Myers Linda K, Tang Bo, Rosioniec Edward F, Stuart John M, Kang Andrew H
Department of Pediatrics, University of Tennessee, Memphis, TN 38163, USA.
Crit Rev Immunol. 2007;27(4):345-56. doi: 10.1615/critrevimmunol.v27.i4.40.
On the basis of the hypothesis that immunity to type II 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-Aq-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 (A260, B261, N263) (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.
基于对II型胶原蛋白（CII）的免疫反应会导致关节炎症这一假设，我们的目标是开发一种免疫疗法，该疗法能够选择性地阻断对特定自身抗原的免疫反应，同时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的自身免疫与人的类风湿性关节炎密切相关。我们实验室之前已鉴定出II型胶原蛋白（CII）的一个区域，即CII245 - 270，该区域在对CII的免疫反应中包含一个突出的T细胞表位。对该决定簇的I - Aq限制性呈递至关重要的残基已得到表征。当开发出在关键位置含有定点取代的合成类似肽时，我们发现CII245 - 270（A260、B261、N263）（A9）能显著抑制胶原蛋白诱导的关节炎。当DBA/1小鼠同时用CII和类似肽免疫时，关节炎的发病率和严重程度与对CII的体液免疫反应一致地大幅降低。此外，这种抑制作用可以通过A9免疫的脾细胞进行传递，并伴有Th2型细胞因子谱。当我们将对A9的T细胞信号与野生型（WT）肽的信号进行比较时，我们发现用WT肽预刺激的抗原呈递细胞（APC）能诱导TCR ζ链和Zap - 70的强烈磷酸化，而A9则不能。由于T细胞显然通过细胞因子分泌对A9作出反应，我们推测A9诱导了一条替代信号通路，并且我们推测该通路涉及Syk的磷酸化，Syk是一种通常由B细胞利用的激酶。这种替代通路的激活是一个新发现，可能代表了改变反应性T细胞表型的一种重要方式。阐明A9预防关节炎的机制可能会导致开发针对自身免疫性疾病的抗原特异性治疗的新型免疫治疗方法。
