Autoantibodies and Neuropathic Pain
Abstract and Keywords
A number of clinical studies indicated an association between autoantibodies and neuropathic pain. This is supported by the observation that immunotherapies that reduce antibody levels alleviate pain in patients and suggests that autoantibodies are not a byproduct of pathology but instead important drivers of neuropathic pain. These autoantibodies can target both neuronal and nonneuronal antigens within the sensory nervous system. Possible pathogenic mechanisms include nerve damage and inflammation as well as disruption of ion channel function. Whether autoantibodies are truly causal to neuropathic pain and exactly what their prevalence is in such pain conditions are important questions that are being addressed with the use of passive transfer in preclinical models and the screening of patient sera. Such studies support the idea that autoantibodies are a mechanism to cause neuropathic pain and provide insight into the molecular components regulating pain sensitivity in a pathological setting. Therefore, this work not only will be applicable to the treatment of patients with autoantibody-mediated pain, but also will facilitate the development of therapies to treat neuropathic pain in the more general context.
Keywords: neuropathic pain, autoantibodies, autoimmune pain, inflammatory neuropathy, neuromyelitis optica, complex regional pain, Voltage-gated potassium channel complex autoantibody, VGKCC, Fibromyalgia
It is now clear that the functions of the immune and nervous systems are intricately linked, and that neuroimmune interactions play an important role in the development of neuropathic pain (Calvo, Dawes, & Bennett, 2012; McMahon, La Russa, & Bennett, 2015). One well-recognized mechanism is through the infiltration of immune cells and release of immune-related factors such as cytokines and chemokines. Cytokines and chemokines released following nerve injury not only result in the recruitment and activation of inflammatory cells, but also many of these factors have a role in sensitizing nociceptors. These same mediators can also work at the level of the central nervous system (CNS), particularly in the dorsal horn of the spinal cord to amplify pain signaling through altering microglial activity in response to nerve injury. Recently, however, another type of neuroimmune interaction, that is the action of autoantibodies, has been suggested as an alternative route through which neuropathic pain can develop.
The link between autoimmunity and pain is not a novel concept. For example, in autoimmune diseases such as rheumatoid arthritis, pain is a common symptom. Traditionally, this pain is believed to be secondary to gross inflammation. However, there are examples where autoantibodies and knee pain are present without obvious signs of inflammation prior to the full development of arthritis. These observations are suggestive of a more pain-specific role for autoantibodies, and studies have shown that autoantibodies from patients with rheumatoid arthritis can induce pain-related behavior in mice independent of inflammation (Wigerblad et al., 2016). These findings support the growing idea that, instead of being separate from the development of pain, autoantibodies have an important role as drivers of pathological pain states. Here, we focus on autoantibodies as a mechanism to cause neuropathic pain.
There are a number of mechanisms related to how autoantibodies might drive neuropathic pain (Figure 1), and one important concept in terms of pathogenicity is that the antigenic target is expressed extracellularly to allow engagement of the antibody within the body. Suggested mechanisms include neural damage due to target disruption or complement activation, targeting of inflammation to the nervous tissue, and perhaps most intriguingly directly disrupting neuronal function without any gross neuronal damage or inflammation. The exact mechanism will be influenced by the antigen as well as the subclass of antibody; for example, immunoglobulin (Ig) G1 and G3 are strong activators of complement and phagocytic cells, whereas IgG4 does not activate complement. Although the location and known function of many of these targets infer pathogenicity, it is not proof of causation. Nevertheless, neuropathic pain in certain conditions can be reduced with immunotherapy and treatments such as plasma exchange (which involves the replacement of a patient’s plasma with a plasma substitute and as a consequence removal of all circulating autoantibodies) or systemic intravenous immunoglobulin (IVIg) treatment (which is thought to disrupt antibody production or binding; Hartung, 2008); both are arguments for the involvement of autoantibodies. However, further studies are needed to discern whether these autoantibodies are truly causal to sensory abnormalities and to ascertain the true prevalence of autoantibody-mediated mechanisms across neuropathic pain patients as a whole. Future work may therefore offer explanations for idiopathic pain conditions and, where the target is known, provide new insights into molecular mechanisms that may be relevant more generally to the development of neuropathic pain.
