. (D) Hematoxylin and eosin (HE) staining of coronal section of nasal cavity. (E) HE staining of nasal lateral mucosa; black square in (D). (F) Periodic acid-Schiff staining of nasal septum; red square in (D). (G) Presence of eosinophils in nasal mucosa. Data representative of three independent experiments (means, SEMs, n = 5). *P<0.05, ***P<0.001. N.D. not detected.</p

Nasal sensitization of ragweed adversely affects allergic inflammation in lungs.

<p>Nasal, ragweed (RW)-sensitized mice were intratracheally challenged with ragweed 3 days after final sensitization. (A) Experimental schema. (B) BALF CD45⁺ cells and eosinophils. Hematoxylin and eosin (C) and Periodic acid-Schiff (D) staining of lungs. Data representative of three independent experiments (means and SEMs, n = 4). *P<0.05, **P<0.01.</p

Local IgE production by nasal ragweed sensitization.

<p>Mice were nasally administered ragweed (RW) pollen on indicated consecutive days. GLTs and PSTs expression in cLN (A) and nasal (B) B cells. (C) qPCR analysis of <i>Aicda</i> expression in cLN and nasal B cells. Data representative of three independent experiments (n = 2). Nasal B cells were pooled from five mice.</p

Acquired immunity is central for pathogenesis of nasally sensitized allergic rhinitis.

<p>WT and <i>Rag2</i>^−/− mice were nasally administered ragweed (RW) pollen or PBS as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103540#pone-0103540-g003" target="_blank">Figure 3A</a>. (A, C) or for 7 consecutive days (B). (A) Number of sneezes. (B, C) Presence of eosinophils in nasal mucosa. Data representative of three independent experiments (means, SEMs n = 4). **P<0.01, ***P<0.001 (in (A), comparing WT to <i>Rag2</i>^−/− mice). ^†P<0.05, ^††P<0.01, ^†††P<0.001 (in (A), comparing to day 0 in <i>Rag2</i>^−/− mice).</p