0-28

The Oxford Handbook of the Neurobiology of Pain
John N. Wood (ed.)
https://doi.org/10.1093/oxfordhb/9780190860509.001.0001
Published: 2018 Online ISBN: 9780190860530 Print ISBN: 9780190860509
CHAPTER
Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

28 Autoantibodies and Neuropathic Pain 
John M. Dawes, David L. Bennett
https://doi.org/10.1093/oxfordhb/9780190860509.013.16 Pages 833–850

Published: 06 November 2019
Abstract
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
in ammation 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
Subject: Sensory and Motor Systems, Molecular and Cellular Systems, Neuroscience
Series: Oxford Handbooks
Collection: Oxford Handbooks Online
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
in ltration 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 in ammatory 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 in ammation. However, there are examples where autoantibodies and knee pain are present without
obvious signs of in ammation prior to the full development of arthritis. These observations are suggestive
of a more pain-speci c role for autoantibodies, and studies have shown that autoantibodies from patients

with rheumatoid arthritis can induce pain-related behavior in mice independent of in ammation
(Wigerblad et al., 2016). These ndings 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
p. 834 28.1), 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 in ammation to the nervous tissue,
and perhaps most intriguingly directly disrupting neuronal function without any gross neuronal damage or
in ammation. The exact mechanism will be in uenced 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 o er 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.
Figure 28.1.

Autoantibodies can target the pain pathway at multiple levels: Autoantibodies (blue) can damage the sensory nervous system by
activation of immune cells or through complement fixation, such as in Guillain-Barré syndrome (GBS) and chronic inflammatory
demyelinating polyneuropathy (CIDP). Autoantibodies (green) can also directly disrupt neuronal function and activity through
internalization of targets that interact with ion channels, such as those targeting the voltage-gated potassium channel complex
(VGKCC). As well as the peripheral nerve, autoantibodies can act centrally and target nonneuronal cells (e.g., astrocytes) in pain
conditions such as neuromyelitis optica (NMO).
p. 835
Inflammatory Neuropathies
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 rst-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 “nonspeci c” 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 a erent 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 bers are also targeted in GBS, and studies have found a reduction in
epidermal nerve ber density (Pan et al., 2003), with dysfunction of these bers associated with
neuropathic pain (Martinez et al., 2010). Indeed, a variant of GBS has been described in which there is
selective loss of small bers with minimal motor involvement. These patients have neuropathic pain that is
p. 836 responsive to IVIg. Use of patient sera showed antibody binding to small bers 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 speci c 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 identi ed (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 pro le 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 in ammatory 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
con ned to the a ected 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, &
p. 837 Sprotte, 2002), which was subsequently supported by a small clinical trial (Goebel et al., 2010). However,
a recent larger study failed to show clear e cacy 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 e ective 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
di erences, but these ndings 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 e ective 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 identi ed. 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 a ected 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-speci c neurons would provide insight into whether CRPS
autoantibodies target this system. To this end, a recent study suggested that puri ed IgG from patients with
CRPS can alter the function of DRG neurons in vitro, albeit in the presence of in ammatory 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-speci c” antigens are
involved.
Fibromyalgia
Fibromyalgia is a chronic condition characterized by widespread pain as well as fatigue and muscle
sti ness. 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 bromyalgia have reduced epidermal
nerve ber density (Üçeyler et al., 2013) and small- ber dysfunction (Serra et al., 2014). Again, the
p. 838 pathophysiological mechanisms causing these changes are not clear, but these ndings do point to
peripheral nerve damage and excitability changes in nociceptors as contributing to pain in patients with
bromyalgia.
Although typically not considered an autoimmune syndrome, bromyalgia 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 bromyalgia. For example, some patients
with bromyalgia 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 bromyalgia
(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 bromyalgia will be

