Compromised ITAM-based platelet receptor function in a patient with immune thrombocytopenic purpura
Compromised ITAM-based platelet receptor function in a patient with immune thrombocytopenic purpura
复制标题
DOI：
10.1111/j.1538-7836.2008.03016.x
复制
发表时间：
2008-07-01
影响因子：
10.4
通讯作者：
Baker, R. I.
中科院分区：
文献类型：
--
作者：
Gardiner, E. E.;Al-Tamimi, M.;Baker, R. I.
背景：血小板上含有免疫受体酪氨酸激活基序(ITAM)的受体包括胶原受体糖蛋白(GP)VI和免疫球蛋白(Ig)的低亲和力受体Fc-Gamma RIIA。目的：我们检测了一例免疫性血小板减少性紫癜(ITP)患者的GPVI和Fc-Gamma RIIA的功能，该患者尽管治疗后血小板计数正常，但仍有不明原因的病理瘀伤。方法和结果：患者的血小板对ADP、花生四烯酸和肾上腺素的反应正常，但对GPVI激动剂、胶原或胶原相关肽不反应，也不对Fc-Gamma RII激活的单抗(MAb)8.26反应，提示ITAM受体功能障碍。血浆中含有MAIPA产生的抗GPVI抗体和聚集的正常血小板。FcγRIIA阻断抗体IV.3可部分阻断(相当于60%)凝集活性，并可被可溶性GPVI胞外结构域完全阻断。患者血小板表面的全长GPVI减少到接近正常水平的10%，Western印迹检测到类似于10 kDa GPVI的胞浆尾部残留物和裂解的Fc-Gamma RIIA，表明血小板受体蛋白降解。患者血浆中含有的可溶性GPVI含量与用ELISA法测得的150 ng mL(-1)相似(正常血浆，类似于15 ng mL(-1))，而从患者血浆中提纯的免疫球蛋白可引起Fc-Gamma RIIA介导的、EDTA敏感的GPVI和Fc-Gamma RIIA对正常血小板的切割。结论：在ITP患者中，血小板自身抗体可抑制血小板受体功能。血小板ITAM受体功能障碍可能是ITP患者出血表型增多的原因之一。
Background: Receptors on platelets that contain immunoreceptor tyrosine-based activation motifs (ITAMs) include collagen receptor glycoprotein (GP) VI, and Fc gamma RIIa, a low affinity receptor for immunoglobulin (Ig) G. Objectives: We examined the function of GPVI and Fc gamma RIIa in a patient diagnosed with immune thrombocytopenic purpura (ITP) who had unexplained pathological bruising despite normalization of the platelet count with treatment. Methods and Results: Patient platelets aggregated normally in response to ADP, arachadonic acid and epinephrine, but not to GPVI agonists, collagen or collagen-related peptide, or to Fc gamma RII-activating monoclonal antibody (mAb) 8.26, suggesting ITAM receptor dysfunction. Plasma contained an anti-GPVI antibody by MAIPA and aggregated normal platelets. Aggregating activity was partially (similar to 60%) blocked by Fc gamma RIIa-blocking antibody, IV.3, and completely blocked by soluble GPVI ectodomain. Full-length GPVI on the patient platelet surface was reduced to similar to 10% of normal levels, and a similar to 10-kDa GPVI cytoplasmic tail remnant and cleaved Fc gamma RIIa were detectable by western blot, indicating platelet receptor proteolysis. Plasma from the patient contained similar to 150 ng mL(-1) soluble GPVI by ELISA (normal plasma, similar to 15 ng mL(-1)) and IgG purified from patient plasma caused Fc gamma RIIa-mediated, EDTA-sensitive cleavage of both GPVI and Fc gamma RIIa on normal platelets. Conclusions: In ITP patients, platelet autoantibodies can curtail platelet receptor function. Platelet ITAM receptor dysfunction may contribute to the increased bleeding phenotype observed in some patients with ITP.