抗IgA Fc受体抗体的作用机制

Mechanism of anti-FcαRI monoantibody treatment

体外实验和动物实验证实,抗IgAFc受体I(FcαRI)单抗具有抑制炎症信号通路,治疗感染性疾病、改善免疫及非免疫相关肾脏疾病肾组织病变等作用。虽然早有研究证实抗FcαRI单抗的疗效与FcαRI中抑制性免疫受体酪氨酸激活基序(immunoreceptor tyrosine-based activation motifs,ITAM)介导的抑制性信号(ITAMi)有关,但直到近期ITAMi的分子机制才被阐明,即低亲和性配体或单克隆抗体与FcαRI结合后可促使FcαRI移位及含Src同源结构域2(Src homology 2,SH2)的酪氨酸磷酸酶1(SHP-1)在细胞膜脂质结构中募集,激活性受体与FcαRI等受体及SHP-1在细胞脂筏上的共区域化促进了大分子抑制体的形成,在SHP-1的作用下激活信号被抑制。这一机制的明确为IgAFcαRI单抗治疗肾脏疾病提供了新的理论依据。

Anti-FcαRI antibody treatment has been reported in recent years to be effective in controlling inflammatory and kidney diseases, such as immune related and nonimmune related renal disease. Inhibitory immunoreceptor tyrosine-based activation motifs （ITAMi） have been found to be involved in the mechanism of treatment other than activating effects ,but mechanisms of inhibitory signaling are poorly understood. New evidence of low avidity ligation of the ITAM-associatedFcαRI explained how ITAM broadly inhibits heterologous receptors, which involves translocation of receptor and the associated inhibitory Src homology 2 （SH2） domain-containing phosphatase-1 （SHP-1） to membrane lipid rafts, colocalization of activating receptors with FcαRI and SHP-1 and trafficking to an inhibitory intracellular compartment termed the inhibisome. Thus, ITAM suppressive signals subvert the activating function of rafts to promote incorporation of receptors into supramolecular domains where signaling molecules are deactivated by SHP-1. These results provided new evidence for anti- FcαRI antibody therapy in the treatment of renal disease.