greatly facilitated by identi cation of the target and immunotherapy given as part of carefully conducted
trials, but still current preliminary ndings point toward the potential of autoantibodies as an explanation
for pathological pain in patients with bromyalgia
Neuromyelitis Optica
Neuromyelitis optica (NMO) is an autoimmune disease characterized by in ammation 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 signi cantly 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
p. 839 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 signi cant 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 su cient 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 speci c 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).
p. 840 In general, patients who are VGKCC-Ab positive do not have signs of in ammation 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 in ammatory 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 bers. These proteins interact with Kv1 channels to form a
protein complex and are crucial for the correct localization of Kv1 channels in myelinated bers 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.
p. 841
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. However, some would dispute this as
de nitive 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 puri ed for
such experimental studies. Systemic administration of puri ed 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 in ammation or neuronal damage (in line with clinical ndings). 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 puri ed 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 e ect
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 re ecting 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 a ected 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 of the super cial spinal cord (Helyes et al 2019). In addition, pain
behavior in mouse fracture/cast models of CRPS seem to be B-cell dependent, mouse autoantibody targets
have been identi ed, and these pain behaviors can be passively transferred to control mice (Guo et al., 2017;
p. 842 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 signi cant 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 e ect 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 bers (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 signi cance 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
p. 843 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 identi ed
as a type I transmembrane protein known as Plexin-D1. Treatment of mouse DRG neurons in vitro
suggested direct pathological e ects, 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 identi cation 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
identi cation of potential therapeutic targets. For example, loss of function mutations in SCN9A lead to
congenital insensitivity to pain (Cox et al., 2006), an extremely rare condition but one that has pointed the
pain eld to the importance of this single sodium channel subunit in pain signaling, and 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 in ammation 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 identi ed in GBS and CIDP. This might just be a re ection 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 a erent 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
a ect 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 su cient to cause neuropathic pain in patients. If the mode of action of CASPR2-Abs is truly
independent of in ammation or nerve damage, and therefore CASPR2 has an important pain-speci c role
in sensory neurons, disruption of CASPR2 by another means should also result in neuronal excitability and
p. 844 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
ndings 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.
Summary
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 con rmation that these autoantibodies are
causal to pain will improve analgesic treatment strategies for these patients. For example, in patients with
VGKCC-Ab, the e ectiveness of immunotherapy in reducing pain has lessened the need for opioid
treatment, resulting in a reprieve from the harmful side e ects 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.
References
Anghelescu, D. L., Goldberg, J. L., Faughnan, L. G., Wu, J., Mao, S., Furman, W. L., … Navid, F. (2015). Comparison of pain
outcomes between two anti-GD2 antibodies in patients with neuroblastoma. Pediatric Blood & Cancer, 62(2), 224–228.
doi:10.1002/pbc.25280 10.1002/pbc.25280
Google Scholar WorldCat Crossref
Aradillas, E., Schwartzman, R. J., Grothusen, J. R., Goebel, A., & Alexander, G. M. (2015). Plasma exchange therapy in patients with
complex regional pain syndrome. Pain Physician, 18(4), 383–394. Retrieved from
http://www.ncbi.nlm.nih.gov/pubmed/26218942

Google Scholar WorldCat
Araki, M., Aranami, T., Matsuoka, T., Nakamura, M., Miyake, S., & Yamamura, T. (2013). Clinical improvement in a patient with
p. 845 neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab. Modern Rheumatology,
23(4), 827–831. doi:10.1007/s10165-012-0715-9 10.1007/s10165-012-0715-9
Crossref
Barry, A. M., Sondermann, J. R., Sondermann, J.-H., Gomez-Varela, D., & Schmidt, M. (2018). Region-resolved quantitative
proteome profiling reveals molecular dynamics associated with chronic pain in the PNS and spinal cord. Frontiers in Molecular
Neuroscience, 11, 259. doi:10.3389/fnmol.2018.00259 10.3389/fnmol.2018.00259
Bhangoo, S., Ren, D., Miller, R. J., Henry, K. J., Lineswala, J., Hamdouchi, C., … White, F. A. (2007). Delayed functional expression
of neuronal chemokine receptors following focal nerve demyelination in the rat: A mechanism for the development of chronic
sensitization of peripheral nociceptors. Molecular Pain, 3, 38. doi:10.1186/1744-8069-3-38 10.1186/1744-8069-3-38
Binks, S., Varley, J., Lee, W., Makuch, M., Elliott, K., Gelfand, J. M., … Irani, S. R. (2018). Distinct HLA associations of LGI1 and
CASPR2-antibody diseases. Brain, 141(8), 2263–2271. doi:10.1093/brain/awy109 10.1093/brain/awy109
Blaes, F., Dharmalingam, B., Tschernatsch, M., Feustel, A., Fritz, T., Kohr, D., … Szalay, G. (2015). Improvement of complex
regional pain syndrome a er plasmapheresis. European Journal of Pain (London, England), 19(4), 503–507.
doi:10.1002/ejp.572 10.1002/ejp.572
Calvo, M., Dawes, J. M., & Bennett, D. L. H. (2012). The role of the immune system in the generation of neuropathic pain. The
Lancet Neurology, 12(7), 629–642.
Calvo, M., Richards, N., Schmid, A. B., Barroso, A., Zhu, L., Ivulic, D., … Bennett, D. L. H. (2016). Altered potassium channel
distribution and composition in myelinated axons suppresses hyperexcitability following injury. ELife, 5(April 1).
doi:10.7554/eLife.12661 10.7554/eLife.12661
WorldCat Crossref
Caro, X. J., Winter, E. F., & Dumas, A. J. (2008). A subset of fibromyalgia patients have findings suggestive of chronic inflammatory
demyelinating polyneuropathy and appear to respond to IVIg. Rheumatology (Oxford, England), 47(2), 208–211.
doi:10.1093/rheumatology/kem345 10.1093/rheumatology/kem345
Choi, B. Y., Oh, H. J., Lee, Y. J., & Song, Y. W. (2016). Prevalence and clinical impact of fibromyalgia in patients with primary
Sjögrenʼs syndrome. Clinical and Experimental Rheumatology, 34(2, Suppl. 96), S9–S13. Retrieved from
Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., … Woods, C. G. (2006). An SCN9A channelopathy
causes congenital inability to experience pain. Nature, 444(7121), 894–898. doi:10.1038/nature05413 10.1038/nature05413
Dawes, J. M., Weir, G. A., Middleton, S. J., Patel, R., Chisholm, K. I., Pettingill, P., … Bennett, D. L. (2018). Immune or genetic-
mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary a erent excitability. Neuron, 97(4), 806–
822.e10. doi:10.1016/j.neuron.2018.01.033 10.1016/j.neuron.2018.01.033
Devaux, J. J., Odaka, M., & Yuki, N. (2012). Nodal proteins are target antigens in Guillain-Barré syndrome. Journal of the
Peripheral Nervous System, 17(1), 62–71. doi:10.1111/j.1529-8027.2012.00372.x 10.1111/j.1529-8027.2012.00372.x

