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Multiple Sclerosis
Increase of IFNAR1 Messenger RNA in Myxovirus-protein-A-induced
Multiple Sclerosis Patients to Oppose Loss of Protein Receptor
a report by
Alessandra Sottini,
1
Federico Serana,
1
Ruggero Capra,
2
Luigi Caimi
1
and Luisa Imberti
1
1. Biotechnology Laboratory, Diagnostics Department; 2. Multiple Sclerosis Centre, Department of Neurology, Civic Hospital, Brescia
Type I Interferons and Their Receptor decoy, or, indirectly, as an agonist, as it protects bound IFN-β from
Human interferons (IFNs), first recognised for their potent antiviral activity degradation and prolongs its half-life.
16
50 years ago, are a group of naturally occurring cytokines with important
immunomodulatory, antiviral, antiangiogenic, antiproliferative and The process of receptor activation involves the initial binding of type I
antitumour activities.
1
They are classified into three major sub-families IFNs to the IFNAR2 subunit
17
followed by the recruitment of the
based on their biological and physical properties. Type I IFNs include IFNAR1 subunit, with subsequent commencement of a signalling
IFN-α, IFN-β, IFN-ε, IFN-κ, IFN-ω, IFN-δ and IFN-τ; among them, IFN-α and cascade
18
that leads to catalytic activation of associated tyrosine kinase
IFN-β are the main types of interest, since IFN-ε and IFN-κ are expressed 2 (Tyk2) and Janus tyrosine kinase 1 (Jak1), which in turn
only in the placenta and in keratinocytes and IFN-δ and IFN-τ are not found phosphorylate signal transducer and activator of transcription (STAT)-
in humans.
2
There are more than 20 different IFN-α genes, of which 13 1 and STAT-2 (although activation of STAT-3, STAT-4, STAT-5 and
STAT-6 has also been reported).
19–22
All of these phenomena ultimately
activate the IFN-stimulated response elements (ISRE) of the gene
As found for most cytokines and
promoter,
23
which in turn regulate the transcription of the several
genes responsible for the IFN-mediated effects.
growth factors, the actions of
interferons are mediated by an
Interferon-β Treatment in Multiple Sclerosis
Multiple sclerosis (MS) is an immune-mediated demyelinating disease
interaction with specific cell
of the central nervous system characterised by bouts of neurological
surface receptors. symptoms (or relapses) and increasing disability. Although this disease
was first described in the 1800s,
24
therapies have become
commercially available only during the last 15–20 years. IFN-β was the
encode functional polypeptides, whereas there is only one type of IFN-β. first drug to be approved and, despite several novel therapies being
Type II IFNs include only IFN-γ, while the new family of type III IFNs has tested and/or recently introduced, it still provides the mainstay of MS
three subtypes of IFN-λ (also termed interleukin [IL]-28A, IL-28B and IL-29), disease-modifying therapies. All of the three recombinant IFN-β
which are co-produced with IFN-β.
1
preparations currently registered for MS therapy – Rebif (IFN-β-1a;
Ares-Serono, Geneva, Switzerland), Avonex (IFN-β-1a; Biogen,
As found for most cytokines and growth factors, the actions of IFNs are Cambridge, MA, US) and Betaferon (IFN-β-1b; Schering AG, Berlin,
mediated by an interaction with specific cell surface receptors. All of the Germany) – have been shown to positively modulate disease activity
type I IFNs share the same receptor complex, whereas type II IFN binds to (relapses and active lesions apparent on magnetic resonance imaging),
a distinct receptor, as do the interferon-like cytokines IL-28A, IL-28B and while therapy advantages on disease progression (disability and total
IL-29.
3
The receptor complex for the type I IFNs consists of two chains, lesion burden) are less consistent.
IFNAR1 and IFNAR2,
4,5
whose genes are clustered on chromosome 21.
Two splice variants of IFNAR1 have been identified in cell lines,
6–8
but one Comparative data across studies on different IFN-β preparations
is probably an artefact or an aberrant transcript found only in particular suggest that the optimal choice of IFN-β subtype, preparation and
tumour cell lines.
9
In contrast, IFNAR2 is expressed in vivo in three
different isoforms, which are generated by alternative splicing, exon
Luisa Imberti works in the Biotechnology Laboratory at Civic
skipping and differential usage of polyadenylation sites and differ in the
Hospital in Brescia, Italy, where she is Chair of the Allergy
length of the carboxyterminal tail and in the signalling capacity.
10
Diagnostic Service. Her main focus is on translational
IFNAR2.2 full-length is the functional isoform, and is made up of
research, and she has contributed to advances in the
biology and management of human primary and secondary
487 amino acids, 251 of which lie in the cytoplasmic portion.
11,12
(HIV) immunodeficiencies. Lately, her research group has
IFNAR2.1 short isoform has a truncated cytoplasmic tail of 67 residues,
been focusing on a multidisciplinary approach to addressing
diagnostically relevant aspects of multiple sclerosis, in
and is partially impaired in the signalling response
11–13
or incapable of
particular through the development of laboratory assays that
complete signalling.
14
IFNAR2.3, lacking both the transmembrane and allow more targeted interventions with patients, as well as benefits and costs containment.
intracytoplasmic domains, is a soluble receptor isoform that has been
Dr Imberti received her MD from the University of Milan, and then undertook extensive
training in tumour immunology in the US.
found in different body fluids.
1,15
Depending on its relative concentration,
the stability of its binding with the ligand and the rate of discharge, it
E: limberti@yahoo.it
may be regarded either as a competitive antagonist, acting as a molecular
© TOUCH BRIEFINGS 2008 87
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