Startseite Expression of interferon type-I receptor isoforms, clinical response and development of neutralizing antibodies in multiple sclerosis patients – results of a prospective study
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Expression of interferon type-I receptor isoforms, clinical response and development of neutralizing antibodies in multiple sclerosis patients – results of a prospective study

  • Angelika Bauer , Dagmar Rudzki , Michael Auer , Harald Hegen und Florian Deisenhammer EMAIL logo
Veröffentlicht/Copyright: 13. Oktober 2015
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Aus der Zeitschrift LaboratoriumsMedizin Band 40 Heft 2

Abstract

Background: One of the first line treatments for relapsing-remitting multiple sclerosis (RRMS) is interferon-β (IFNb), a cytokine with immune-modulatory effects. There is a high degree of variability in the response to the drug which is, among other factors, due to the presence of neutralizing antibodies (NABs) occurring late during therapy.

Methods: The objective of this study was to determine whether the response to IFNb therapy and NAB development can be predicted based on the expression levels of the type-I interferon receptors IFNAR1, IFNAR2a, IFNAR2b, and IFNAR2c before start of treatment. The IFNAR expression levels in 163 samples of patients with relapsing-remitting MS were measured by real-time polymerase chain reaction (PCR).

Results: Pre-treatment IFNAR2c expression levels were somewhat lower in patients who developed NAB during treatment compared to NAB-negative patients. No significant differences in the expression levels of other IFNAR subtypes and isotypes were found. Baseline IFNAR levels were not predictive of the clinical response after 2 years.

Conclusions: Overall, there was a small, non-significant effect of IFNAR2c baseline levels on NAB development but no relation to clinical endpoints. Lower expression of IFNAR2c receptors could lead to higher IFNb levels inducing a higher rate of antibody response.

Zusammenfassung

Hintergrund: Multiple Sklerose (MS) ist eine chronisch-entzündliche Erkrankung des zentralen Nervensystems, die unter anderem mit Interferon-β (IFNb) behandelt werden kann. Der Therapieerfolg ist jedoch sehr variabel, wobei neutralisierende Antikörper (NAB) gegen IFNb mit fehlendem Ansprechen assoziiert sind. NAB treten erst relativ spät nach Therapiebeginn auf.

Methoden: Ziel dieser Studie war es festzustellen, ob NAB, aber auch das klinische Ansprechen auf IFNb durch das Ausmaß der Expression von Interferon Typ-I Rezeptoren IFNAR1, IFNAR2a (2.3), IFNAR2b (2.1) und IFNAR2c (2.2), vor Therapiebeginn vorhergesagt werden können. Hierfür wurden die IFNAR Expressionswerte von 163 MS PatientInnen mittels real-time PCR bestimmt.

Ergebnisse: Niedrige Expression von IFNAR2c vor Therapiebeginn war grenzwertig signifikant mit späterer NAB Entwicklung assoziiert (Wahrscheinlichkeitsquotient: 2,40). Signifikante Unterschiede der Expression zwischen NAB positiven und negativen PatientInnen konnte bei allen anderen IFNAR Untertypen nicht gefunden werden. Auch das klinische Ansprechen konnte mit der IFNAR Expression nicht vorhergesagt werden. Wir vermuten, dass die geringere Verfügbarkeit von IFNAR2c zu erhöhten IFNb Spiegeln, und damit zu erhöhter Immunogenität dieses Präparats führen kann.

Reviewed Publication:

Tumani H. Zettl U.K.

Keywords: interferon-β (IFNb); multiple sclerosis (MS); myxovirus protein A (MxA); neutralising antibodies (NAB); polymerase chain reaction (PCR); type-I interferon receptor (IFNAR)
Schlüsselwörter:: Interferon-β (IFNb); Interferon Typ-I Rezeptor (IFNAR); Multiple Sklerose (MS); Myxovirus Protein A (MxA); neutralisierend-wirkende Antikörper (NAB); Polymerase Kettenreaktion (PCR)

Introduction

Interferon-β (IFNb) has been used in the treatment of MS for roughly 20 years. It acts by binding to the specific receptor (IFNAR) leading to activation of cytoplasmic signal transducers and kinases ultimately controlling thousands of genes [1–3]. The IFNAR comprises 2 subunits, IFNAR1 and IFNAR2. The subunits are detached in the membrane and combine during the binding process of IFNb forming a stable complex [2, 4–7].