Dinerman, H., Goldenberg, D. L., & Felson, D. T. (1986). A prospective evaluation of 118 patients with the fibromyalgia syndrome:
Prevalence of Raynaudʼs phenomenon, sicca symptoms, ANA, low complement, and Ig deposition at the dermal-epidermal
junction. The Journal of Rheumatology, 13(2), 368–373. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3487650
Doppler, K., Appeltshauser, L., Villmann, C., Martin, C., Peles, E., Krämer, H. H., … Sommer, C. (2016). Auto-antibodies to
contactin-associated protein 1 (Caspr) in two patients with painful inflammatory neuropathy. Brain, 139(10), 2617–2630.
doi:10.1093/brain/aww189 10.1093/brain/aww189
p. 846 Dubuis, E., Thompson, V., Leite, M. I., Blaes, F., Maihöfner, C., Greensmith, D., … Goebel, A. (2014). Longstanding complex
regional pain syndrome is associated with activating autoantibodies against alpha-1a adrenoceptors. Pain, 155(11), 2408–2417.
doi:10.1016/j.pain.2014.09.022 10.1016/j.pain.2014.09.022
Fujii, T., Yamasaki, R., Iinuma, K., Tsuchimoto, D., Hayashi, Y., Saitoh, B.-Y., … Kira, J.-I. (2018). A novel autoantibody against
plexin D1 in patients with neuropathic pain. Annals of Neurology, 84(2), 208–224. doi:10.1002/ana.25279 10.1002/ana.25279
Gadoth, A., Pittock, S. J., Dubey, D., McKeon, A., Britton, J. W., Schmeling, J. E., … Klein, C. J. (2017). Expanded phenotypes and
outcomes among 256 LGI1/CASPR2-IgG positive patients. Annals of Neurology, 82(1), 79–92.
doi:10.1002/ana.24979 10.1002/ana.24979
Goebel, A., Baranowski, A., Maurer, K., Ghiai, A., McCabe, C., & Ambler, G. (2010). Intravenous immunoglobulin treatment of the
complex regional pain syndrome: A randomized trial. Annals of Internal Medicine, 152(3), 152–158. doi:10.7326/0003-4819-152-3-
201002020-00006 10.7326/0003-4819-152-3-201002020-00006
Goebel, A., Bisla, J., Carganillo, R., Frank, B., Gupta, R., Kelly, J., … Ambler, G. (2017). Low-dose intravenous immunoglobulin
treatment for long-standing complex regional pain syndrome. Annals of Internal Medicine, 167(7), 476. doi:10.7326/M17-
0509 10.7326/M17-0509
Goebel, A., Leite, M. I., Yang, L., Deacon, R., Cendan, C. M., Fox-Lewis, A., & Vincent, A. (2011). The passive transfer of
immunoglobulin G serum antibodies from patients with longstanding complex regional pain syndrome. European Journal of
Pain (London, England), 15(5), 504.e1–504.e6. doi:10.1016/j.ejpain.2010.10.005 10.1016/j.ejpain.2010.10.005
Goebel, A., Moore, A. P., & Jacob, A. (2018). Delayed onset of severe chronic pain in CASPR2 autoantibody-associated Morvan
syndrome in a former UK swine abattoir worker. Pain Reports, 3(5), e675.
doi:10.1097/PR9.0000000000000675 10.1097/PR9.0000000000000675
Goebel, A., Netal, S., Schedel, R., & Sprotte, G. (2002). Human pooled immunoglobulin in the treatment of chronic pain
syndromes. Pain Medicine (Malden, MA), 3(2), 119–127. doi:10.1046/j.1526-4637.2002.02018.x 10.1046/j.1526-4637.2002.02018.x
Gong, Y., Tagawa, Y., Lunn, M. P. T., Laroy, W., He er-Lauc, M., Li, C. Y., … Sheikh, K. A. (2002). Localization of major gangliosides in
the PNS: Implications for immune neuropathies. Brain, 125(Pt. 11), 2491–2506. Retrieved from