Guillain-Barré syndrome (GBS), which can be subtyped based on clinical presentation, is caused by an autoimmune response directed against the peripheral nervous system, resulting in both motor and sensory symptoms. GBS has an acute onset, is commonly secondary to an infection, and is characterized by progressive sensory loss and weakness, leading in the most severe cases to paralysis and respiratory compromise. Pain is a common symptom, described as moderate to severe in the majority of patients (~89%) (Moulin, Hagen, Feasby, Amireh, & Hahn, 1997) and interestingly can often precede muscle weakness. Autoantibodies have been recognized in GBS, and their pathogenicity is predicted since first-line treatment options include plasma exchange and IVIg, where sensory as well as motor symptoms are improved (van Doorn, Ruts, & Jacobs, 2008).
Antiganglioside antibodies are best known in GBS and target these molecules either individually or in glycolipid complexes (Rinaldi et al., 2013). These antibodies arise due to the process of molecular mimicry, where cross-reactivity occurs between antibodies directed against bacterial cell wall products and the gangliosides themselves (Kaida, Ariga, & Yu, 2009). Gangliosides are glycolipids found in the plasma membrane and have a number of important biological functions, including cell growth, cell-to-cell interaction (e.g., in myelinated nerves), and signal transduction. A whole series of these molecules are synthesized through complex biochemical pathways, which are abundantly expressed throughout the nervous system. Some of these molecules are enriched in peripheral nerve, and such molecules are clearly expressed by a variety of primary sensory neurons (Gong et al., 2002).
The role of antiganglioside antibodies in GBS pathology includes complement activation as well as immune complex formation and subsequent Fc receptor stimulation of macrophages (He, Zhang, Liu, Gao, & Sheikh, 2015; Willison et al., 2008); therefore, pain may arise through this “nonspecific” pathway due to the action of cytokines and chemokines, which can sensitize or activate sensory neurons. Demyelination is of course a major feature of GBS and is a cause of neuropathic pain; for example, experimental demyelination of the sciatic nerve in rats caused ectopic primary afferent activity and neuropathic pain-like behavior (Bhangoo et al., 2007).
Patient ganglioside antibodies are cytotoxic, particularly toward large sensory neurons both in vitro and in vivo (Ohsawa, Miyatake, & Yuki, 1993; Takada, Shimizu, & Kusunoki, 2008), and interestingly can cause ectopic activity of both myelinated and unmyelinated nociceptors in rodent models (Xiao, Yu, & Sorkin, 1997). This suggests that small fibers are also targeted in GBS, and studies have found a reduction in epidermal nerve fiber density (Pan et al., 2003), with dysfunction of these fibers associated with neuropathic pain (Martinez et al., 2010). Indeed, a variant of GBS has been described in which there is selective loss of small fibers with minimal motor involvement. These patients have neuropathic pain that is responsive to IVIg. Use of patient sera showed antibody binding to small fibers in mouse skin and dorsal root ganglion (DRG) sections, as well as live DRG neurons in vitro. Although the antibody target is unknown, importantly this binding was lost when using sera from the convalescent stage (i.e., when the patient’s pain had recovered), suggesting an important role in the development of pain (Yuki et al., 2018).
Another mechanism by which autoantibodies might cause damage to sensory neurons and hence pain in GBS is through disruption of protein function, particularly in terms of structural proteins important in nodal subdomain formation. For example, around 43% of GBS patient sera showed IgG binding to the node (Devaux, Odaka, & Yuki, 2012). Demarcation of these domains and clustering of specific ion channels are essential for normal nerve function, and disruption of the node is evident in experimental models of neuropathic pain (Calvo et al., 2016). Again, gangliosides may represent important targets here (Susuki et al., 2012), although autoantibodies to other nodal proteins, such as neurofascin, gliomedin, and contactin, have been identified (Devaux et al., 2012).
