Dysregulated Epstein-Barr virus infection in patients with CIDP

https://doi.org/10.1016/j.jneuroim.2009.11.003Get rights and content

Abstract

Ubiquitous viruses have frequently been proposed as a cause or trigger of chronic immune-mediated diseases. Infections are reported to be temporally associated with clinical exacerbations in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We examined immunological parameters of herpesvirus infections in untreated patients with CIDP compared to demographically matched controls. Patients with CIDP were uniformly seropositive for EBV-specific IgG and the disease was associated with a moderately enhanced IgG reactivity to EBV-encoded antigens expressed during both B cell transformation and productive viral replication. Moreover, cellular EBV copy numbers were 3-fold increased in patients with CIDP. In contrast, humoral immune responses to other herpesviruses (HCMV, HSV) as well as virus-specific IgM responses were unchanged in CIDP. These data indicate that host–pathogen interactions during chronic EBV infection are dysregulated in treatment-naïve patients with CIDP.

Introduction

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired peripheral nerve disorder of autoimmune origin. Both cell-mediated and humoral immune responses directed against incompletely characterized peripheral nerve antigens have been considered to contribute to the development of CIDP. Detailed clues concerning the initiation and perpetuation of the inflammatory demyelinating process in CIDP are, however, still sparse (Koller et al., 2005) (Hughes et al., 2006).

Infectious pathogens and antiviral immune responses trigger autoimmune pathologies in a variety of experimental models (Munz et al., 2009) and have been reported to be temporally associated with the development of neurological deficits in CIDP patients (McCombe et al., 1987) (Bouchard et al., 1999). Due to their ability to cause persistent infections that periodically reactivate, human herpesviruses such as the alpha-herpesvirus herpes simplex virus (HSV), the beta-herpesvirus cytomegalovirus (HCMV) and the gamma-herpesvirus Epstein-Barr virus (EBV) are candidate triggers of autoimmune diseases development and exacerbation. We previously analyzed clinical, laboratory and electrophysiological features in a large cohort of patients with CIDP (Tackenberg et al., 2007). Here, we investigated a possible association between CIDP and host–pathogen interactions during chronic infections with ubiquitous herpesviruses.

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Patients and controls

Patient data and serum samples were collected in the Department of Neurology, Philipps-University, Marburg, and Charité University Medicine Berlin, Germany. The modified AAN (Saperstein et al., 2001) and the EFNS (2005) criteria were used for the diagnosis of CIDP (Tackenberg et al., 2007). From a total of 66 retrospective patients with chronic autoimmune neuropathies, current infection and history of immunosuppressive drug treatment 2 months prior to the time of blood drawing led to exclusion

Increased EBV-specific IgG titer in CIDP

First, we evaluated IgM and IgG antibody responses to EBV-, HCMV-, and HSV-encoded antigens in retrospective serum samples from patients with CIDP compared to demographically matched controls. The ELISA plate for detection of EBV-specific IgG was coated with a mixture of epitopes derived from early antigens (EA), viral capsid antigens (VCA), and the EBV nuclear antigen 1 (EBNA1). To differentiate between predominantly lytic and latent EBV antigen-specific IgG responses, we additionally employed

Discussion

Our study demonstrates that untreated patients with CIDP patients show increased IgG responses to pooled lytic and latent EBV antigens which are involved in both B cell transformation and productive viral replication, as well as higher levels of cell-associated viral genomes in circulating blood cells. These data indicate that host–EBV interactions are dysregulated in patients with CIDP and suggest a possible link between the immunopathogenesis of CIDP and EBV infection.

Viral infections are

Acknowledgements

We thank Brady Messmer (Institute for Experimental Immunology, Zurich), Babette von Hagen (Department of Neurology, Marburg), Britta Kreuzer (Institute of Neuroimmunology, Berlin), and Gabriele Kerger (Institute of Virology, Berlin) for continuous technical help, and Andrew Mason (Institute of Neuroimmunology, Berlin) for critically reviewing this manuscript.

J.D.L. is a recipient of the Dana Foundation and Irvington Institute's Human Immunology Fellowship and is supported by an Institutional

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These authors contributed equally to this work.

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