TY - JOUR
T1 - Type i interferon signature is high in lupus and neuromyelitis optica but low in multiple sclerosis
AU - Feng, Xuan
AU - Reder, Nicholas P.
AU - Yanamandala, Mounica
AU - Hill, Addie
AU - Franek, Beverly S.
AU - Niewold, Timothy B.
AU - Reder, Anthony T.
AU - Javed, Adil
N1 - Funding Information:
This study was supported by Brain Research Foundation grants (Drs. Javed and Feng) and NIH K08 AI083790, NIH P30 DK42086, NIAID Clinical Research Loan Repayment AI071651, NIH CTSA Core Subsidy Grant and CTSA Pilot Grants from UL1 RR024999, Lupus Research Institute Novel Research Grant, Alliance for Lupus Research Target Identification in Lupus Grant, and Arthritis National Research Foundation Eng Tan Scholar Award (Dr. Niewold).
PY - 2012/2/15
Y1 - 2012/2/15
N2 - Objective: Neuromyelitis optica (NMO) is characterized by selective inflammation of the spinal cord and optic nerves but is distinct from multiple sclerosis (MS). Interferon (IFN)-β mitigates disease activity in MS, but is controversial in NMO, with a few reports of disease worsening after IFN-β therapy in this highly active disease. In systemic lupus erythematosus (SLE), IFNs adversely affect disease activity. This study examines for the first time whether serum IFN-α/β activity and IFN-β-induced responses in peripheral blood mononuclear cells (MNC) are abnormally elevated in NMO, as they are in SLE, but contrast to low levels in MS. Methods: Serum type I IFN-α/β activity was measured by a previously validated bioassay of 3 IFN-stimulated genes (RT-PCR sensitivity, 0.1 U/ml) rather than ELISA, which has lower sensitivity and specificity for measuring serum IFNs. IFN responses in PBMNC were assessed by in vitro IFN-β-induced activation of phospho-tyrosine-STAT1 and phospho-serine-STAT1 transcription factors, and MxA proteins using Western blots. Results: Serum IFN-α/β activity was highest in SLE patients, followed by healthy subjects and NMO, but was surprisingly low in therapy-naïve MS. In functional assays in vitro, IFN-β-induced high levels of P-S-STAT1 in NMO and SLE, but not in MS and controls. IFN-β-induced MxA protein levels were elevated in NMO and SLE compared to MS. Conclusions: Serum IFN activity and IFN-β-induced responses in PBMNC are elevated in SLE and NMO patients versus MS. This argues for similarities in pathophysiology between NMO and SLE and provides an explanation for IFN-induced disease worsening in NMO.
AB - Objective: Neuromyelitis optica (NMO) is characterized by selective inflammation of the spinal cord and optic nerves but is distinct from multiple sclerosis (MS). Interferon (IFN)-β mitigates disease activity in MS, but is controversial in NMO, with a few reports of disease worsening after IFN-β therapy in this highly active disease. In systemic lupus erythematosus (SLE), IFNs adversely affect disease activity. This study examines for the first time whether serum IFN-α/β activity and IFN-β-induced responses in peripheral blood mononuclear cells (MNC) are abnormally elevated in NMO, as they are in SLE, but contrast to low levels in MS. Methods: Serum type I IFN-α/β activity was measured by a previously validated bioassay of 3 IFN-stimulated genes (RT-PCR sensitivity, 0.1 U/ml) rather than ELISA, which has lower sensitivity and specificity for measuring serum IFNs. IFN responses in PBMNC were assessed by in vitro IFN-β-induced activation of phospho-tyrosine-STAT1 and phospho-serine-STAT1 transcription factors, and MxA proteins using Western blots. Results: Serum IFN-α/β activity was highest in SLE patients, followed by healthy subjects and NMO, but was surprisingly low in therapy-naïve MS. In functional assays in vitro, IFN-β-induced high levels of P-S-STAT1 in NMO and SLE, but not in MS and controls. IFN-β-induced MxA protein levels were elevated in NMO and SLE compared to MS. Conclusions: Serum IFN activity and IFN-β-induced responses in PBMNC are elevated in SLE and NMO patients versus MS. This argues for similarities in pathophysiology between NMO and SLE and provides an explanation for IFN-induced disease worsening in NMO.
KW - Interferon
KW - MS
KW - MxA
KW - NMO
KW - SLE
KW - STAT1
UR - http://www.scopus.com/inward/record.url?scp=84855604535&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84855604535&partnerID=8YFLogxK
U2 - 10.1016/j.jns.2011.09.032
DO - 10.1016/j.jns.2011.09.032
M3 - Article
C2 - 22036215
AN - SCOPUS:84855604535
SN - 0022-510X
VL - 313
SP - 48
EP - 53
JO - Journal of the neurological sciences
JF - Journal of the neurological sciences
IS - 1-2
ER -