Autoantibodies to CASPR (contactin-associated protein), a protein important for the formation and integrity of the paranode, have also been found in patients with GBS and are particularly associated with neuropathic pain, which can be relieved with plasma exchange (Doppler et al., 2016). When tested on mouse DRG sections, patient sera preferentially bound to neurons expressing the nociceptive marker TRPV1 (transient receptor potential channel vanilloid 1) (and presumably CASPR). The expression profile of CASPR in DRG neurons has not yet been characterized, but it might well be the case that CASPR expression is highest in thinly myelinated or unmyelinated nociceptors, which prompt such autoantibodies to preferentially target these sensory neurons and cause pain.
CASPR autoantibodies have also been found in a patient with chronic inflammatory demyelinating polyneuropathy (CIDP), again associated with prominent neuropathic pain (Doppler et al., 2016). In general, pain is also common in CIDP, and symptoms are responsive to IVIg and plasma exchange. Additional autoantibody targets include other nodal proteins, such as contactin and isoforms of neurofascin (-155 and 186) (Querol, Devaux, Rojas-Garcia, & Illa, 2017), although their precise relationship to neuropathic pain is not yet known.
Complex Regional Pain Syndrome
Complex regional pain syndrome (CRPS) is a pain condition that results following injury, typically to a single limb. Neuropathic pain can develop along with swelling and reddening of the skin, which is usually confined to the affected area. The idea that autoantibodies have a role in this process initially came from the observation that IVIg can provide substantial pain relief in patients with CRPS (Goebel, Netal, Schedel, & Sprotte, 2002), which was subsequently supported by a small clinical trial (Goebel et al., 2010). However, a recent larger study failed to show clear efficacy of IVIg compared to placebo in reducing pain in patients with CRPS (Goebel et al., 2017). While this may question the validity of pathogenic autoantibodies in CRPS, interestingly IVIg was effective at reducing pain in patients with the more rare type II version of CRPS, which, unlike type I CRPS, involves direct nerve injury. The trial was not powered to detect subgroup differences, but these findings suggest that IVIg, and as a result autoantibodies, might drive pain in subsets of patients with CRPS, in particular those who have a clear neuropathy. Furthermore, additional studies have shown that plasma exchange is similarly effective in relieving pain in CRPS (Aradillas, Schwartzman, Grothusen, Goebel, & Alexander, 2015; Blaes et al., 2015), which again supports the notion that autoantibody-mediated mechanisms have a role.
Importantly, autoantibodies have been detected in patients with CRPS and targets identified. These include antibodies against the beta-2 adrenergic receptor, the muscarinic 2 receptor, and the alpha-1a adrenergic receptor. Here, the antibodies are thought to act as agonists to these receptors, which are expressed by the autonomic nervous system (Dubuis et al., 2014; Kohr et al., 2011) and therefore might be particularly important in the reddening and swelling of the affected limb typically seen in patients with CRPS. In terms of the relationship of these targets to pain, there is evidence to suggest sympathetic nervous system involvement in neuropathic pain development (Strong, Zhang, & Schaible, 2018), and some of these receptors are expressed by sensory neurons following peripheral nerve injury (Hayashida, Bynum, Vincler, & Eisenach, 2006).
Further studies looking more directly at pain-specific neurons would provide insight into whether CRPS autoantibodies target this system. To this end, a recent study suggested that purified IgG from patients with CRPS can alter the function of DRG neurons in vitro, albeit in the presence of inflammatory mediators, therefore proposing sensory neurons as targets of autoantibodies in CRPS (Reilly et al., 2016). However, evaluation of exactly where these autoantibodies are binding in terms of both sensory neuron subtype and neuronal compartment are lacking, and it is unclear whether additional “pain-specific” antigens are involved.
