In RA, synovial fibroblasts and T cells form a costimulatory circuit to perpetuate the inflammation. RASF could inhibit the apoptotic process of T cells and elicit their spontaneous proliferation; the increased inflammatory T cells then in turn induce more robust RASF activation. Cell-cell contact and soluble factors, such as inflammatory cytokines, contribute to this Danshensu interaction. As demonstrated in our study, after TLR ligation, RASF could secrete more inflammatory mediators and express higher levels of surface TSP-1, SDF-1, and IL-15. These factors together with other unknown elements may eventually lead to the amplification of Th1 and Th17 cells. Thus TLRs also contribute to the maintenance and perpetuation of the inflammation in RA. Given the integral roles of TLRs in the initiation, propagation, and perpetuation of the inflammation in RASF as well as T cells, targeting TLRs would be a preferred therapeutic strategy. In fact, several groups have been testing the feasibility of this hypothesis by both animal and human studies. In a serum-transfer model, disease duration was shortened in TLR4 null mice. In the pristane-induced arthritis rat model, TLR3 expression was significantly upregulated during early disease stages. TLR3 agonist stimulation augmented the disease severity, and small interfering RNAtargeting TLR3 in vivo reduced disease severity. The recombinant analogue of chaperonin 10, XToll, targeting TLR4 developed by Cbio Ltd, is now being tested in a phase II clinical trial for RA treatment given by subcutaneous injection. Antibodies targeting TLR2, OPN-305 and OPN-301, have been proved to be able to abrogate spontaneous cytokine release by RASF. DNA-based TLR7/9 antagonist, IMO3100, has been tested in phase I clinical trials and showed promising results for RA. All these prove that targeting TLRs or their activation Ganoderic-acid-G represents an attractive therapeutic option for RA. However, we should notice that there are different types of TLRs in RA as demonstrated in our study. They might interact or work cooperatively with each other during the disease. Targeting one specific TLR might not suffice for RA amelioration. More indepth studies should be taken to further elucidate the pathogenic roles of TLRs in RA and the potential of targeting them for overcoming the chronic and persistent disease. Autophagy is a highly conserved housekeeping pathway that plays a critical role in the removal of aged or damaged intracellular organelles and their delivery to lysosomes for degradation. There are three major autophagic pathways that have been described, microautophagy, chaperone-mediated autophagy, and macroautophagy. Autophagy can be stimulated by a number of events including nutrient deprivation, exposure to pathogens, and oxidative stress. Microautophagy involves 
the direct phagocytosis of cytoplasmic elements and subsequent degradation of the elements in the lysosomal lumen. The second major type of autophagy is chaperone-mediated autophagy. Chaperone-mediated autophagy involves the delivery of proteins directly to the lysosome via chaperones such as Hsc70. The third and the best-characterized autophagic pathway is macroautophagy. Autophagy follows a specific series of events, starting with initiation of formation of the phagophore. The phagophore elongates, engulfing a portion of cytoplasm containing the cargo to be degraded, and closes off to form the autophagosome.