Guo, T.-Z., Shi, X., Li, W.-W., Wei, T., Clark, J. D., & Kingery, W. S. (2017). Passive transfer autoimmunity in a mouse model of
complex regional pain syndrome. Pain, 158(12), 2410–2421.
doi:10.1097/j.pain.0000000000001046 10.1097/j.pain.0000000000001046
Hao, J., Padilla, F., Dandonneau, M., Lavebratt, C., Lesage, F., Noël, J., & Delmas, P. (2013). Kv1.1 channels act as mechanical
brake in the senses of touch and pain. Neuron, 77(5), 899–914. doi:10.1016/j.neuron.2012.12.035 10.1016/j.neuron.2012.12.035
Hartung, H.-P. (2008). Advances in the understanding of the mechanism of action of IVIg. Journal of Neurology, 255(S3), 3–6.
doi:10.1007/s00415-008-3002-0 10.1007/s00415-008-3002-0
Hayashida, K.-I., Bynum, T., Vincler, M., & Eisenach, J. C. (2006). Inhibitory M2 muscarinic receptors are upregulated in both
axotomized and intact small diameter dorsal root ganglion cells a er peripheral nerve injury. Neuroscience, 140(1), 259–268.
doi:10.1016/j.neuroscience.2006.02.013 10.1016/j.neuroscience.2006.02.013
Hayes, R. L., Mao, J., Price, D. D., Germano, A., dʼAvella, D., Fiori, M., & Mayer, D. J. (1992). Pretreatment with gangliosides reduces
abnormal nociceptive responses associated with a rodent peripheral mononeuropathy. Pain, 48(3), 391–396. Retrieved from
p. 847 He, L., Zhang, G., Liu, W., Gao, T., & Sheikh, K. A. (2015). Anti-ganglioside antibodies induce nodal and axonal injury via Fcγ
receptor-mediated inflammation. The Journal of Neuroscience: The O icial Journal of the Society for Neuroscience, 35(17), 6770–
6785. doi:10.1523/JNEUROSCI.4926-14.2015 10.1523/JNEUROSCI.4926-14.2015
Crossref
Helyes, Z., Tekus, V., Szentes, N., Pohoczky, K., Botz, B., Kiss, T., Kemeny, A., … Goebel, A. (2019). Transfer of complex regional
pain syndrome to mice via human autoantibodies is mediated by interleukin-1-induced mechanisms. PNAS, 116(26), 13067–
13076.
Hillebrand, S., Schanda, K., Nigritinou, M., Tsymala, I., Böhm, D., Peschl, P., … Bradl, M. (2019). Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat. Acta Neuropathologica, 138(3), 467–485.
doi:10.1007/s00401-018-1950-8 10.1007/s00401-018-1950-8
Irani, S. R., Alexander, S., Waters, P., Kleopa, K. A., Pettingill, P., Zuliani, L., … Vincent, A. (2010). Antibodies to Kv1 potassium
channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis,
Morvanʼs syndrome and acquired neuromyotonia. Brain, 133(9), 2734–2748. doi:10.1093/brain/awq213 10.1093/brain/awq213
Irani, S. R., Pettingill, P., Kleopa, K. A., Schiza, N., Waters, P., Mazia, C., … Vincent, A. (2012). Morvan syndrome: Clinical and
serological observations in 29 cases. Annals of Neurology, 72(2), 241–255. doi:10.1002/ana.23577 10.1002/ana.23577
Ji, R.-R., Berta, T., & Nedergaard, M. (2013). Glia and pain: Is chronic pain a gliopathy? Pain, 154(Suppl.), S10–S28.
doi:10.1016/j.pain.2013.06.022 10.1016/j.pain.2013.06.022
Kaida, K., Ariga, T., & Yu, R. K. (2009). Antiganglioside antibodies and their pathophysiological e ects on Guillain-Barre syndrome
and related disorders—A review. Glycobiology, 19(7), 676–692. doi:10.1093/glycob/cwp027 10.1093/glycob/cwp027

