Submitted by Shan (Sarah) Chen, MD, PhD, News Science Editorial Board
Additional comments by David B. Rosenfield, MD, News Science Editorial Board
Dawes JM, Weir GA, Middleton SJ, et al. Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability
. 2018 Feb 21;97(4):806-822.e10. doi: 10.1016/j.neuron.2018.01.033. Epub 2018 Feb 8.
Contactin-associated protein-like 2 (CASPR2) is a neuronal adhesion molecule of the neurexin superfamily known to form a protein complex with shaker-type voltage-gated potassium channels such as Kv1.1 and Kv1.2. In fact, antibodies to VGKCC are not directed against Kv 1 channels, but to the complex.
Human autoantibodies to CASPR2 have been associated with neuromyotonia and Morvan’s syndrome. A common feature in these patients is neuropathic pain. However, the mechanism by which CASPR2 modulates nociceptive function is unknown.
Dawes et al isolated CASPR2 autoantibodies from 2 patients with very high titers of CASPR2 IgG and injected them into healthy mice for 2 or 3 weeks. These mice had high CASPR2 titers at the end of the experiment and these antibodies were found mostly on the surface of sensory neurons, i.e., dorsal root ganglion (DRG), only some in the sciatic nerve, and none in spinal cord and they resulted in mechanical pain-related hypersensitivity in the absence of neural injury or overt inflammation.
Genetic knockout mice lacking CASPR2 (Cntnap2-/-
) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli and heat. They showed that both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2-/-
They further demonstrated that CASPR2 regulates DRG excitability and membrane Kv1 channel expression at the soma membrane.
Dr. Chen’s Comments:
Pain is one of the cardinal signs of inflammation. Increasing studies have been linking immune system to the pathogenesis of pain. Previously it was thought that autoantibodies cause tissue damage and inflammatory reactions.
This work showed that patient CASPR2-antibodies cause a loss of Kv1 channel membrane expression and hyperexcitability in DRG without nerve injuries or inflammatory responses. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder. This group further showed that either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. Therefore, CASPR2 has a key role in regulating DRG excitability. Interestingly, CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. This work provides a rationale for testing CASPR2 antibodies in chronic pain patients and possible immunotherapy.
Also commented in “Autoantibodies Hurt: Transfer of Patient-Derived CASPR2 Antibodies Induces Neuropathic Pain in Mice” in the February 21, 2018 edition of Neuron
Dr. Rosenfield’s Summary and Comments:
All of us see patients with pain that is difficult to explain and treat. In this article in Neuron
, the authors discuss that contactin-associated protein-like 2 (CASPR2) antibodies cause loss of Kv1 channel membrane expression and hyperexcitability in Dorsal Root Ganglion (DRG) without preexisting nerve injury or inflammation. These authors demonstrate in mice that one can passively transfer an autoimmune peripheral neuropathic disorder in which CASPR2 has an important role in regulating DRG excitability and posit that these antibodies might even have a role in autism spectrum disorders.