O'Neill Shannon K, Cao Yanxia, Hamel Keith M, Doodes Paul D, Hutas Gabor, Finnegan Alison
Department of Immunology/Microbiology, Rush University, Medical Center, Chicago, IL 60612, USA.
J Immunol. 2007 Oct 15;179(8):5109-16. doi: 10.4049/jimmunol.179.8.5109.
Depletion of B cells in rheumatoid arthritis is therapeutically efficacious. Yet, the mechanism by which B cells participate in the inflammatory process is unclear. We previously demonstrated that Ag-specific B cells have two important functions in the development of arthritis in a murine model of rheumatoid arthritis, proteoglycan (PG)-induced arthritis (PGIA). PG-specific B cells function as autoantibody-producing cells and as APCs that activate PG-specific T cells. Moreover, the costimulatory molecule CD86 is up-regulated on PG-specific B cells in response to stimulation with PG. To address the requirement for CD80/CD86 expression on B cells in the development of PGIA, we generated mixed bone marrow chimeras in which CD80/CD86 is specifically deleted on B cells and not on other APC populations. Chimeras with a specific deficiency in CD80/CD86 expression on B cells are resistant to the induction of PGIA. The concentration of PG-specific autoantibody is similar in mice sufficient or deficient for CD80/86-expressing B cells, which indicates that resistance to PGIA is not due to the suppression of PG-specific autoantibody production. CD80/86-deficient B cells failed to effectively activate PG-specific autoreactive T cells as indicated by the failure of T cells from PG-immunized CD80/86-deficient B cell chimeras to transfer arthritis into SCID mice. In vitro secondary recall responses to PG are also dependent on CD80/86-expressing B cells. These results demonstrate that a CD80/86:CD28 costimulatory interaction between B cells and T cells is required for autoreactive T cell activation and the induction of arthritis but not for B cell autoantibody production.
在类风湿性关节炎中，B细胞的耗竭具有治疗效果。然而，B细胞参与炎症过程的机制尚不清楚。我们之前证明，在蛋白聚糖（PG）诱导的关节炎（PGIA）这一类风湿性关节炎小鼠模型中，抗原特异性B细胞在关节炎发展过程中具有两个重要功能。PG特异性B细胞作为产生自身抗体的细胞以及激活PG特异性T细胞的抗原呈递细胞（APC）发挥作用。此外，共刺激分子CD86在PG特异性B细胞上因PG刺激而上调。为了研究PGIA发展过程中B细胞上CD80/CD86表达的必要性，我们构建了混合骨髓嵌合体，其中CD80/CD86在B细胞上而非其他APC群体上被特异性删除。B细胞上特异性缺乏CD80/CD86表达的嵌合体对PGIA的诱导具有抗性。在表达或不表达CD80/86的B细胞充足的小鼠中，PG特异性自身抗体的浓度相似，这表明对PGIA的抗性并非由于PG特异性自身抗体产生受到抑制。如来自PG免疫的CD80/86缺陷型B细胞嵌合体的T细胞无法将关节炎转移至严重联合免疫缺陷（SCID）小鼠所示，CD80/86缺陷型B细胞无法有效激活PG特异性自身反应性T细胞。对PG的体外二次回忆反应也依赖于表达CD80/86的B细胞。这些结果表明，B细胞与T细胞之间的CD80/86:CD28共刺激相互作用是自身反应性T细胞激活和关节炎诱导所必需的，但不是B细胞自身抗体产生所必需的。