Fibromyalgia is a chronic condition characterized by widespread pain as well as fatigue and muscle stiffness. It is generally considered to be a quintessential idiopathic pain condition, predominantly thought to be driven by enhanced central processing of sensory input. However, the mechanisms driving these putative changes remain unknown. More recently, studies have pointed to pathology of the peripheral nervous system as an underlying cause. For example, patients with fibromyalgia have reduced epidermal nerve fiber density (Üçeyler et al., 2013) and small-fiber dysfunction (Serra et al., 2014). Again, the pathophysiological mechanisms causing these changes are not clear, but these findings do point to peripheral nerve damage and excitability changes in nociceptors as contributing to pain in patients with fibromyalgia.
Although typically not considered an autoimmune syndrome, fibromyalgia is associated with a number of autoimmune conditions, such as systemic lupus erythematosus (Middleton, McFarlin, & Lipsky, 1994); rheumatoid arthritis (Wolfe & Michaud, 2004); and Sjögren syndrome (Choi, Oh, Lee, & Song, 2016). Therefore, autoantibodies have been discovered in patients with fibromyalgia. For example, some patients with fibromyalgia have positive antinuclear antibody (ANA) tests (Dinerman, Goldenberg, & Felson, 1986), indicating that, in a subset of patients, the immune system may have the ability to target self-antigens and cause disease. However, clear pathogenic autoantibodies, particularly ones targeting the pain pathway, are yet to be discovered.
Nevertheless, a few small studies have successfully used IVIg to treat pain in patients with fibromyalgia (Caro, Winter, & Dumas, 2008; Goebel et al., 2002), suggesting that such pathogenic autoantibodies may exist. Of course, testing the idea that autoantibodies can drive pain in patients with fibromyalgia will be greatly facilitated by identification of the target and immunotherapy given as part of carefully conducted trials, but still current preliminary findings point toward the potential of autoantibodies as an explanation for pathological pain in patients with fibromyalgia
Neuromyelitis optica (NMO) is an autoimmune disease characterized by inflammation and degeneration of the optic nerve and spinal cord. Pain is a common feature, with 60%–80% of patients experiencing neuropathic pain, which is predominantly severe and hugely debilitating (Qian et al., 2012; S. Zhao, Mutch, Elsone, Nurmikko, & Jacob, 2014). There is an association of autoantibodies and NMO; in the majority of cases, patients have autoantibodies directed against the water channel aquaporin 4 (Lennon, Kryzer, Pittock, Verkman, & Hinson, 2005) and a smaller subset against myelin oligodendrocyte glycoporotein (MOG) (Nakajima et al., 2015). Studies using animal models indicated that these autoantibodies are pathogenic (Hillebrand et al., 2019; Kinoshita et al., 2009), and both plasma exchange and IVIg are treatment options for patients with NMO. In terms of pain, tocilizumab, which is an anti-interleukin (IL) 6 receptor monoclonal antibody, has been shown to reduce the production of aquaporin 4 autoantibodies in patients and significantly reduce neuropathic pain (Araki et al., 2013; Ringelstein et al., 2015). Furthermore, when compared to patients with seronegative NMO, patients with MOG antibodies reported higher levels of pain (Nakajima et al., 2015).
Activation of the complement pathway has been shown in patients with NMO (Nytrova et al., 2014), and in terms of MOG antibodies this likely contributes to demyelination at the level of the spinal cord and as a consequence pain. Aquaporin 4 is predominantly expressed by astrocytes not only in the CNS but also in the DRG by satellite glia, albeit to a much lower extent (Kato et al., 2014). Genetic ablation of aquaporin 4 produced no obvious pain phenotype in mice (Kato et al., 2014), suggesting that this channel is not involved in pain transmission per se but instead allows these autoantibodies to target astrocytes.