Kato, J., Takai, Y., Hayashi, M. K., Kato, Y., Tanaka, M., Sohma, Y., … Yasui, M. (2014). Expression and localization of aquaporin-4 in
sensory ganglia. Biochemical and Biophysical Research Communications, 451(4), 562–567.
doi:10.1016/j.bbrc.2014.08.026 10.1016/j.bbrc.2014.08.026
Kinoshita, M., Nakatsuji, Y., Kimura, T., Moriya, M., Takata, K., Okuno, T., … Sakoda, S. (2009). Neuromyelitis optica: Passive
transfer to rats by human immunoglobulin. Biochemical and Biophysical Research Communications, 386(4), 623–627.
doi:10.1016/j.bbrc.2009.06.085 10.1016/j.bbrc.2009.06.085
Klein, C. J., Lennon, V. A., Aston, P. A., McKeon, A., OʼToole, O., Quek, A., & Pittock, S. J. (2013). Insights From LGI1 and CASPR2
potassium channel complex autoantibody subtyping. JAMA Neurology, 70(2), 229.
doi:10.1001/jamaneurol.2013.592 10.1001/jamaneurol.2013.592
Klein, C. J., Lennon, V. A., Aston, P. A., McKeon, A., & Pittock, S. J. (2012). Chronic pain as a manifestation of potassium channel-
complex autoimmunity. Neurology, 79(11), 1136–1144. doi:10.1212/WNL.0b013e3182698cab 10.1212/WNL.0b013e3182698cab
Kohr, D., Singh, P., Tschernatsch, M., Kaps, M., Pouokam, E., Diener, M., … Blaes, F. (2011). Autoimmunity against the β2
adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome. Pain, 152(12), 2690–2700.
doi:10.1016/j.pain.2011.06.012 10.1016/j.pain.2011.06.012
Crossref
Lahoria, R., Pittock, S. J., Gadoth, A., Engelstad, J. K., Lennon, V. A., & Klein, C. J. (2017). Clinical-pathologic correlations in
voltage-gated Kv1 potassium channel complex-subtyped autoimmune painful polyneuropathy. Muscle & Nerve, 55(4), 520–525.
doi:10.1002/mus.25371 10.1002/mus.25371
Lancaster, E., Huijbers, M. G. M., Bar, V., Boronat, A., Wong, A., Martinez-Hernandez, E., … Dalmau, J. (2011). Investigations of
caspr2, an autoantigen of encephalitis and neuromyotonia. Annals of Neurology, 69(2), 303–311.
doi:10.1002/ana.22297 10.1002/ana.22297
Lennon, V. A., Kryzer, T. J., Pittock, S. J., Verkman, A. S., & Hinson, S. R. (2005). IgG marker of optic-spinal multiple sclerosis binds
to the aquaporin-4 water channel. The Journal of Experimental Medicine, 202(4), 473–477.
doi:10.1084/jem.20050304 10.1084/jem.20050304
p. 848 Li, W.-W., Guo, T.-Z., Shi, X., Czirr, E., Stan, T., Sahbaie, P., … Clark, D. J. (2014). Autoimmunity contributes to nociceptive
sensitization in a mouse model of complex regional pain syndrome. Pain, 155(11), 2377–2389.
doi:10.1016/j.pain.2014.09.007 10.1016/j.pain.2014.09.007
Martinez, V., Fletcher, D., Martin, F., Orlikowski, D., Sharshar, T., Chauvin, M., … Attal, N. (2010). Small fibre impairment predicts
neuropathic pain in Guillain–Barré syndrome. Pain, 151(1), 53–60. doi:10.1016/j.pain.2010.05.017 10.1016/j.pain.2010.05.017
McMahon, S. B., La Russa, F., & Bennett, D. L. H. (2015). Crosstalk between the nociceptive and immune systems in host defence
and disease. Nature Reviews. Neuroscience, 16(7), 389–402. doi:10.1038/nrn3946 10.1038/nrn3946
Meeusen, J. W., Klein, C. J., Pirko, I., Haselkorn, K. E., Kryzer, T. J., Pittock, S. J., … Lennon, V. A. (2012). Potassium channel
complex autoimmunity induced by inhaled brain tissue aerosol. Annals of Neurology, 71(3), 417–426.
doi:10.1002/ana.22674 10.1002/ana.22674

