Rankin Andrew L, Reed Amy J, Oh Soyoung, Cozzo Picca Cristina, Guay Heath M, Larkin Joseph, Panarey Laura, Aitken Malinda K, Koeberlein Brigitte, Lipsky Peter E, Tomaszewski John E, Naji Ali, Caton Andrew J
The Wistar Institute, Department of Surgery, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
J Immunol. 2008 Jan 15;180(2):833-41. doi: 10.4049/jimmunol.180.2.833.
We have examined processes leading to the spontaneous development of autoimmune inflammatory arthritis in transgenic mice containing CD4+ T cells targeted to a nominal Ag (hemagglutinin (HA)) and coexpressing HA driven by a MHC class II promoter. Despite being subjected to multiple tolerance mechanisms, autoreactive CD4+ T cells accumulate in the periphery of these mice and promote systemic proinflammatory cytokine production. The majority of mice spontaneously develop inflammatory arthritis, which is accompanied by an enhanced regional immune response in lymph nodes draining major joints. Arthritis development is accompanied by systemic B cell activation; however, neither B cells nor Ab is required for arthritis development, since disease develops in a B cell-deficient background. Moreover, arthritis also develops in a recombinase activating gene-deficient background, indicating that the disease process is driven by CD4+ T cells recognizing the neo-self HA Ag. These findings show that autoreactive CD4+ T cells recognizing a single self-Ag, expressed by systemically distributed APCs, can induce arthritis via a mechanism that is independent of their ability to provide help for autoantibody production.
我们研究了在含有靶向一种名义抗原（血凝素（HA））的CD4⁺ T细胞并由MHC II类启动子驱动共表达HA的转基因小鼠中，自身免疫性炎性关节炎自发发展的过程。尽管这些小鼠经历了多种耐受机制，但自身反应性CD4⁺ T细胞仍在其外周积聚，并促进全身促炎细胞因子的产生。大多数小鼠会自发发展为炎性关节炎，同时在主要关节引流的淋巴结中出现增强的局部免疫反应。关节炎的发展伴随着全身B细胞的激活；然而，关节炎的发展既不需要B细胞也不需要抗体，因为在B细胞缺陷的背景下疾病仍会发生。此外，关节炎在重组酶激活基因缺陷的背景下也会发展，这表明疾病过程是由识别新自身HA抗原的CD4⁺ T细胞驱动的。这些发现表明，识别由全身分布的抗原呈递细胞表达的单一自身抗原的自身反应性CD4⁺ T细胞，可以通过一种独立于其为自身抗体产生提供帮助能力的机制诱导关节炎。