There is a wealth of preclinical data advocating an important role of astrocytes in neuropathic pain via their release of numerous cytokines and chemokines (Ji, Berta, & Nedergaard, 2013). Therefore, it is of note that an alternative explanation for the pain relief caused by tocilizumab treatment could well be due to blocking downstream cytokine production by astrocytes rather than autoantibody reduction. Nevertheless, there is a strong association of autoantibodies and NMO pain, and aquaporin 4 autoantibodies provide support from the clinic that astrocytes contribute to neuropathic pain.
Voltage-Gated Potassium Channel Complex Autoantibodies
There are a number of neurological conditions, such as neuromyotonia, Morvan syndrome, and limbic encephalitis, that are secondary to the presence of autoantibodies directed against the voltage-gated potassium channel complex (VGKCC). Originally it was thought these autoantibodies directly targeted the potassium channel subunits (Kv1.1, 1.2, and 1.6), but further studies instead showed that proteins with which the Kv1 channels interact, such as CASPR2, leucine-rich glioma inactivated 1 (LGI1), and contactin 2, are the targets (Irani et al., 2010). Syndromes associated with VGKCC–autoantibodies (Abs) are characterized by neuronal hyperexcitability, as highlighted by muscle fasciculations in neuromyotonia and seizures in limbic encephalitis, and it is now apparent that neuropathic pain is a common feature and in some cases is the sole presenting symptom (Irani et al., 2012; Klein et al., 2013; Klein, Lennon, Aston, McKeon, & Pittock, 2012). Neuropathic pain seems to be particularly prominent in patients with CASPR2-Abs, with more than 60% of seropositive patients having pain that is positively correlated with the presence of CASPR2-Abs (Klein et al., 2012; Lancaster et al., 2011; van Sonderen, Ariño, et al., 2016). A more recent study showed that neuropathic pain is also a significant feature of patients with LGI1-Abs (Gadoth et al., 2017), and although rare among patients with VGKCC-Ab, patients with contactin-2-Abs similarly have a high incidence of pain (Vincent et al., 2018).
Importantly, pain can be relieved with the use of immunotherapies such as IVIg and plasma exchange, and in some cases the extent of pain relief is sufficient to allow weaning from problematic medications such as narcotics (Gadoth et al., 2017; Klein et al., 2012). It is unclear exactly why patients develop VGKCC-Abs; some cases are associated with tumors, and there is a specific HLA association (Binks et al., 2018). Interestingly these complexes may be involved in autoimmunization, with reports of abattoir workers exposed to aerosolized brain tissue developing neuropathic pain and being seropositive for VGKCC-Abs (Goebel, Moore, & Jacob, 2018; Meeusen et al., 2012).
In general, patients who are VGKCC-Ab positive do not have signs of inflammation within peripheral nerves (Lahoria et al., 2017; van Sonderen, Schreurs, et al., 2016), and although mild axonal loss has been reported in a few patients (Lahoria et al., 2017), nerve damage is not obvious, and typically nerve conduction studies are normal (Klein et al., 2012; van Sonderen, Ariño, et al., 2016). This suggests that neuropathic pain in these patients is not caused by a gross inflammatory reaction or cell damage, but instead may arise as a consequence of autoantibodies binding to neuronal antigens and disrupting their function.
Broadly speaking, potassium channels act to limit neuronal excitability; therefore, a loss of their activity may well underlie neuronal hyperexcitability in these patients. In terms of pain, both Kv1.1 and 1.2 are known to be important determinants of sensory neuronal excitability and contribute to neuropathic pain in preclinical models (Hao et al., 2013; X. Zhao et al., 2013). CASPR2 is a neurexin-like molecule with a large extracellular domain that interacts with contactin 2 (expressed both axonally and by myelinating cells) to help form the juxtaparanode in myelinating fibers. These proteins interact with Kv1 channels to form a protein complex and are crucial for the correct localization of Kv1 channels in myelinated fibers in both the CNS and peripheral nerves (Poliak et al., 2003), therefore having an important impact on their function. Both CASPR2 and contactin 2 are expressed by DRG neurons (Dawes et al., 2018; Poliak et al., 2003). Importantly, a recent study has shown that CASPR2-Abs can target these neurons in vitro (Dawes et al., 2018). The binding of patient CASPR2-Ab increases excitability in both small and medium-size DRG neurons (mostly nociceptors) as a consequence of reduced Kv1 channel current. This most likely occurs due to VGKCC internalization through antibody binding because Kv1 channel expression is reduced at the cell membrane (Dawes et al., 2018), providing an explanation for the development of neuropathic pain in patients with CASPR2-Ab.
