Anti-autonomic nervous system antibodies in CRPS
April 15, 2011 at 9:43am
Article in Press
Pain® printed by IASP
Commentary / PAIN xxx (2011) xxx–xxx
Anti-autonomic nervous system antibodies in CRPS
There is a long history of discovery of autoantibodies in the peripheral nervous system, in disorders such as myasthenia gravis and in certain types of peripheral neuropathies. Autoantibodies are also recognized as pathogenic in disorders of the central nervous system, including encephalitis, neuromyelitis optica, seizures and psychiatric disorders. The mechanisms by which autoantibodies induce disease are especially intriguing, often elucidating the Pathophysiology of a disease, as in the so-called channelopathies, in which autoantibodies are directed against neuronal ion channels [9]. Even antibodies to intracellular antibodies can induce disease, via very specific pathophysiological mechanisms [2]. In many chronic pain disorders, however, the pathophysiology is still incompletely understood. Identifying an autoantibody as the culprit would be not only intellectually satisfying but would also open up entirely new treatment options. This objective has, of course, long been an aim in enigmatic disorders, as for example, fibromyalgia syndrome [3], where anti-muscle protein antibodies were found in about half of the fibromyalgia patients, but in none of the controls. The latter finding is intriguing, but needs to be replicated.
Complex regional pain syndrome (CRPS) is another chronic pain condition the pathophysiology of which is not entirely understood. Insufficient resolution of inflammation and other immunemediated processes have been implicated in the early stages of CRPS [6]. B-lymphocytes have not yet been studied in CRPS but changes in mast cells and monocytes have been reported. Interestingly, Blaes and colleagues detected surface-binding autoantibodies in a subgroup of CRPS patients. These antibodies were directed against antigens of the autonomic nervous system, as shown by reactivity of patient sera with sympathetic and myenteric plexus neurons as well as cholinergic neuroblastoma cells. [5] The origin of the antibodies was unknown, and their specificity was not established. It was also not known whether the antibodies were already present before the trauma.
In the present issue of PAIN, Kohr and colleagues [4] present follow-up data on this project. Here their objective was to identify the autoantigens to the antibodies and to assess the functional activity of the antibodies. They found that some CRPS patients had functionally active autoantibodies against the muscarinic 2 receptor(M2R) and the beta2 adrenergic receptor (b2AR). Intriguingly, their initial investigations did not target the nervous system, but eventually they returned to it. The authors first used neonatal rat cardiomyocytes as well as Chinese hamster ovary (CHO) cells that overexpressed human autonomic nervous receptors, including the human muscarinic 2 receptor (hM2R), and the b1-, or b2-adrenergic receptors (hb1- or hb2AR). The spontaneously beating cardiomyocytes provided the functional assay, namely an effect of the patients’ IgG on beat frequency. Having found a change in beat frequency, the authors next used different receptor antagonists to profile pharmacologically the mechanism of IgG action. The CHO cells provided morphological evidence of receptor binding by the patients’ IgG and using calcium imaging, CHO cells provided additional functional data. With this combination of elegant methods, the authors showed that CRPS IgG had agonistic effects on the b2AR and the M2R. In fact, IgG from most CRPS patients had both specificities.
With all respect to these intriguing findings, before speaking of ‘‘clear evidence of an autoimmune etiology of CRPS‘‘, Witebsky’s criteria for an autoimmune disease [7] should be considered. These criteria include (1) demonstration of a specific antigen, (2) circumstantial evidence of an autoimmune or inflammatory disorder from clinical clues, and (3) reproduction of clinical features in recipient animals by passive transfer of putatively pathogenetic antibodies. Point 3 is still outstanding and should be addressed in future studies.
The authors discuss the somewhat paradoxical presence of localized CRPS symptoms when there is systemic autoantibodies and speculate about altered receptor expression in neurons that innervate damaged tissue. This hypothesis is an interesting one, although it is one that would be difficult to prove in humans. Indeed, Vargas et al. [8] recently demonstrated that degenerating nerve tissue is targeted by preexisting endogenous antibodies [8]. That finding might be another clue as to the selectivity of antibody effects after trauma.
What could be the clinical implication of the finding that a subset of CRPS patients has functionally active agonistic antibodies that recognize the b2AR and the M2R? The b2 adrenergic receptor can mediate relaxation of arteries in certain conditions. The fact that vasodilatation is increased in acute CRPS, may provide a direct link between the in vitro findings and the clinical picture. M2 muscarinic receptor agonists, in contrast, have been shown to desensitize nociceptors and to reduce neurogenic inflammation [1].
Theoretically, the agonistic M2R antibodies found in the CRPS patients should thus be protective and should counteract the pathological process in CRPS. Of course, the effect of M2R antibodies may be different in in vitro and in vivo settings. For this reason, any conclusions drawn must be considered tentative. In particular, before treatment is directed at the autoantibodies, more information as to their function, i.e. whether they are pathogenic or potentially protective,, should be collected.
0304-3959/$36.00 [1] 2011 Published by Elsevier B.V. on behalf of International Association for the Study of Pain. doi:10.1016/j.pain.2011.07.008
Conflict of interest statement – The author has no conflict of interest regarding this commentary.
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