Controversial Correlation Between Fcγ Receptor IIB and Toll-like Receptor 2 in Rheumatoid Arthritis: Comment on the Article by Abdollahi-Roodsaz et al


We read with great interest the recent research article by Abdollahi-Roodsaz and colleagues regarding the ability of Toll-like receptor 2 (TLR-2) to control acute immune complex–driven arthritis in mice by regulating Fcγ receptor IIB (FcγRIIB) ([1]). That study showed that TLR-2 deficiency accelerated the onset and markedly increased the severity of acute immune complex–driven arthritis by controlling the macrophage FcγR response. In addition, TLR-2 deficiency resulted in a substantial increase in joint inflammation, bone erosion, and cartilage pathology. These results are of great importance, because they revealed a clear protective role of TLR-2 in immune complex–mediated arthritis.

To date, TLR-2 expression in rheumatoid arthritis (RA) synovial tissue has been demonstrated at sites of attachment and invasion into cartilage and bone, on CD16+ monocytes, and on synovial macrophages. In RA fibroblast-like synoviocytes, TLR-2 is up-regulated by tumor necrosis factor α and interleukin-1β (IL-1β) ([2, 3]). Recently, Huang and associates showed that an intact TLR-2 pathway modulates immune complex–mediated arthritis through the induction of IL-10 in the anti–glucose-6-phosphate isomerase (anti–GPI) mouse serum transfer model, supporting a potential role for neutralizing TLR-2 as a therapeutic approach in RA ([4]).

It is well known that FcγRs regulate the immune response to IgG, alone or as part of an immune complex. The balance between these activating FcγRs and inhibitory FcγRIIB is critical for determining whether inflammatory signals ensue. In addition, the development and resolution of collagen-induced arthritis and K/BxN mouse serum–induced arthritis depend mainly on the expression of FcγRIIB and FcγRIII ([5, 6]). Abdollahi-Roodsaz et al used the model of passive experimental arthritis induced by arthritogenic serum from K/BxN mice. K/BxN mouse serum contains autoantibodies directed against the ubiquitously expressed enzyme GPI. Most importantly, they demonstrated that TLR-2 stimulation specifically up-regulated FcγRIIB, but not the activating FcγRs, on macrophages ([1]).

Notably, however, a recent study showed a slight reduction of FcγRIV messenger RNA expression levels in TLR-2−/− macrophages but no other difference in activating FcγR isoforms and no decrease of the inhibitory FcγRIIB isoform between TLR-2−/− and control mice ([4]). In this study, K/BxN mice were generated, anti-GPI serum was collected at 8–9 weeks of age, and arthritis was induced by peritoneal injection of anti-GPI serum.

Although many investigators agree with the facts that TLR-2 and FcγRIIB are involved in the pathogenesis of RA ([7, 8]), based on the current evidence, the correlation between TLR-2 and FcγRIIB seems to be controversial. To ascertain the exact mechanisms of action of TLR-2 in RA, especially targeting FcγRIIB, additional human studies, with larger patient populations, and animal studies will be needed. Unraveling the relationship between TLR-2 and FcγRIIB may then allow for the identification of relevant targets for therapeutic intervention.


Supported by grant 81273526 from the National Natural Science Foundation of China.