Anti-cytokine autoantibodies in postherpetic neuralgia.
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.
Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA. ahmadbayat@hotmail.com.
Ahmad
A
Bayat
Dental Clinical Research Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA. burbelop@nidcr.nih.gov.
Peter D
PD
Burbelo
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA. Sarah.Browne@fda.hhs.gov.
Sarah K
SK
Browne
Division of Infection and Immunity, University College London, London, WC1E 6BT, UK. Mark.Quinlivan@gosh.nhs.uk.
Mark
M
Quinlivan
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA. bianca.martinez@vanderbilt.edu.
Bianca
B
Martinez
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA. SHOLLAND@niaid.nih.gov.
Steven M
SM
Holland
Department of Anesthesiology, Rush University Medical Center, Chicago, IL, 60612, USA. asokumar@aol.com.
Asokumar
A
Buvanendran
Department of Anesthesiology, Rush University Medical Center, Chicago, IL, 60612, USA. Jeffrey_Kroin@rush.edu.
Jeffrey S
JS
Kroin
Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA. amannes@mail.nih.gov.
Andrew J
AJ
Mannes
Division of Infection and Immunity, University College London, London, WC1E 6BT, UK. j.breuer@ucl.ac.uk.
Judith
J
Breuer
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA. jcohen@niaid.nih.gov.
Jeffrey I
JI
Cohen
Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA. miadarol@cc.nih.gov.
Michael J
MJ
Iadarola
D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000097:blood*; D015331:Cohort Studies; D020918:Complex Regional Pain Syndromes / Q000097:blood / Q000276:immunology*; D016207:Cytokines / Q000097:blood*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood; D006562:Herpes Zoster / Q000097:blood / Q000276:immunology*; D014645:Herpesvirus 3, Human; D006801:Humans; D016898:Interferon-alpha / Q000097:blood; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009437:Neuralgia / Q000097:blood / Q000276:immunology; D051474:Neuralgia, Postherpetic / Q000097:blood / Q000276:immunology*; D055815:Young Adult
D001323:Autoantibodies; D016207:Cytokines; C554156:IFNA1 protein, human; C573415:IFNG protein, human; C508600:IL6 protein, human; D016898:Interferon-alpha; D015850:Interleukin-6; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor