Autoantibodies contribute to joint pain by binding to Fcγ receptors (FcγRs) expressed on sensory neurons, even in the absence of inflammation, according to evidence from two new studies.

In one study, Lintao Qu and colleagues showed that IgG immune complexes (IgG-ICs) activate joint sensory neurons in an FcγRI-dependent manner. In wild-type mice, local administration of IgG-ICs induced acute joint pain without obvious inflammation. Notably, this pronociceptive effect was diminished in Fcgr1–/– mice and in mice with conditional knockout of Fcgr1 in sensory neurons. “These conditional knockout mice allow us to unambiguously dissect the contributions of neuronal versus non-neuronal FcγRI to arthritis pain and define the neuronal subtypes involved,” explains Qu.

Next, using a model of antigen-induced arthritis (AIA), Qu and colleagues demonstrated that FcγRI signalling is upregulated in sensory neurons in mice with AIA. Pain-related behaviour was attenuated in Fcgr1–/– as compared with wild-type mice over the course of AIA, but with no differences between the two genotypes in the occurrence of joint inflammation. Furthermore, in wild-type mice with AIA, pharmacological blockade of FcγRI by local injection of anti-CD64 antibody reduced established arthritis pain but not joint inflammation. Together, the results provide evidence of the contributions of peripheral IgG-IC–FcγRI signalling to joint pain, independent of inflammation, in both naive and arthritic states. “These findings could define a promising candidate therapeutic target for patients with pain arising from rheumatoid arthritis or other autoimmune-related diseases in whom anti-inflammatory therapies are inadequate, unaffordable or poorly tolerated,” says Qu.

In a separate study, Rikard Holmdahl, Camilla Svensson and their collaborators explored the mechanisms by which antibodies with reactivity to cartilage induce pain in the collagen-antibody-induced arthritis (CAIA) model. They observed that injection of antibodies against type II collagen (CII) or to cartilage oligomeric matrix protein (COMP) induced a pain response in mice before the onset of signs of joint inflammation, independently of the complement cascade or changes in cartilage structure. Notably, intra-articular injection of CII immune complexes (CII-ICs) induced pain-like behaviour in wild-type mice, but not in FcRγ-chain deficient mice. The researchers also established that the pronociceptive effect of anti-CII antibodies requires both epitope recognition and interaction between immune complexes and FcγRs on neurons. Through a series of further experiments, the researchers determined that the critical FcR for the development of immune-complex-mediated pain-like behaviour was neuronal FcγRI, consistent with the results of the study by Qu et al.

“From a medical viewpoint, this study explains why arthralgia develops before the onset of clinical arthritis during the onset of RA. From the physiological viewpoint, it gives us an explanation for how antibodies aggregating in a specific tissue could activate peripheral nociceptors,” says Svensson.

“We want to expand our work to examine if local formation of immune complexes is a general mechanism of pain in rheumatic and autoimmune diseases. Such insights would give us a new angle on how to prohibit the development of pain that is caused by antibodies,” adds Holmdahl.