Unlike CASPR2 or contactin 2, LGI1 is a secreted molecule and is known to be expressed in the CNS. There is little evidence to suggest expression in the juxtaparanode; instead it is expressed at the level of the synapse, where it interacts with Kv1 channels presynaptically (Schulte et al., 2006). LGI1-Abs can disrupt the expression and function of Kv1.1, as well as AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid class of glutamate receptor) receptors, leading to changes in synaptic transmission (Ohkawa et al., 2013; Petit-Pedrol et al., 2018). Furthermore, genetic ablation of LGI1 can lead to increases in intrinsic neuronal excitability, while application of LGI1 protein leads to hypoexcitability; both are the result of a Kv1-dependent mechanism (Seagar et al., 2017). Traditionally, the peripheral nerve has not been thought to express LGI1. Therefore, in terms of pain LGI1-Abs might well act centrally to enhance pain transmission. However, with the advent of recent transcriptomic and proteomic databases, it is clearly evident that LGI1 is expressed in the DRG (Barry, Sondermann, Sondermann, Gomez-Varela, & Schmidt, 2018; Ray et al., 2018), and single-cell RNA sequencing databases suggest high expression in nonpeptidergic nociceptors (Zeisel et al., 2018). Therefore, primary sensory neurons, particularly nociceptors, could be the target of LGI1-Abs in patients with neuropathic pain.
Are Autoantibodies Causal to Neuropathic Pain?
As discussed, there are a number of neurological conditions for which autoantibodies have been detected, and neuropathic pain is common or even the sole presenting symptom. However, this association does not denote causation. Of course, the observation that immunotherapies (which reduce or completely remove autoantibodies) attenuate pain in these patients is a strong argument. Some would dispute this as definitive proof; for example, the exact mechanism of IVIg is still unclear, and although plasma exchange allows you to remove circulating autoantibodies, it also removes numerous other circulating proteins and factors whose contribution may well also be important. Therefore, another approach in determining causality is the passive transfer of these patient samples into experimental animals where their ability to recapitulate pathology can be assessed in a controlled environment.
One recent clear example of this is from studies looking at the role of VGKCC-Abs in neuropathic pain. Plasma exchange generates large quantities of patient plasma from which autoantibodies can be purified for such experimental studies. Systemic administration of purified IgG from neuropathic pain patients with CASPR2-Abs resulted in pain-related behavior in mice when compared to mice receiving IgG from an age- and sex-matched healthy volunteer. Tissue analysis showed that antibodies targeted sensory neurons in vivo but did not cause any gross inflammation or neuronal damage (in line with clinical findings). Instead, CASPR2-Abs disrupted Kv1 channel function, leading to neuronal hyperexcitability and pain hypersensitivity (Dawes et al., 2018). This study strongly supported the idea that CASPR2-Abs are directly causative to neuropathic pain in patients and points to the idea that other VGKCC-Abs, such as LGI1-Ab and contactin-2-Abs, may well cause pain through similar mechanisms.