Middleton, G. D., McFarlin, J. E., & Lipsky, P. E. (1994). The prevalence and clinical impact of fibromyalgia in systemic lupus
erythematosus. Arthritis and Rheumatism, 37(8), 1181–1188. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8053957
Moulin, D. E., Hagen, N., Feasby, T. E., Amireh, R., & Hahn, A. (1997). Pain in Guillain-Barré syndrome. Neurology, 48(2), 328–331.
Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9040715
Nakajima, H., Motomura, M., Tanaka, K., Fujikawa, A., Nakata, R., Maeda, Y., … Tsujino, A. (2015). Antibodies to myelin
oligodendrocyte glycoprotein in idiopathic optic neuritis. BMJ Open, 5(4), e007766. doi:10.1136/bmjopen-2015-
007766 10.1136/bmjopen-2015-007766
Nie, D.-Y., Zhou, Z.-H., Ang, B.-T., Teng, F. Y. H., Xu, G., Xiang, T., … Xiao, Z.-C. (2003). Nogo-A at CNS paranodes is a ligand of Caspr:
+
Possible regulation of K channel localization. The EMBO Journal, 22(21), 5666–5678.
doi:10.1093/emboj/cdg570 10.1093/emboj/cdg570
Crossref
Nytrova, P., Potlukova, E., Kemlink, D., Woodhall, M., Horakova, D., Waters, P., … Trendelenburg, M. (2014). Complement
activation in patients with neuromyelitis optica. Journal of Neuroimmunology, 274(1–2), 185–191.
doi:10.1016/j.jneuroim.2014.07.001 10.1016/j.jneuroim.2014.07.001
Ohkawa, T., Fukata, Y., Yamasaki, M., Miyazaki, T., Yokoi, N., Takashima, H., … Fukata, M. (2013). Autoantibodies to epilepsy-
related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. The Journal of
Neuroscience: The O icial Journal of the Society for Neuroscience, 33(46), 18161–18174. doi:10.1523/JNEUROSCI.3506-
13.2013 10.1523/JNEUROSCI.3506-13.2013
Ohsawa, T., Miyatake, T., & Yuki, N. (1993). Anti-B-series ganglioside-recognizing autoantibodies in an acute sensory neuropathy
patient cause cell death of rat dorsal root ganglion neurons. Neuroscience Letters, 157(2), 167–170. Retrieved from
Pan, C.-L., Tseng, T.-J., Lin, Y.-H., Chiang, M.-C., Lin, W.-M., & Hsieh, S.-T. (2003). Cutaneous innervation in Guillain-Barré
syndrome: Pathology and clinical correlations. Brain, 126(Pt. 2), 386–397. Retrieved from
Petit-Pedrol, M., Sell, J., Planagumà, J., Mannara, F., Radosevic, M., Haselmann, H., … Geis, C. (2018). LGI1 antibodies alter Kv1.1
and AMPA receptors changing synaptic excitability, plasticity and memory. Brain, 141(11), 3144–3159.
doi:10.1093/brain/awy253 10.1093/brain/awy253
Poliak, S., Salomon, D., Elhanany, H., Sabanay, H., Kiernan, B., Pevny, L., … Peles, E. (2003). Juxtaparanodal clustering of Shaker-
+
like K channels in myelinated axons depends on Caspr2 and TAG-1. Journal of Cell Biology, 162(6), 1149–1160.
doi:10.1083/jcb.200305018 10.1083/jcb.200305018
Crossref
Qian, P., Lancia, S., Alvarez, E., Klawiter, E. C., Cross, A. H., & Naismith, R. T. (2012). Association of neuromyelitis optica with
severe and intractable pain. Archives of Neurology, 69(11), 1482. doi:10.1001/archneurol.2012.768 10.1001/archneurol.2012.768

