Interferon-β exacerbates Th17-mediated inflammatory disease

doi:10.1016/j.it.2011.03.008

Trends in Immunology

Volume 32, Issue 6, June 2011, Pages 272-277

https://doi.org/10.1016/j.it.2011.03.008 Get rights and content

Interferon (IFN)-β is the treatment most often prescribed for relapsing–remitting multiple sclerosis (RRMS). 30–50% of MS patients, however, do not respond to IFN-β. In some cases, IFN-β exacerbates MS, and it consistently worsens neuromyelitis optica (NMO). To eliminate unnecessary treatment for patients who are non-responsive to IFN-β, and to avoid possible harm, researchers are identifying biomarkers that predict treatment outcome before treatment is initiated. These biomarkers reveal insights into the mechanisms of disease. Recent discoveries on human samples from patients with RRMS, NMO, psoriasis, rheumatoid arthritis, systemic lupus erythematosus and ulcerative colitis, indicate that IFN-β is ineffective and might worsen clinical status in diverse diseases when a Th17 immune response is prominent.

Section snippets

Relapse-remitting multiple sclerosis (RRMS) and interferon (IFN)-β therapy: unmet need for rational prescriptions

Type I IFNs, which include the various IFN-β and IFN-α molecules, were first discovered in virally infected chick embryo cells [1]. They bestow cells with virus resistance. This pleotropic cytokine family is now known to have antiviral, antitumor and immunoregulatory functions. In autoimmunity and inflammation, type I IFNs possess both pro- and anti-inflammatory functions depending on the context of the particular pathology.

The various forms of recombinant IFN-β are collectively the most

Understanding the mode of action of IFN-β treatment: lessons from EAE

Understanding the mechanism whereby IFN-β is effective in RRMS is formidable. Obtaining well-characterized MS tissue at various stages of disease, both before and during treatment is rare. Such specimens are usually limited to the blood. Given the barrier of obtaining such samples from RRMS patients, various models of EAE in rodents, primarily mice, have been used to dissect mechanisms of action for therapy with IFN-β 8, 9, 10, 19, 20. However, identifying the mechanism whereby IFN-β attenuates

Understanding IFN-β response in RRMS

The clinical trials that have led to the approval of IFN-β in RRMS patients have indicated that some patients do not respond to treatment. One theory that explains the lack of response to treatment is poor bioavailability of IFN-β in these patients. One well known cause for the decreased bioavailability is the development of neutralizing antibodies to IFN-β. Several studies have identified that, in some non-responders, repeated injections of recombinant IFN-β elicits an antibody response

Role of IFN-β in autoimmune diseases other than RRMS

RRMS is the one of the few known autoimmune diseases in which the anti-inflammatory effects of IFN-β can be harnessed as a therapy. IFN-β is notably ineffective in RA, for example [34]. In fact, it is striking that the main treatment for RA, tumor necrosis factor (TNF) blockade, has been shown to worsen MS symptoms, and this drug carries an FDA black box warning against this contraindication http://www.fda.gov/OHRMS/DOCKETS/ac/01/briefing/3779b2_01_cber_safety%20_revision2.pdf. However, trials

Concluding remarks

RRMS is a complex disease that has an unpredictable clinical course, with variable pathological patterns. RRMS might not be a single disease, but rather a collection of different syndromes that cause inflammatory demyelination. This heterogeneity is illuminated by the variability in responses to IFN-β. This variability poses a challenge to clinicians and researchers to develop ways to identify responsiveness early after treatment begins, or better yet, before treatment is initiated.

In this

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NMOSD is recognized as a B cell-mediated humoral immune disease. However, accumulating evidence suggests that T helper (Th) 17 cell-mediated immunity may be involved in the pathogenesis of NMOSD (Barros et al., 2016; Li et al., 2011; Axtell et al., 2011). Previous reports have been showed that CSF levels of IL-6 and IL-17 A, which prefer B-cell activation, survival, and AQP4-IgG production, are elevated in NMOSD patients.
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Trends in Immunology

ReviewInterferon-β exacerbates Th17-mediated inflammatory disease

Section snippets

Relapse-remitting multiple sclerosis (RRMS) and interferon (IFN)-β therapy: unmet need for rational prescriptions

Understanding the mode of action of IFN-β treatment: lessons from EAE

Understanding IFN-β response in RRMS

Role of IFN-β in autoimmune diseases other than RRMS

Concluding remarks

Virus interference. I. The interferon

Proc. R. Soc. Lond. B: Biol. Sci.

Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis

Clin. Ther.

Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients

Ann. Neurol.

Interferon beta-1b exacerbates multiple sclerosis with severe optic nerve and spinal cord demyelination

J. Neurol. Sci.

Early relapse in multiple sclerosis-associated optic neuritis following the use of interferon beta-1a in Chinese patients

Jpn. J. Ophthalmol.

Development of extensive brain lesions following interferon beta therapy in relapsing neuromyelitis optica and longitudinally extensive myelitis

J. Neurol.

Does Epstein–Barr virus infection in the brain drive the development of multiple sclerosis?

Brain

T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis

Nat. Med.

Beta interferon restricts the inflammatory potential of CD4+ cells through the boost of the Th2 phenotype, the inhibition of Th17 response and the prevalence of naturally occurring T regulatory cells

Mol. Immunol.

Interferon-beta is a key regulator of proinflammatory events in experimental autoimmune encephalomyelitis

Mult. Scler.

Type I interferons as anti-inflammatory mediators

Sci. STKE

Interferon and granulopoiesis signatures in systemic lupus erythematosus blood

J. Exp. Med.

Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients

Ann. Rheum. Dis.

In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-alpha sensitivity is unaltered

J. Invest. Dermatol.

IFNbeta-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum

Neurology

Interferon beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers

Arch. Neurol.

Different responses to interferon beta-1b treatment in patients with neuromyelitis optica and multiple sclerosis

Eur. J. Neurol.

New lessons about old molecules: how type I interferons shape Th1/Th17-mediated autoimmunity in the CNS

Trends Mol. Med.

Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system

Immunity

The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice

J. Clin. Invest.

How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis

Ann. Neurol.

IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis

J. Immunol.

Encephalitogenicity of complete Freund's adjuvant relative to CpG is linked to induction of Th17 cells

J. Immunol.

Adjuvant treatment suppresses IL-17 production by T cell-independent myeloid sources in nonobese diabetic mice

Mol. Immunol.

T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta

Ann. Neurol.

IFN-beta inhibits human Th17 cell differentiation

J. Immunol.

Using measurements of neutralizing antibodies: the challenge of IFN-beta therapy

Eur. J. Neurol.

Time course transcriptomics of IFNB1b drug therapy in multiple sclerosis

Autoimmunity

Interferon-beta induces transient systemic IP-10/CXCL10 chemokine release in patients with multiple sclerosis

J. Neuroimmunol.

IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice

J. Clin. Invest.

Human Th17 cells comprise heterogeneous subsets including IFN-gamma-producing cells with distinct properties from the Th1 lineage

J. Immunol.

A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis

Brain

Differential expression of interleukin-17A and -17F is coupled to T cell receptor signaling via inducible T cell kinase

Immunity

A randomized, controlled trial of interferon-beta-1a (Avonex(R)) in patients with rheumatoid arthritis: a pilot study [ISRCTN03626626]

Arthritis Res. Ther.

Suppression of inflammation in ulcerative colitis by interferon-{beta}-1a is accompanied by inhibition of IL-13 production

Gut

Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production

Arthritis Rheum.

Review
Interferon-β exacerbates Th17-mediated inflammatory disease