IFNAR2, the major ligand binding subunit, can be expressed in three different isoforms; the IFNAR2a-isoform (or IFNAR2.3) is regarded as a soluble receptor subunit and has been found in different body fluids. Furthermore, there are the IFNAR2b-isoform (or IFNAR2.1), the transmembrane short form, and the IFNAR2c-isoform (or IFNAR2.2), the transmembrane long subunit [2, 7–10]. IFNAR2b consists of a truncated cytoplasmic tail and therefore, is unable to perform signal transduction [2, 8, 11] while the functional isoform IFNAR2c is able to perform signal transduction [2, 12, 13].

Due to a high degree of variability of the IFNb response and the fact that therapy failure is usually only detected more than one year after therapy [14], the aim of our study was to test if the IFNb response can be predicted by IFNAR expression levels before treatment using NAB development, MxA levels at baseline (a reliable biomarker to evaluate IFNb bioactivity [15, 16]), and the clinical outcome as endpoints. Similar studies have been performed previously in retrospective analyses not showing a predictive value of pre-treatment IFNAR expression on NAB development [17]. However, here we have also investigated IFNAR expression in context with clinical endpoints in a prospective setting.

Materials and methods

Study population

This study included 163 patients with definite relapsing-remitting MS according to the McDonald criteria [18]. For this work the majority of samples with data on NAB and clinical status from a previous study (NABINMS [19]) were reused.

RRMS-patients received one of three available IFNb preparations, intramuscular (IM) IFNb-1a (Avonex®, Biogen Idec, Cambridge, MA, USA), subcutaneous (SC) IFNb-1a (Rebif®, Merck Serono, Geneva, Switzerland) or SC-IFNb-1b (Betaferon®, Bayer Schering, Berlin, Germany) [19].

Patients were followed for at least 2 years with visits at baseline, 3, 12 and 24 months on treatment. Blood was collected at all visits. A patient was considered NAB positive if NAB were present at 24 months. Clinical non-response was defined as an increase of at least one step on the expanded disability status scale (EDSS) confirmed at 6 months OR a decrease in relapse rate of less than 50% compared with 2 years before therapy.

One step EDSS increase was defined as an increase in EDSS of 1.5 points for patients with baseline EDSS score of 0; 1 point for scores from 1.0 to 5.0; 0.5 points for scores equal or higher to 5.5 [20].

NAB tests were done as previously described [19].

IFNAR1, IFNAR2 isoforms and MxA quantification

After spectrophotometric quantification at 260 and 280 nm, 10 ng of total RNA, extracted from whole blood, was reversely transcribed with the High Capacity Reverse Transcription Kit (Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA). After that polymerase chain reaction (PCR) was performed using the Applied Biosystems – 7300 real-time PCR system and ABI Prism 7000 Sequence Detection System (Thermo Fisher Scientific, Waltham, MA, USA).

Primer and probe sequences (provided by Applied Biosystems on demand according to reference # 17) for IFNAR2a, IFNAR2b and IFNAR2c were as follows (5′–3′):

IFNAR2a (2.3): forward: GAG CAA GCA GTA ATA AAG TCT CCC TTT A; reverse: GGC TAA AAA GTT ATG AAA ATT CTG ATT CC; probe: FAM-AAT GCA CCC TCC TTC CAC CTG GC-TAMRA

IFNAR2b (2.1): forward: CTT GAG GCA AGG TCT CGC TAA G; reverse: GGA GTT TCA GTG TAG TGC ATT ATG A; probe: FAM-CTG GAA TGC AGT GGC TAT TCA CAG GTG C-TAMRA

IFNAR2c (2.2): forward: CCC AAA GTC TTG AAT TTT CAT AAC TT; reverse: AAA TGA CCT CCA CCA TAT CCA; probe: FAM-ACC TGC CAC CGT TGG AAG CC-TAMRA

For IFNAR1 a TaqMan Assay-on demand gene expression kit was used (Hs00265057_m1; Thermo Fisher Scientific, Waltham, MA, USA).