p. 849 Querol, L., Devaux, J., Rojas-Garcia, R., & Illa, I. (2017). Autoantibodies in chronic inflammatory neuropathies: Diagnostic and
therapeutic implications. Nature Reviews. Neurology, 13(9), 533–547. doi:10.1038/nrneurol.2017.84 10.1038/nrneurol.2017.84
Ray, P., Torck, A., Quigley, L., Wangzhou, A., Neiman, M., Rao, C., … Price, T. J. (2018). Comparative transcriptome profiling of the
human and mouse dorsal root ganglia: An RNA-seq-based resource for pain and sensory neuroscience research. Pain, 159(7),
1325–1345. doi:10.1097/j.pain.0000000000001217 10.1097/j.pain.0000000000001217
Reilly, J. M., Dharmalingam, B., Marsh, S. J., Thompson, V., Goebel, A., & Brown, D. A. (2016). E ects of serum immunoglobulins
from patients with complex regional pain syndrome (CRPS) on depolarisation-induced calcium transients in isolated dorsal root
ganglion (DRG) neurons. Experimental Neurology, 277, 96–102.
doi:10.1016/j.expneurol.2015.12.009 10.1016/j.expneurol.2015.12.009
Rinaldi, S., Brennan, K. M., Kalna, G., Walgaard, C., van Doorn, P., Jacobs, B. C., … Willison, H. J. (2013). Antibodies to heteromeric
glycolipid complexes in Guillain-Barré syndrome. PLoS One, 8(12), e82337.
doi:10.1371/journal.pone.0082337 10.1371/journal.pone.0082337
Ringelstein, M., Ayzenberg, I., Harmel, J., Lauenstein, A.-S., Lensch, E., Stögbauer, F., … Kleiter, I. (2015). Long-term therapy with
interleukin 6 receptor blockade in highly active neuromyelitis optica spectrum disorder. JAMA Neurology, 72(7), 756–763.
doi:10.1001/jamaneurol.2015.0533 10.1001/jamaneurol.2015.0533
Schmid, A. B., Bland, J. D. P., Bhat, M. A., & Bennett, D. L. H. (2014). The relationship of nerve fibre pathology to sensory function
in entrapment neuropathy. Brain, 137(12), 3186–3199. doi:10.1093/brain/awu288 10.1093/brain/awu288
Schulte, U., Thumfart, J.-O., Klöcker, N., Sailer, C. A., Bildl, W., Biniossek, M., … Fakler, B. (2006). The epilepsy-linked Lgi1 protein
assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1. Neuron, 49(5), 697–706.
doi:10.1016/j.neuron.2006.01.033 10.1016/j.neuron.2006.01.033
Seagar, M., Russier, M., Caillard, O., Maulet, Y., Fronzaroli-Molinieres, L., De San Feliciano, M., … El Far, O. (2017). LGI1 tunes
intrinsic excitability by regulating the density of axonal Kv1 channels. Proceedings of the National Academy of Sciences of the
United States of America, 114(29), 7719–7724. doi:10.1073/pnas.1618656114 10.1073/pnas.1618656114
Serra, J., Collado, A., Solà, R., Antonelli, F., Torres, X., Salgueiro, M., … Bostock, H. (2014). Hyperexcitable C nociceptors in
fibromyalgia. Annals of Neurology, 75(2), 196–208. doi:10.1002/ana.24065 10.1002/ana.24065
Slart, R., Yu, A. L., Yaksh, T. L., & Sorkin, L. S. (1997). An animal model of pain produced by systemic administration of an
immunotherapeutic anti-ganglioside antibody. Pain, 69(1–2), 119–125. Retrieved from
Strong, J. A., Zhang, J.-M., & Schaible, H.-G. (2018). The sympathetic nervous system and pain. In J. N. Wood (Ed.), The Oxford
Handbook of the Neurobiology of Pain. Oxford, England: Oxford University Press.
doi:10.1093/oxfordhb/9780190860509.013.6 10.1093/oxfordhb/9780190860509.013.6
Google Scholar Google Preview WorldCat COPAC Crossref
Susuki, K., Yuki, N., Schafer, D. P., Hirata, K., Zhang, G., Funakoshi, K., & Rasband, M. N. (2012). Dysfunction of nodes of Ranvier: A
mechanism for anti-ganglioside antibody-mediated neuropathies. Experimental Neurology, 233(1), 534–542.

