RESUMO
BACKGROUND: Toll-like receptor 2 (TLR2) is a widely expressed pattern recognition receptor critical for innate immunity. TLR2 is also a key regulator of mucosal immunity implicated in the development of allergic disease. TLR2 activators are found in many common foods, but the role of TLR2 in oral tolerance and allergic sensitization to foods is not well understood. OBJECTIVE: The purpose of this study was to evaluate the impacts of TLR2 expression and TLR2 activation on oral tolerance to food antigens in a murine model. METHODS: Mice were fed ovalbumin (OVA) or peanut butter with or without the addition of low doses of TLR2 activators Pam3 CSK4 or FSL-1. Oral tolerance was assessed by analysing antibody responses after a systemic antigen challenge. OVA-specific Tregs were assessed in the Peyer's patches, mesenteric lymph nodes, and spleen in wild-type and TLR2(-/-) mice. Low-dose Pam3 CSK4 was also tested as an oral adjuvant. RESULTS: Oral tolerance was successfully induced in both wild-type and TLR2(-/-) recipient mice, with an associated regulatory T-cell response. Oral TLR2 activation, with low-dose Pam3 CSK4 or FSL-1, during oral antigen exposure was found to alter oral tolerance and was associated with the development of substantial IgE and IgA responses to foods upon systemic challenge. Low-dose oral Pam3 CSK4 treatment also selectively enhanced antigen-specific IgA responses to oral antigen exposure. CONCLUSIONS AND CLINICAL RELEVANCE: TLR2 is not necessary for oral tolerance induction, but oral TLR2 activation modulates humoral IgE and IgA responses during tolerance development. Low-dose Pam3 CSK4 is also an effective oral adjuvant that selectively enhances IgA production. These observations are pertinent to the optimization of oral allergen immunotherapy and oral vaccine development.
Assuntos
Alérgenos/imunologia , Hipersensibilidade Alimentar/imunologia , Alimentos/efeitos adversos , Tolerância Imunológica , Receptor 2 Toll-Like/agonistas , Adjuvantes Imunológicos , Animais , Diglicerídeos/farmacologia , Modelos Animais de Doenças , Hipersensibilidade Alimentar/genética , Hipersensibilidade Alimentar/metabolismo , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/genética , Imunidade Humoral/efeitos dos fármacos , Imunoglobulina A/imunologia , Lipopeptídeos/farmacologia , Camundongos , Camundongos Knockout , Oligopeptídeos/farmacologia , Ovalbumina/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismoRESUMO
The cellular reaction to injury in the mature central nervous system (CNS) has been extensively studied in both man and animals, while a detailed study of the reaction of the immature CNS to injury is lacking in the literature. This study was undertaken to elucidate the response of young astrocytes following injection injury to developing brain. Colloidal carbon was applied because it is a suitable marker for phagocytosis, it is nontoxic, and it is readily identifiable by light and electron microscopy. The cerebral cortex of the neonatal rat was injected with 0.1 microliter of colloidal carbon solution. The animals were allowed to survive from 1 hour to 30 days postoperation. The brains were fixed by vascular perfusion and processed for light and electron microscopy. Carbon particles were ingested in membrane-bound vacuoles and sequestered in lysosomes of young astrocytes. Astrocytes, loaded with carbon particles, were identified after 4 days, and were seen in abundance between 10 to 21 days postoperation. Carbon-laden astrocytes were seen in the immediate vicinity of the site of the injection; in the surrounding, apparently normal, neuropil; and in the perivascular regions. This study demonstrates the ability of young astrocytes to engulf foreign particles injected into the developing brain. The presence of carbon particles in astrocytes located further away from the site of injection is discussed.
