Anti-cytokine autoantibodies in postherpetic neuralgia

Abstract

Background: The 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.

Methods: Sera 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.

Results: Six 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.

Conclusions: These 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.

Fig. 1

Anti-cytokine autoantibodies in herpes zoster (HZ), post-herpetic neuralgia (PHN) and complex regional pain/neuropathic pain (CRPS/NP) subjects. Each point represents an individual sample from the cohorts composed of 248 samples divided into three groups: HZ (N = 115), PHN (N = 83), and CRPS/NP (N = 50). All samples were screened for autoantibodies to IFN-α, IFN-γ, IL-6 and GM-CSF by LIPS. The blue lines represent the geometric mean with 95 % CI. The dotted line is the cutoff value

Fig. 2

Evaluation of antibodies against VZV and EBV in the HZ and PHN cohorts. Serum samples were assayed for antibodies against VZV and EBV by LIPS. a The antibody levels against the gE glycoprotein antigen of VZV and b antibody levels to the p23 capsid protein of EBV in the HZ and PHN groups. For VZV antibodies, the dotted line represents the previously established cutoff value [16]. The red square corresponds to patient #226 (see Table 2) who is the IL-6 seropositive PHN patient who was seronegative for VZV antibodies