An altered peptide ligand of type II collagen suppresses autoimmune arthritis
An altered peptide ligand of type II collagen suppresses autoimmune arthritis
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DOI：
10.1615/critrevimmunol.v27.i4.40
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发表时间：
2007-01-01
影响因子：
1.3
通讯作者：
Kang, Andrew H.
中科院分区：
文献类型：
--
作者：
Myers, Linda K.;Tang, Bo;Kang, Andrew H.
基于对11型胶原蛋白（CII）的免疫有助于关节炎症的假设，我们的目标是开发一种免疫疗法，能够选择性地阻断对特定自身抗原的免疫，而不干扰免疫系统的有益功能。CII是关节软骨的主要蛋白质成分，对CII的自身免疫与人类类风湿关节炎密切相关。我们的实验室之前已经确定了II型胶原（CII）的一个区域，CII245-270，在对CII的免疫反应中包含一个突出的t细胞表位。对这个行列式的I-A(q)限制性表示至关重要的残基已经被表征。当合成的类似肽在关键位置含有位点定向取代时，我们发现CII245-270 (A(260), b (261), N-263) (A9)，深刻地抑制胶原诱导的关节炎。当DBA/1小鼠与CII和类似肽共同免疫时，关节炎的发生率和严重程度大大降低，这与CII的体液免疫反应一致。此外，这种抑制可以通过a9免疫脾细胞转移，并伴有th2型细胞因子谱。当我们比较A9和野生型（WT）肽对t细胞信号的响应时，我们发现WT肽预脉冲的APCs诱导了TCR zeta链和Zap-70的强烈磷酸化，而A9则没有。由于T细胞明显响应A9分泌细胞因子，我们假设A9诱导了另一条信号通路，我们推测这条通路涉及Syk的磷酸化，Syk是B细胞通常使用的激酶。这种替代途径的激活是一种新的观察结果，可能代表了应答T细胞表型改变的重要手段。阐明A9预防关节炎的机制可能会导致抗原特异性治疗自身免疫的新免疫治疗方法的发展。
On the basis of the hypothesis that immunity to type 11 collagen (CII) contributes to joint inflammation, our goal is to develop an immunotherapy capable of selectively blocking immunity to a particular autoantigen without interfering with the beneficial functions of the immune system. CII is the major protein component of articular cartilage and autoimmunity to CII is strongly associated with rheumatoid arthritis in man. Our laboratory has previously identified a region of type II collagen (CII), CII245-270, that contains a prominent T-cell epitope in the immune response to CII. Residues critical to the I-A(q)-restricted presentation of this determinant have been characterized. When synthetic analog peptides were developed that contain site-directed substitutions in critical positions, we found that that CII245-270 (A(260), B-261, N-263) (A9), profoundly suppressed collagen-induced arthritis. When DBA/1 mice were coimmunized with CII and the analog peptide, the incidence and severity of arthritis was greatly reduced concordant with the humoral immune responses to CII. Moreover, the suppression could be transferred with A9-immune spleen cells and was accompanied by a Th2-type cytokine profile. When we compared T-cell signals in response to A9 to those of wild-type (WT) peptide, we found that APCs prepulsed with WT peptide induced strong phosphorylation of both TCR zeta chain and Zap-70, while A9 did not. Since T cells clearly respond to A9 with cytokine secretion, we hypothesize that A9 induces an alternate signaling pathway and we speculate that this pathway involves phosphorylation of Syk, a kinase ordinarily utilized by B cells. Activation of this alternative pathway is a novel observation and may represent an important means by which the phenotype of the responding T cell is altered. Elucidation of the mechanism by which A9 prevents arthritis may lead to development of novel immunotherapeutic approaches to antigen specific treatment of autoimmunity.