Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein (Nature, 2009, 457:585-588)

報告日期: 2009/03/17
報告時間: 15:10/16:00
報告學生: 林嬿琳(英文報告)
講評老師: 余俊強
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/980317-1.pdf

Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein

Nature 457, 585-588 (2009)

Speaker: Lin Yen Lin 

Commentator: Dr. Yu Chun-Keung

Time: 15:10-16:00, Mar 17, 2009

Place: Room 602

 

Abstract:

Allergic asthma is the chronic disease with airway inflammation and airway hyperresponsiveness. Finally, it’s difficult to breathe for atopic individuals. The characteristic of immunopathogenesis is T cell differentiation toward IL-4-secreting T helper 2 cells. However, why these environmental allergens are able to bring about abnormal immune responses has been obscure. It was reported protease activities derived from allergens can increase IgE production and eosinophil infiltration and explain the part of reasons why allergens cause airway inflammation. However, Der p 2, another major allergen of house dust mite, without protease activities, can still efficiently trigger airway inflammation. The structural analysis reveals Der p2 has highly conserved homology with MD2. MD2 is essential for LPS recognition and TLR-4 signaling. The process can induce hosts to generate innate defense against Gram-negative bacteria and develop potent adaptive immunity. Moreover, the previous research indicates the development of airway inflammation must depend on the low level LPS exposure(0.1μg) via TLR-4 signaling in the albumin(OVA)-induced animal model. Therefore, the author hypothesizes Der p 2 may function as MD2 based on their similar structure and initiate airway inflammation. With the stimulation of LPS, HEK293 cells co-expressing CD14, TLR4 and Der p2 could synthesize IL-8 when MD2 was absent. If MD2 existed, IL-8 production was increased. These data may indicate Der p2 could re-form and magnify LPS-driven TLR4 signaling. Moreover, like the interaction between MD2 and TLR4, Der p2 could directly associate with TLR4 or LPS by co-immunoprecipitation assay. It’s well-known the activation of dendritic cells through Toll-like receptors plays the important role on generating immune responses. The author found Derp2 contaminated with LPS could also stimulate bone marrow-derived dendritic cells to produce pro-inflammatory TNF-a, with or without MD2. But the level of TNF-a detected in the former was much higher. In the further experiments in vivo, under Der p2 and LPS sensitization and challenge, airway inflammation happened accompanied by IgE synthesis, eosinophil infiltration and mucous production in wild-type mice, but not in TLR-4 deficient mice. It represented the allergenicity of Derp 2 was dependent on TLR-4 signaling. Besides, without MD2, Der p2 and LPS inhalation could also result in typical allergic responses in experimental asthma. This paper may provide the mechanism that can explain harmless lipid-binding proteins tend to cause allergic asthma.        

 

References:

1.   Williams, L. K. et al. The role of endotoxin and its receptors in allergic disease. Ann. Allergy Asthma Immunol. 94, 323–332 (2005).

2.   Trompette, A., et al. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature. 457, 585-588 (2009).