MxA, an indicator of IFNb bioavailability [15, 16], was measured by real-time PCR also using the TaqMan Assay-on demand gene expression kit (Hs00182073_m1; Thermo Fisher Scientific, Waltham, MA, USA). All PCR reactions were set up in 96 well plates with a final volume of 25 μL and the cDNA in a concentration of 10 ng.

PCR amplification started with a first step at 50 °C for 2 min and continued with a heating step at 95 °C for 10 min. This was followed by the elongation, annealing and elongation steps at 95 ° for 15 s and 60 °C for 1 min. For all receptors 40 cycles were chosen, except 50 cycles for the IFNAR2a (2.3) receptor.

Results were expressed as ΔCt, which is the difference of the target gene and the ΔCt of the housekeeping gene. In our work 18S rRNA (VIC) was used as housekeeping gene for reference.

To reduce the effect of varying mRNA amount in PCR on the results, the ΔCt-method was favored to the raw Ct-values.

Of note, the lower the ΔCt-value the higher the expression level.

Statistical methods

Data were analysed using nonparametric statistical tests and are described as median and inter-quartile ranges (IQR) between 10% and 90% percentile as well as ranges.

Comparisons between two groups were performed using the Mann-Whitney U test. Furthermore, a receiver operating characteristics (ROC) analysis was calculated for the determination of likelihood ratio, sensitivity, and specificity. All reported p-values are based on two-tailed statistical tests. p-Values of <0.05 were considered significant. All analyses were performed using GraphPad PRISM, version 5.03 (GraphPad Software, La Jolla, CA, USA).

Ethics

The study has been approved by the Ethical Committees of all participating centers. All subjects signed the informed consent form before participation. The study was performed in accordance with the declaration of Helsinki.

Results

At baseline, all patients were negative for NABs. In 19 (11.7%) patients neutralizing antibodies (NAB) occurred during treatment and 144 (88.3%) were NAB-negative at every time when blood was collected. There were no transient NAB-positive patients.

In a subset of 124 patients (17 of whom were NAB-positive) with available clinical data, 60 (48.4%) were classified as clinical non-responders and 64 (51.6%) patients as responders, based on the criteria described in the Materials and methods – Study population section.

Ten (15.6%) patients in the responder-group and seven (11.7%) patients in the non-responder-group were NAB-positive.

Of these 124 patients 65 received IM-IFNb-1a (52%), 30 patients were treated with IFNb-1b (24%), and 29 patients with SC-IFNb-1a (23%).

In the responder-group, 10 patients developed NABs (eight on IFNb-1b, one on each of the other IFNb preparations), whereas seven of the 60 non-responders were NAB-positive (all on IFNb-1b).

The number of patients on each IFNb preparation and NAB as well as clinical responder status are shown in Table 1. The number of patients on the different IFNb preparations did not differ significantly between responders and non-responders.

Table 1

Treatment allocation, NAB and clinical response status per IFNb preparation.

N treatedNAB+NAB–Clinical responderClinical non-responder
IM-IFNb-1a651643431
SC-IFNb-1a291281613
IFNb-1b3015151416

There were no significant differences in the median basal expression of IFNAR1, IFNAR2a and IFNAR2b (p≥0.32) between NAB+ and NAB– patients (Table 2). This also applies to the MxA expression between the two groups of patients (p=0.56).

Table 2

Descriptive parameters based on the NAB status.

MxAIFNAR1IFNAR2aIFNAR2bIFNAR2c
NAB–NAB+NAB–NAB+NAB–NAB+NAB–NAB+NAB–NAB+
Median-ΔCt16.716.217.318.426.626.917.617.815.516.7
90% IQR±5.4±5.8±8.4±6.9±6.0±7.8±5.6±5.6±7.5±11.9
Range (min–max)11.8–23.011.8–20.79.6–25.69.6–23.721.7–34.922.2–31.712.0–21.311.2–19.89.4–29.110.4–24.8

IFNAR2c expression levels were slightly lower in NAB+ compared to NAB– patients (p=0.07; Figure 1).