Tajerian, M., Hung, V., Khan, H., Lahey, L. J., Sun, Y., Birklein, F., … Clark, J. D. (2017). Identification of KRT16 as a target of an
autoantibody response in complex regional pain syndrome. Experimental Neurology, 287(Pt. 1), 14–20.
Takada, K., Shimizu, J., & Kusunoki, S. (2008). Apoptosis of primary sensory neurons in GD1b-induced sensory ataxic neuropathy.
Experimental Neurology, 209(1), 279–283. doi:10.1016/j.expneurol.2007.09.010 10.1016/j.expneurol.2007.09.010
p. 850 Tékus, V., Hajna, Z., Borbély, É., Markovics, A., Bagoly, T., Szolcsányi, J., … Goebel, A. (2014). A CRPS-IgG-transfer-trauma model
reproducing inflammatory and positive sensory signs associated with complex regional pain syndrome. Pain, 155(2), 299–308.
doi:10.1016/j.pain.2013.10.011 10.1016/j.pain.2013.10.011
Üçeyler, N., Zeller, D., Kahn, A.-K., Kewenig, S., Kittel-Schneider, S., Schmid, A., … Sommer, C. (2013). Small fibre pathology in
patients with fibromyalgia syndrome. Brain, 136(6), 1857–1867. doi:10.1093/brain/awt053 10.1093/brain/awt053
van Doorn, P. A., Ruts, L., & Jacobs, B. C. (2008). Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome. The
Lancet Neurology, 7(10), 939–950. doi:10.1016/S1474-4422(08)70215-1 10.1016/S1474-4422(08)70215-1
van Sonderen, A., Ariño, H., Petit-Pedrol, M., Leypoldt, F., Körtvélyessy, P., Wandinger, K.-P., … Titulaer, M. J. (2016). The clinical
spectrum of Caspr2 antibody–associated disease. Neurology, 87(5), 521–528.
doi:10.1212/WNL.0000000000002917 10.1212/WNL.0000000000002917
van Sonderen, A., Schreurs, M. W. J., de Bruijn, M. A. A. M., Boukhrissi, S., Nagtzaam, M. M. P., Hulsenboom, E. S. P., …
Titulaer, M. J. (2016). The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology, 86(18), 1692–
1699. doi:10.1212/WNL.0000000000002637 10.1212/WNL.0000000000002637
Vincent, A., Pettingill, P., Pettingill, R., Lang, B., Birch, R., Waters, P., … Kiernan, M. C. (2018). Association of leucine-rich glioma
inactivated protein 1, contactin-associated protein 2, and contactin 2 antibodies with clinical features and patient-reported pain
in acquired neuromyotonia. JAMA Neurology, 75(12), 1519. doi:10.1001/jamaneurol.2018.2681 10.1001/jamaneurol.2018.2681
Wigerblad, G., Bas, D. B., Fernades-Cerqueira, C., Krishnamurthy, A., Nandakumar, K. S., Rogoz, K., … Svensson, C. I. (2016).
Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism.
Annals of the Rheumatic Diseases, 75(4), 730–738. doi:10.1136/annrheumdis-2015-208094 10.1136/annrheumdis-2015-208094
Willison, H. J., Halstead, S. K., Beveridge, E., Zitman, F. M. P., Greenshields, K. N., Morgan, B. P., & Plomp, J. J. (2008). The role of
complement and complement regulators in mediating motor nerve terminal injury in murine models of Guillain-Barré
syndrome. Journal of Neuroimmunology, 201–202(Sep 15), 172–182.
doi:10.1016/j.jneuroim.2008.05.028 10.1016/j.jneuroim.2008.05.028
WorldCat Crossref
Wolfe, F., & Michaud, K. (2004). Severe rheumatoid arthritis (RA), worse outcomes, comorbid illness, and sociodemographic
disadvantage characterize ra patients with fibromyalgia. The Journal of Rheumatology, 31(4), 695–700. Retrieved from

Xiao, W. H., Yu, A. L., & Sorkin, L. S. (1997). Electrophysiological characteristics of primary a erent fibers a er systemic
administration of anti-GD2 ganglioside antibody. Pain, 69(1–2), 145–151. Retrieved from
Yuki, N., Chan, A. C., Wong, A. H. Y., Inoue, T., Yokai, M., Kurihara, T., … Wilder-Smith, E. (2018). Acute painful autoimmune
neuropathy: A variant of Guillain-Barré syndrome. Muscle & Nerve, 57(2), 320–324. doi:10.1002/mus.25738 10.1002/mus.25738
Zeisel, A., Hochgerner, H., Lönnerberg, P., Johnsson, A., Memic, F., van der Zwan, J., … Linnarsson, S. (2018). Molecular
architecture of the mouse nervous system. Cell, 174(4), 999–1014.e22. doi:10.1016/j.cell.2018.06.021 10.1016/j.cell.2018.06.021
Zhao, S., Mutch, K., Elsone, L., Nurmikko, T., & Jacob, A. (2014). Neuropathic pain in neuromyelitis optica a ects activities of daily
living and quality of life. Multiple Sclerosis (Houndmills, Basingstoke, England), 20(12), 1658–1661.
doi:10.1177/1352458514522103 10.1177/1352458514522103
Zhao, X., Tang, Z., Zhang, H., Atianjoh, F. E., Zhao, J.-Y., Liang, L., … Tao, Y.-X. (2013). A long noncoding RNA contributes to
neuropathic pain by silencing Kcna2 in primary a erent neurons. Nature Neuroscience, 16(8), 1024–1031.
doi:10.1038/nn.3438 10.1038/nn.3438

0-28

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

0-28

Uploaded by

Copyright:

Available Formats

The Oxford Handbook of the Neurobiology of Pain

John N. Wood (ed.)

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

https://doi.org/10.1093/oxfordhb/9780190860509.013.16 Pages 833–850

Keywords: neuropathic pain, autoantibodies, autoimmune pain, inflammatory neuropathy, neuromyelitis

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Neuromyelitis optica (NMO) is an autoimmune disease characterized by in ammation and degeneration of

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Prevalence of Autoantibody-Mediated Neuropathic Pain, the

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

It is becoming apparent that autoantibodies contribute to neuropathic pain in a range of neurological

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

Downloaded from https://academic.oup.com/edited-volume/34282/chapter/290643317 by OUP site access user on 03 April 2024

You might also like