Anti-cytokine autoantibodies in postherpetic neuralgia

Abstract

BackgroundThe mechanisms by which varicella zoster virus (VZV) reactivation causes postherpetic neuralgia (PHN), a debilitating chronic pain condition, have not been fully elucidated. Based on previous studies identifying a causative role for anti-cytokine autoantibodies in patients with opportunistic infections, we explored this possibility in PHN.MethodsSera from herpes zoster (HZ) patients without and with PHN (N = 115 and 83, respectively) were examined for the presence of autoantibodies against multiple cytokines, and other known autoantigens. In addition, a cohort of patients with complex regional pain syndrome or neuropathic pain was tested for autoantibodies against selected cytokines. Antibody levels against VZV, Epstein Barr virus, and herpes simplex virus-2 were also measured in the HZ and PHN patients. Patient sera with high levels of anti-cytokine autoantibodies were functionally tested for in vitro neutralizing activity.ResultsSix PHN subjects demonstrated markedly elevated levels of single, autoantibodies against interferon-α, interferon-γ, GM-CSF, or interleukin-6. In contrast, the HZ and the pain control group showed low or no autoantibodies, respectively, against these four cytokines. Further analysis revealed that one PHN patient with high levels of anti-interleukin-6 autoantibodies had a markedly depressed antibody level to VZV, potentially reflecting poor T cell immunity against VZV. In vitro functional testing revealed that three of the five anti-cytokine autoantibody positive PHN subjects had neutralizing autoantibodies against interferon-α, GM-CSF or interleukin-6. In contrast, none of the HZ patients without PHN had neutralizing autoantibodies.ConclusionsThese results suggest the possibility that sporadic anti-cytokine autoantibodies in some subjects may cause an autoimmune immunodeficiency syndrome leading to uncontrolled VZV reactivation, nerve damage and subsequent PHN.

Cellular Stress Response to Varicella-Zoster Virus Infection of Human Skin Includes Highly Elevated Interleukin-6 Expression

“…For example, 2 patients with herpes zoster/postherpetic neuralgia (HZ/PHN) had high IL-6 transcription levels in affected skin [27]. In another study, 6 patients with herpes zoster had anti-IL-6 antibodies [28]. In a third study, elevated levels of IL-6 protein were found in the cerebrospinal fluid of patients with central nervous system disease secondary to VZV vasculopathy [29].…”

Clinical features of Sjögren's syndrome patients with autoantibodies against interferons

“…Using an established in vitro assay [20,25,29,37,44,45], the neutralizing capacity of specific anti-interferon autoantibodies, were evaluated using control peripheral blood mononuclear cells (PBMC). In these experiments, PBMC were incubated in the presence of 10% healthy volunteer or patient sera and left unstimulated or stimulated with the cytokine recognized by the specific anticytokine autoantibody found in the serum samples.…”

“…This is because LIPS is a fluidphase immunoassay that presents autoantigens such as cytokines in solution, allowing them to adopt native structures. Numerous studies have shown LIPS to generate highly informative anticytokine autoantibody profiles in multiple human disorders [20,25,28,30,[37][38][39][40]. In one study, LIPS was shown to strongly track the anticytokine autoantibodies observed by ELISA and protein array, but LIPS demonstrated autoantibody levels spanning a larger dynamic range of detection [30].…”

Electrophysiological characteristics of the frontal nerve in patients with herpetic ophthalmic neuralgia

“…Clinical neurophysiology and the techniques used to study the trigeminal functions remain convenient diagnostic and research tools to document clinically evident lesions or to uncover subclinical abnormalities. Certain impaired fibers may initiate chronic pain states after the development of subsequent localized nerve lesions due to VZV infection . Blink reflexes, which are mediated by nonnociceptive myelinated A‐beta fibers, and trigeminal laser‐evoked potentials, which are mediated by nociceptive myelinated A‐delta and unmyelinated C fibers, have been used to evaluate afferent pathways of V1 in patients with PHN .…”

“…Certain impaired fibers may initiate chronic pain states after the development of subsequent localized nerve lesions due to VZV infection. [9][10][11] Blink reflexes, which are mediated by nonnociceptive myelinated A-beta fibers, 12,13 and trigeminal laserevoked potentials, which are mediated by nociceptive myelinated A-delta and unmyelinated C fibers, 14,15 have been used to evaluate afferent pathways of V1 in patients with PHN. 16 Sensory nerve conduction (SNC) studies enable the direct measurement of sensory nerve action potentials (SNAPs), amplitudes and sensory conduction velocities (SCVs), thus providing quantitative measures of the functions of large fibers in the nerve.…”