Figure 1: IFNAR subtypes in NAB– and NAB+ patients.IFN-type I receptors in NAB+ and NAB– patients before treatment are both equally expressed and show no significant difference. There is a trend showing IFNAR2c receptor is less present in NAB+ patients. Of note: The lower the ΔCt-value the higher the expression levels.
Figure 1:

IFNAR subtypes in NAB– and NAB+ patients.

IFN-type I receptors in NAB+ and NAB– patients before treatment are both equally expressed and show no significant difference. There is a trend showing IFNAR2c receptor is less present in NAB+ patients. Of note: The lower the ΔCt-value the higher the expression levels.

ROC analysis for IFNAR1, IFNAR2a and IFNAR2b showed a poor performance (AUC≤0.55). For IFNAR2c ΔCt-levels of >16.42 the sensitivity in predicting NAB development was 68% and the specificity was 72% with a likelihood ratio of 2.40 (AUC 0.63, p=0.068).

The basal IFNAR expressions of all isoforms did not differ significantly based on the clinical response-status after 24 months of treatment.

Correlations between MxA and different IFNAR expression levels are shown in Table 3. In summary, IFNAR1 levels correlated weakly and negatively with MxA (rSpearman=–0.165; p=0.035), whereas there was no correlation between MxA and the different IFNAR2 isotypes. IFNAR1 and the different IFNAR2 isotypes correlated significantly, however weakly to moderately, with each other.

Table 3

Correlation coefficients (r) and p-values of different IFNAR and MxA.

MxAIFNAR1IFNAR2bIFNAR2cIFNAR2a
r (MxA)–0.1650.0650.037–0.106
p (MxA)0.0350.4080.6380.177
r (IFNAR1)–0.1650.1730.4860.439
p (IFNAR1)0.0350.027<0.001<0.001
r (IFNAR2b)0.0650.1730.6040.612
p (IFNAR2b)0.4080.027<0.001<0.001
r (IFNAR2c)0.0370.4860.6040.703
p (IFNAR2c)0.638<0.001<0.001<0.001
r (IFNAR2a)–0.1060.4390.6120.703
p (IFNAR2a)0.177<0.001<0.001<0.001

Discussion

We found that the clinical response to IFNb based on EDSS and relapse rates, as well as development of NABs, cannot be reliably predicted through the basal expression of IFNb-receptors.

IFNAR2c was the only isoform that had some predictive value for NAB development with a borderline p-value. NAB-positive patients had lower pre-treatment IFNAR2c expression levels than NAB-negative subjects. Similarly, Gilli et al. [17] found a significantly lower expression of IFNAR2c in NAB-positive patients. One explanation is the hypothesis of hyperstimulation stating that a lower binding capacity leads to higher free IFNb levels promoting an anti-IFNb immune response. One reason why we did not find such a strong effect as Gilli et al. might be that we extracted mRNA from whole blood including granulocytes rather than from PBMCs.

The number of NAB-positive patients per IFNb preparation is slightly distorted towards IFNb-1b resulting in an under-representation of IFNb-1a preparations. At least NAB-positive rates in patients treated with IM-IFNb-1a were as expected [21, 22]. One of the imminent problems when using NAB as an outcome is the distribution of IFNb preparations in the study population. In particular, IM-IFNb-1a rarely induces NAB. If patients on this IFNb preparation had been treated with a more immunogenic IFNb, the NAB-positive rate would have been correspondingly higher. As NAB-positive rates were very low in SC-IFNb-1a and IM-IFNb-1a patients, we could not perform a separate analysis in these groups. However, if analyzing IFNb-1b treated patients only we found no significant difference of pre-treatment IFNAR expression levels between NAB-positive and negative patients (data not shown).

Among the different isoforms IFNAR2c is expressed at the highest levels (Figure 2). This can be interpreted in view of the functional role of IFNAR2c being the crucial subunit for the IFNb response. Moreover, its response seems more important than the protection of the IFNb bound from degradation through IFNAR2a [23]. It has been suggested that the therapeutic effect of IFNb-therapy is associated with the relatively high baseline expression of the IFNAR2c [17].

