Wang Julia Y, Roehrl Michael H
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14362-7. doi: 10.1073/pnas.222536599. Epub 2002 Oct 21.
Rheumatoid arthritis (RA) is a chronic, systemic, and inflammatory disease of connective tissue with unknown etiology. We investigated whether aberrant immune responses to glycosaminoglycans (GAGs), a major component of joint cartilage, joint fluid, and other soft connective tissue, causes this disease. Here we show that injection of GAGs such as hyaluronic acid, heparin, and chondroitin sulfates A, B, and C induce arthritis, tendosynovitis, dermatitis, and other pathological conditions in mice. We developed a technique by staining tissue specimens with fluorochrome- or biotin-labeled GAGs to visualize the direct binding between cells and GAGs. We discovered that inflammatory infiltrates from the affected tissue are dominated by a distinct phenotype of GAG-binding cells, a significant portion of which are CD4(+) T cells. GAG-binding cells seem to be expanded in bone marrow of GAG-immunized mice. Furthermore, we identified GAG-binding cells in inflamed synovial tissue of human patients with RA. Our findings suggest that carbohydrate self-antigenic GAGs provoke autoimmune dysfunctions that involve the expansion of GAG-binding cells which migrate to anatomical sites rich in GAGs. These GAG-binding cells might, in turn, promote the inflammation and pathology seen both in our murine model and in human RA.
类风湿性关节炎（RA）是一种病因不明的慢性、全身性结缔组织炎症性疾病。我们研究了对糖胺聚糖（GAGs）（关节软骨、关节液及其他软结缔组织的主要成分）的异常免疫反应是否会引发这种疾病。在此我们表明，注射透明质酸、肝素以及硫酸软骨素A、B和C等GAGs可在小鼠中诱发关节炎、腱鞘炎、皮炎及其他病理状况。我们开发了一种技术，通过用荧光染料或生物素标记的GAGs对组织标本进行染色，以可视化细胞与GAGs之间的直接结合。我们发现，来自受影响组织的炎性浸润以一种独特表型的GAG结合细胞为主，其中很大一部分是CD4(+) T细胞。GAG结合细胞似乎在GAG免疫小鼠的骨髓中扩增。此外，我们在人类RA患者的发炎滑膜组织中鉴定出了GAG结合细胞。我们的研究结果表明，碳水化合物自身抗原性GAGs引发自身免疫功能障碍，涉及GAG结合细胞的扩增，这些细胞迁移至富含GAGs的解剖部位。反过来，这些GAG结合细胞可能会促进我们在小鼠模型和人类RA中所见到的炎症和病理变化。
