A report from the Center for Disease Control (CDC) estimates that in 2016, approximately 50 million people in the US suffered from chronic pain, with 19.6 million of those people having “high-impact chronic pain” that affected one or more life activities (work, recreational, self-care, etc.) (1). Chronic pain has become so prevalent that some clinicians have argued for chronic pain as a new classification of disease (2,3). While this idea is controversial, the prevalence of chronic pain and its economic burden necessitates research seeking to understanding chronic pain pathophysiology (4,5).
As with traditional diseases, we have learned much about the underlying biological mechanisms of pain by developing animal models of pain and studying pain-like behavior (6). For a disease like rheumatoid arthritis (RA) where chronic pain can severely affect quality of life, the Adjuvant-Induced Arthritis model and the Collagen-Induced Arthritis model have been used to study the role of inflammation in the pain process. These models have revealed how the influx of pro-inflammatory cytokines and immune cells to acute areas can initiate a cascade of biological events that lead to the hypersensitization of neuronal bodies and the development of chronic pain (7). Recently, a new possible pain pathway utilizing immune complexes with autoantibodies has been elucidated that is distinct from previously identified pain pathways in autoimmune diseases that rely on autoantibodies (7).
When using the Collagen Antibody-Induced Arthritis (CAIA) model, the Farinotti et al. found that pain-like behavior (in this case decreased withdrawal threshold and decreased locomotor activity) appeared on day 3 and 5, before visible joint inflammation and without increases in the mRNA expression of several inflammatory mediators (TNF, IL-1β, IL-6, Cox2, Mcpt4 and MMPs) (8). The appearance of pain-like behavior on day 5 before LPS injection suggests that anti-type II collagen antibodies may play a role for inducing nociception.
To determine the mechanism behind this pre-inflammatory pain, the researchers administered a complement component 5a receptor (C5aR) antagonist to mice daily starting 1 day before the initial CAIA immunization and continuing for the course of the experiment. The C5aR antagonist did not affect the pre-arthritis pain-like behavior, indicating that this pain mechanism is not reliant on the activation of the complement cascade. Additionally, administration of a non-arthritogenic anti-type II collagen antibody was able to induce mechanical hypersensitivity without cartilage damage, leading the researchers to conclude that the pain mechanism in their study did not rely on changes in cartilage structure.
Given these findings, the researchers analyzed Fcγ receptor (FcγR) activation as another mechanism that could explain the pre-inflammatory pain-like behavior. Analyzing mRNA expression in mouse sensory neurons and immunostaining of mouse dorsal root ganglion (DRG) neurons found both FcγRI and FcγRIIb to be expressed on dorsal root ganglion (DRG) neurons of mice. FcγRIIb was found on both the DRG cell bodies and axons, while FcγRI was only found on the peripheral axon of DRG neurons in vivo.
Interestingly, an type II collagen-antibody immune complex (CII-IC) treatment was found to activate cultured DRG neuronal cells, causing increased intracellular Ca2+ concentration and an inward current. Furthermore, CII-IC induced the release of calcitonin gene-related peptide (CGRP) from DRG cells. CGRP is primarily released from sensory neurons and has been implicated in the pain pathway. These physiological changes indicate that CII-IC can activate FcγRs on mouse DRG neurons and initiate pain a CGRP pain mechanism.
To confirm these findings in vivo, WT mice received intra-articular (i.a.) injection (ankle) of CII-IC. These mice developed mechanical hypersensitivity in the ipsilateral paw only 3 hours after injection. FcγR-/- mice that received either CII-IC arthritogenic antibody cocktail i.a. or intravenously (i.v.) did not developed pain-like behavior. However, another experiment using FcγRIV-/- mice that received the Arthrogen-CIA 5-Clone Cocktail did still develop mechanical hypersensitivity, suggesting that activation of the FcγRI is primarily responsible for the pain-like behavior elicited by CII-IC.
To evaluate the plausibility of this pain pathway in humans, Farinotti et el. performed IHC on human DRGs and obtained some promising results. FcγRI was expressed on non-neuronal cells in human DRGs, which the researchers speculate are macrophages. The researchers also identified significantly high FcγRIIIA mRNA expression in human DRGS, indicating it may be a potential target for human studies of this pathway.
This research does not rule out the possibility that pre-arthritis pain-like behavior in CAIA mice is due to inflammatory cells being activated by the type II collagen immune complex. However, it suggests an alternative pain pathway, one which does not rely on traditional inflammatory pain pathways. If the immune complex of an autoantigen and autoantibody can directly activate sensory neurons and induce pain, it could provide another avenue for treatment of chronic pain in many autoimmune disease patients. Further research is needed to confirm this potential pain pathway.