Cyclophilins in rheumatoid arthritis—stepping into an undiscovered country?

Abstract

Recent years have seen enormous progress in understanding the pathogenesis of rheumatoid arthritis (RA), an autoimmunological disorder that primarily affects the joints and leads to their progressive destruction. Advances in molecular biology techniques such as the use of gene transfer and gene silencing technology, the utilization of novel animal models of destructive arthritis–particularly in conjunction with newly established transgenic and knockout mice–and the observation of very early stages of human disease have provided exciting novel insights into key mechanisms that ultimately lead to the development of established RA in humans and that contribute to joint destruction. It has become increasingly clear that the mechanisms of rheumatoid joint destruction are linked closely to changes that occur predominantly at sites of interaction between the rheumatoid synovium and articular cartilage and bone [1]. Numerous data have shown that cells of the inflamed synovium constitute a highly interdependent network, in which the interaction of stromal cells–specifically synovial fibroblasts–with infiltrating inflammatory cells such as lymphocytes and macrophages creates a unique environment that results in the development of chronic destructive synovitis [2]. Thickening of the RA synovium is largely due to a hyperplasia of the most superficial lining layer that in the course of disease grows from 2–4 layers of cells to more than 10 layers. About two-thirds of the cells in the lining layer express macrophage markers such as CD11b, CD14, CD33, and CD68 as well as major histocompatibility complex (MHC) class II molecules and can thus be