Cartilage-binding antibodies induce pain through immune complex–mediated activation of neurons

Abstract

Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.

Understanding the Molecular Mechanisms Underlying the Pathogenesis of Arthritis Pain Using Animal Models

“…The K/BxN model exhibits persistent pain with mechanical hypersensitivity, which does not return to baseline levels during disease progression and outlasts inflammation [155]. Table 2 briefly summarizes the pathology and pain behaviors reported in RA models [134,137,[153][154][155][156][157][158][159][160][161][162][163][164][165][166][167]. CIA, collagen-induced arthritis; CAIA, collagen antibody-induced arthritis; AIA, antigen-induced arthritis; TNF-Tg, tumor necrosis factor transgene; IL-1RA-/-, interleukin-1 receptor antagonist knockout; CII, collagen type II; Ab, antibody; mBSA, methylated bovine serum albumin; GPI, glucose-6-phosphateisomerase; hTNF, human tumor necrosis factor; RA, rheumatoid arthritis; d, day; wk, week(s); Cat S, cathepsin S; FKN, fractalkine; TLR-4, toll-like receptor 4; IL-1RI, interleukin-1 receptor type I; pCREB, phospho-CREB.…”

“…In a study that employed AIA and CFA models, FcγR1 signaling was upregulated in joint sensory neurons, while the blockade or global genetic deletion of FcγR1 significantly attenuated arthritis pain and hyperactivity of joint sensory neurons without changes in joint inflammation [176]. Antibodies specific for CII or cartilage oligomeric matrix protein (COMP) were found to elicit mechanical hypersensitivity in mice independent of inflammation [160]. Interestingly, CII-immune complex and CII antibodies did not induce mechanical hypersensitivity or pain-like behavior in FcγR chain-deficient mice, suggesting functional coupling between autoantibodies and pain transmission.…”

Immune System Sex Differences May Bridge the Gap Between Sex and Gender in Fibromyalgia

“…TLR8 is especially important because of its pro-autoimmunity potential (Peng et al, 2005). A recent study with BALB/c and C57BL/6 mice suggests that circulating immunoglobulin G (IgG)-type immune complexes may directly mediate hyperalgesia at the level of dorsal root ganglia (Bersellini Farinotti et al, 2019) where macrophages and neurons have receptors for IgG1 and IgG2b (Bersellini Farinotti et al, 2019). If this mechanism were to be confirmed in humans, it would make women more vulnerable, because women are more inclined to humoral adaptive immune responses than men (see Section Sex Differences in the Immune System).…”

Bioelectronic medicine: an unexpected path to new therapies

“…In addition, nociceptor sensory neurons sense microbial invasion and interact with the immune system to modulate responses to bacterial infection . Also, autoantibodies in experimental models of arthritis activate sensory neurons and contribute to pain sensation . As detailed by Crosson et al .…”

“…In addition, nociceptor sensory neurons sense microbial invasion and interact with the immune system to modulate responses to bacterial infection [5]. Also, autoantibodies in experimental models of arthritis activate sensory neurons and contribute to pain sensation [6]. As detailed by Crosson et al in this issue, sensory neurons express receptors for a wide range of molecules involved in microbial invasion, traumatic injury and other factors associated with perturbation of homeostasis [7].…”