Passive transfer of purified IgG from patients with CRPS has also been used to support the idea that autoantibodies are pathogenic for pain. Initial passive transfer experiments did not show an obvious effect on sensory behavior in mice (Goebel et al., 2011). However, when this approach was used in the context of injury (as would be the case in patients) to the hind limb, patient IgG, but not healthy control IgG, enhanced mechanical hypersensitivity and caused swelling of the injured limb reflecting the clinical condition (Tekus et al 2014, Helyes et al 2019). As well as providing evidence for the causal role of autoantibodies in CRPS, development of such models allows for mechanistic insight. For example elevated levels of substance P (a neuropeptide known to be expressed and released by nociceptors) are found in the affected skin and more recently studies have linked the augmented pain behaviour caused by CRPS patient IgG to enhanced glia activation and IL-1β signaling at the level superficial spinal cord (Helyes et al 2019).— In addition, pain behavior in mouse fracture/cast models of CRPS seems to be B-cell dependent, mouse autoantibody targets have been identified, and these pain behaviors can be passively transferred to control mice (Guo et al., 2017; Li et al., 2014; Tajerian et al., 2017). However, the relevance of these targets to the human condition is not yet clear.
A recent study using serum from two patients with a particularly painful variant of GBS showed that intrathecal delivery caused transient but significant heat hypersensitivity in mice. Interestingly, serum from the same patients taken when their symptoms had recovered did not induce pain behavior in mice, indicating that the precovalescent serum contained autoantibodies that were potentially pathogenic in terms of pain. Although the target is unknown, patient IgG bound nociceptors, indicating these as the site of action (Yuki et al., 2018). In terms of antiganglioside antibodies, an example of their ability to cause pain comes from the therapeutic use of anti-GD2 antibodies in the treatment of neuroblastoma. Neuropathic pain is an extremely common side effect of anti-GD2 antibody treatment, so much so that opioids are typically given at the time of injection (Anghelescu et al., 2015). Application of these antibodies to animal models further highlights their pathogenicity; they are able to cause neuropathic pain-like behaviors and increase the excitability of nociceptive fibers (Slart, Yu, Yaksh, & Sorkin, 1997; Xiao et al., 1997).
Prevalence of Autoantibody-Mediated Neuropathic Pain, the Relevance to Neuropathic Pain Generally, and Insights for Future Therapies
Of the conditions discussed, all are rare. Therefore, one might question the significance of autoantibody-mediated mechanisms in terms of patients with neuropathic pain as a whole. IVIg has been reported in a small case series to be successful in treating pain across a variety of neuropathic pain conditions (e.g., postherpetic neuralgia, trigeminal neuralgia, and traumatic nerve injury) (Goebel et al., 2002), indicating that autoantibodies might well play a more widespread role in neuropathic pain than currently believed.
Screening of patients with neuropathic pain for autoantibody involvement may help to provide information on the prevalence of this mechanism in neuropathic pain, and a recent study has used this approach. The authors used pain-relevant mouse tissue (DRG and spinal cord) as a screening platform and assayed patient serum for binding of human IgG. Using sera from control patients, no immunoreactivity was seen. However, 10% of serum from patients with neuropathic pain showed a distinct pattern of IgG binding to small DRG neurons (positive for nociceptive markers, Isolectin-B4 , Calcitonin gene-related peptide , TRPV1, and P2X purinoceptor 3) and their terminals in the dorsal horn of the spinal cord. Neurological conditions included myelitis as well as erythromelalgia (without a causal mutation in SCN9A (sodium voltage-gated channel alpha subunit 9), SCN10A, SCN11A or TRPA1 (transient receptor potential cation subfamily A member 1)), suggestive of a wider role for autoantibodies in neuropathic pain. Importantly, the IgG binding looked membranous (i.e., would be able to target the antigen in vivo), and the antigen was subsequently identified as a type I transmembrane protein known as Plexin-D1. Treatment of mouse DRG neurons in vitro suggested direct pathological effects, although the causal role of Plexin-D1 autoantibodies regarding pain is yet to be tested (Fujii et al., 2018). This study is important as it showed the utility of this screening method in both recognizing potential pathogenic autoantibody involvement and target identification and paves the way for future studies and a better understanding of the relevance of autoantibodies to neuropathic pain in general.
