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Multiple Sclerosis
Figure 1: Myoxovirus Protein A and IFNAR1 Messenger
a body of arguments suggests that the differential affinities for IFNARs
RNA Expression
govern the diverse biological activities among members of type I IFN
families sharing the same receptor,
17,18
it is also likely that differences
AB
in the amount of IFN-β and IFNAR binding may account for the
40
differential therapeutic activity of the cytokine in different patients.
Finally, the cell surface concentration of IFNAR and lateral organisation
35
of its two chains into microdomains might be other important cellular
30
parameters that shape responsiveness to IFNs.
35
For example, the
25
autocrine production of IFN-β from LPS- and poly I:C-matured
20
dendritic cells can induce a marked decline in the level of the two
MxA (NR)
15
IFNAR subunits,
35
and a modulation in receptor expression has been
10
observed in the course of therapy with IFN-α in both HCV and chronic
5 myelogenous leukaemia patients.
36,37
0
CTRL MS-naïve IFN-β-treated MxA- MxA+
If we consider the rather low number of IFNAR molecules on the cell
surface,
12
especially on lymphocytes,
38
providing a limited safety margin
MxA MS IFN
3.0
Induction Course Subtype
for response, it is evident that even a minimal modulation of IFNAR
RR SP 1α 1β
component expression may interfere with the biological activity of
2.5
MxA+ 19 6 19 6
MxA- 22 4 10 16 IFN-β in MS patients. Up to now, only a few studies have investigated
2.0 the role of all IFNAR components in human diseases or under conditions
of chronic receptor stimulation, and only a few studies have analysed
1.5
the expression of all of the different isoforms of IFNAR2 at the same
IFNAR 1 (NR)
1.0
time.
39–41
A quantitative realtime polymerase chain reaction (PCR) assay
0.5
that measures concomitantly IFNAR1 and IFNAR2 subunit mRNA and
the three IFNAR2 isoforms is now available.
40
Using this method we
0.0
have previously demonstrated that IFNAR1 and total IFNAR2 subunits
CTRL MS-naïve IFN-β-treated MxA- MxA+
are both expressed at high levels, and that IFNAR2.2 is significantly the
most represented isoform, while IFNAR2.3 is found, on average, at
A: Myxovirus protein A (MxA) and IFNAR1 levels expressed as normalisation ratio (NR) in
barely detectable levels. However, the distribution of IFNAR2.3 isoform
control subjects (CTRL), therapy-naïve multiple sclerosis (MS) patients and a group of MS
values is rather wide, indicating that it is possible to find higher levels
patients undergoing interferon (IFN)-β treatment for at least 24 months. B: MxA and IFNAR1
messenger RNA (mRNA) levels in treated MS patients classified as MxA-induced (MxA+) or of soluble receptor in the sera of a few samples.
40
We then used this
non-induced (MxA-) on the basis of their MxA level above or under the cut-off (99th
laboratory test to quantify mRNA expression for all IFNAR components
percentile of controls, dotted line). Table shows characteristics of MxA-induced and non-
induced patients. in a group of long-term IFN-β-treated MS patients selected among
dose regimen is an important determinant of drug efficacy. Indeed,
IFN-β is effective in only a percentage of patients, since after six to 18
Comparative data across studies
months of treatment some of them develop binding (BAb) and
on different interferon (IFN)-β
neutralising (NAb) anti-IFN-β antibodies, leading to loss of drug
bioactivity.
25–27
Because the response to IFN-β can be assessed on a
preparations suggest that the optimal
clincal basis only after a relatively prolonged treatment, the
choice of IFN-β subtype, preparation
quantification of NAb has for many years been the gold standard
laboratory test for monitoring IFN-β therapy efficacy. Recently,
and dose regimen is an important
alternative methods for measuring IFN-β biologic activity have been
determinant of drug efficacy.
developed and, among these, the determination of the IFN-β-inducible
gene product Myxovirus protein A (MxA) has proved to be the most
reliable because this protein and its messenger RNA (mRNA) are those undergoing routine MxA determination in our laboratory. Their
induced in a dose-dependent manner by type I IFNs.
25
MxA induction IFNAR mRNA levels were compared with those of a control group and
loss, if measured exactly 12 hours after IFN-β injection, correlates well of therapy-naïve MS patients in order to ascertain receptor modulation
with the presence of anti-IFN-β antibodies; therefore, it can be during prolonged receptor stimulation by IFN-β. Our results indicated
considered an appropriate test to determine IFN-β bioavailability.
27–30
that the overall pattern of expression of the various subunits and
However, some patients are unresponsive to treatment even in the isoforms in peripheral blood cells of MS patients is similar to that
absence of anti-IFN-β antibodies,
31
and therefore other reasons for observed in healthy controls and in HIV patients.
42
lack of therapy efficacy still have to be identified.
IFNAR1 Subunits in Interferon-β-treated Patients
Involvement of IFNAR in Interferon-β Activity We also found that naïve and IFN-β-treated MS patients showed a
It has been proposed that the biological response to IFN-β could be significantly decreased expression of mRNA for the IFNAR1 but not the
affected not only by the presence of BAb or NAb, but also by other IFNAR2 subunit in comparison with healthy controls (see Figure 1).
competing serum factors,
32,33
such as soluble IFNAR.
34
Furthermore, as Notably, the expression of IFNAR1 and IFNAR2 also appears to be
88 EUROPEAN NEUROLOGICAL REVIEW
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