Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles väg 2, 171 77, Stockholm, Sweden.
Arthritis Res Ther. 2011 Mar 28;13(2):R54. doi: 10.1186/ar3298.
Collagen-induced arthritis (CIA) is a mouse model for rheumatoid arthritis (RA) and is induced after immunization with type II collagen (CII). CIA, like RA, is an autoimmune disease leading to destruction of cartilage and joints, and both the priming and inflammatory phases have been suggested to be dependent on proteases. In particular, the cysteine proteases have been proposed to be detrimental to the arthritic process and even immunomodulatory. A natural inhibitor of cysteine proteases is cystatin C.
Cystatin C-deficient, sufficient and heterozygous mice were tested for onset, incidence and severity of CIA. The effect of cystatin C-deficiency was further dissected by testing the inflammatory effector phase of CIA; that is, collagen antibody-induced arthritis model and priming phase, that is, T cell response both in vivo and in vitro. In addition, in order to determine the importance of T cells and antigen-presenting cells (APCs), these cell populations were separated and in vitro T cell responses determined in a mixed co-culture system. Finally, flow cytometry was used in order to further characterize cell populations in cystatin C-deficient mice.
Here, we show that mice lacking cystatin C, develop arthritis at a higher incidence and an earlier onset than wild-type controls. Interestingly, when the inflammatory phase of CIA was examined independently from immune priming then cystatin C-deficiency did not enhance the arthritis profile. However, in line with the enhanced CIA, there was an increased T cell and B cell response as delayed-type hypersensitivity reaction and anti-CII antibody titers were elevated in the cystatin C-deficient mice after immunization. In addition, the ex vivo naïve APCs from cystatin C-deficient mice had a greater capacity to stimulate T cells. Interestingly, dendritic cells had a more activated phenotype in naïve cystatin C-deficient mice.
The lack of cystatin C enhances CIA and primarily affects in vivo priming of the immune system. Although the mechanism of this is still unknown, we show evidence for a more activated APC compartment, which would elevate the autoimmune response towards CII, thus resulting in an enhanced development of chronic arthritis.
胶原诱导性关节炎（CIA）是一种用于类风湿关节炎（RA）的小鼠模型，通过免疫 II 型胶原（CII）而引发。CIA 与 RA 一样，是一种自身免疫性疾病，导致软骨和关节破坏，而引发和炎症两个阶段都被认为依赖于蛋白酶。特别是，半胱氨酸蛋白酶被认为对关节炎进程有害，甚至具有免疫调节作用。半胱氨酸蛋白酶的天然抑制剂是胱抑素 C。
对胱抑素 C 缺乏、充足和杂合子小鼠进行 CIA 的发病、发病率和严重程度测试。通过测试 CIA 的炎症效应阶段，进一步剖析胱抑素 C 缺乏的影响；即胶原抗体诱导关节炎模型和引发阶段，即在体内和体外检测 T 细胞反应。此外，为了确定 T 细胞和抗原呈递细胞（APC）的重要性，将这些细胞群分离，并在混合共培养系统中测定体外 T 细胞反应。最后，使用流式细胞术进一步表征胱抑素 C 缺乏小鼠中的细胞群。
在这里，我们表明缺乏胱抑素 C 的小鼠比野生型对照更早和更高的发病率发展为关节炎。有趣的是，当独立于免疫引发检查 CIA 的炎症阶段时，胱抑素 C 缺乏并未增强关节炎特征。然而，与增强的 CIA 一致，在免疫后，胱抑素 C 缺乏小鼠中的 T 细胞和 B 细胞反应升高，表现为迟发型超敏反应和抗 CII 抗体滴度升高。此外，来自胱抑素 C 缺乏小鼠的体外幼稚 APC 具有更强的刺激 T 细胞的能力。有趣的是，在幼稚的胱抑素 C 缺乏小鼠中，树突状细胞具有更活跃的表型。
缺乏胱抑素 C 增强 CIA，主要影响免疫系统的体内引发。尽管其机制尚不清楚，但我们提供了 APC 部分更活跃的证据，这将提高针对 CII 的自身免疫反应，从而导致慢性关节炎的发展增强。