Of course a lot can be learned from rare pain conditions in terms of both mechanistic insight and identification of potential therapeutic targets. For example, loss of function mutations in SCN9A led to congenital insensitivity to pain (Cox et al., 2006), an extremely rare condition but one that has pointed the pain field to the importance of this single sodium channel subunit in pain signaling. It is the focus of numerous drug development programs. Although in general autoantibody targets in GBS might be most important in contributing to disease pathology by aiming inflammation to the peripheral nerve, it is also possible these targets are more directly related to the development of neuropathic pain. For example, in a rodent model of traumatic nerve injury, treatment with gangliosides attenuated neuropathic pain behaviors independent of autoimmunity, suggestive of a role for gangliosides in pain processing (Hayes et al., 1992).
A number of nodal targets have been identified in GBS and CIDP. This might just be a reflection of antigen accessibility, but it could also point to the node itself as an important neuronal compartment in terms of neuropathic pain development. For instance, in animal models of traumatic nerve injury, disruption of nodal structures was correlated with spontaneous primary afferent activity and pain behavior (Calvo et al., 2016). This is also true clinically in patients with Morton neuroma, and nodal changes have also been observed in patients with other entrapment neuropathies, such as carpal tunnel syndrome, where neuropathic pain is highly prevalent (Schmid, Bland, Bhat, & Bennett, 2014). Therefore, treatments aimed at stabilizing nodal structures, potentially through the manipulation of pathways involving autoantibody targets, could be useful for patients with neuropathic pain. Furthermore, it has been suggested that CASPR can interact with ion channels (Nie et al., 2003); therefore, autoantibodies targeting CASPR may directly affect neuronal excitability.
The study of VGKCC-Abs in this context is particularly exciting because the targets are clearly linked to ion channels and can therefore directly regulate neuronal excitability. This concept is supported by the study of CASPR2-Abs, which reduce Kv1 channel function in DRG neurons, leading to their increased excitability and neuropathic pain-like behavior in mice (Dawes et al., 2018). This raises the intriguing idea that disruption of CASPR2 is sufficient to cause neuropathic pain in patients. If the mode of action of CASPR2-Abs is truly independent of inflammation or nerve damage, and therefore CASPR2 has an important pain-specific role in sensory neurons, disruption of CASPR2 by another means should also result in neuronal excitability and pain. Indeed, this is the case; for example, genetic ablation of CASPR2 also reduces Kv1 channel function in sensory neurons and increases pain-related behavior in mice. These data indicate that CASPR2 represents an important intrinsic molecular component regulating the excitability of sensory neurons and further highlights the importance of Kv1 channels in neuropathic pain. Because neuronal hyperexcitability, particularly at the level of the DRG, is a characteristic feature of many neuropathic pain conditions, these findings suggest that therapeutically targeting CASPR2 might represent a viable treatment strategy. In line with this idea, overexpression of CASPR2 in vitro reduces the excitability of mouse sensory neurons and opens up the possibility of using this approach to reduce the excitability of these neurons and therefore treat neuropathic pain in the more general context. Further study of the other VGKCC-Ab targets will lend weight to the importance of this complex in neuropathic pain generally and also give further insights into the molecular mechanisms regulating sensory neuron excitability.
It is becoming apparent that autoantibodies contribute to neuropathic pain in a range of neurological conditions. In some cases, these autoantibodies clearly evoke injury (e.g., GBS or transverse myelitis); in others, they appear to directly regulate excitability of the sensory nervous system. There are immunotherapies that can reduce autoantibody levels, and confirmation that these autoantibodies are causal to pain will improve analgesic treatment strategies for these patients. For example, in patients with VGKCC-Ab, the effectiveness of immunotherapy in reducing pain has lessened the need for opioid treatment, resulting in a reprieve from the harmful side effects of narcotics and better pain management (Gadoth et al., 2017). An improved understanding of the prevalence of autoantibodies is needed and may provide an explanation for certain idiopathic pain conditions. Moreover, the work on autoantibodies can be used as a tool to provide insight into clinically relevant mechanisms controlling pain sensitivity in the more general context and help steer the future development of therapies to treat neuropathic pain.
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