Figure 2: Expression levels of the different IFNAR types.Among the different isoforms, IFNAR2c is expressed at the highest levels, as shown by low ΔCt-values. IFNAR2a, the soluble receptor subunit, is expressed at very low levels in MS patients before IFNb treatment.
Figure 2:

Expression levels of the different IFNAR types.

Among the different isoforms, IFNAR2c is expressed at the highest levels, as shown by low ΔCt-values. IFNAR2a, the soluble receptor subunit, is expressed at very low levels in MS patients before IFNb treatment.

Our data suggest that IFNARs are regulated agonistic. There was a significant and strong correlation between the IFNAR subunits and isotypes in a non-stimulated setting. Upon receptor activation this pattern changes with down-regulation of the IFNAR2b and -2c receptors and up-regulation of IFNAR2a as a regulatory factor [17].

We found only a weak correlation between MxA and IFNAR expression levels which probably reflects the non-stimulated status of IFNARs in untreated patients.

We could not detect a predictive value of MxA expression level in pre-treatment relapsing-remitting multiple sclerosis (RRMS)-patients. This is in line with previous observations by Oliver et al. [24] and can be explained by the fact that MxA is a marker of IFNAR activation and does not correlate with IFNAR baseline expression levels. One study showed a positive correlation between the clinical response and MxA expression during IFNb treatment [25], although the results might have been confounded by NABs.

In a study by Hundeshagen et al. [26], neither the number of relapses nor the increase in EDSS differed between patients with high and low MxA levels at baseline which is in line with the present results.

Unfortunately, we could not detect a difference of baseline IFNAR levels between clinical responders and non-responders. In contrast, a study by Comabella et al. [27] showed elevated expression of CD14+ specific IFNAR1 in IFNb non-responders compared to responders which was later validated by Bustamante et al. [28]. One could argue that cell type restricted IFNAR expression might better predict IFNb. However, the above results should be confirmed by an independent group.

Serana et al. [29] found the same trend in IFNAR ΔCt-value distribution (Figure 2), except for the fact that their ΔCt-values were markedly lower than ours. However, due to the fact that Serena et al. used GAPDH as the housekeeping gene, with a different expression-value level than 18S, they received lower ΔCt-values compared to our ΔCt-values.

Limitations need to be mentioned, such as the low number of NAB-positive patients which may have influenced the statistics. As this project was originally designed as an exploratory study [19], a formal pre-study power calculation was not performed, mainly because there were no clear assumptions of expected differences between groups.

Other factors such as the genetic background, including IFNAR1 and IFNAR2 polymorphisms and human leukocyte antigen (HLA) status, need to be considered but could not be determined due to limited sample material. In fact, HLA-DRB1*0401 and HLA-DRB1*0408 are strongly associated with NAB development [30]. In context with IFNAR expression levels, this association might become even stronger.

Finally, we showed that the clinical response to interferon-therapy of multiple sclerosis patients cannot be predicted through the basal expression of interferon-receptors. However, there were somewhat lower pre-treatment IFNAR2c concentrations in later NAB-positive patients indicating a possible role of this IFNAR isotype in the regulation of IFNb bioactivity.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: The study was sponsored by: A grant of the European Union (LSHB-CT-2005-018926); An unrestricted research grant from Merck Austria; The Austrian Ministry of Science and Research (GZ 651.106/0001-II/2/2007).

Employment or leadership: None declared.

Honorarium: Dr. Deisenhammer has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Bayer Healthcare, Biogen Idec, Genzyme-Sanofi, Merck, Novartis Pharma, and Teva-Ratiopharm.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Correspondence: Univ. Prof. Dr. Florian Deisenhammer, MSc, Neurologie Labor, Innrain 66, 6020 Innsbruck, Austria, Tel.: +43 512 504 24264

References

1. Hesse D, Sellebjerg F, Sorensen PS. Absence of MxA induction by interferon beta in patients with MS reflects complete loss of bioactivity. Neurology 2009;73:372–7.10.1212/WNL.0b013e3181b04c98Suche in Google Scholar

2. Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol 2014;14:36–49.10.1038/nri3581Suche in Google Scholar

3. Borden EC, Sen GC, Uze G, Silverman RH, Ransohoff RM, Foster GR. Interferon at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov 2007;6:975–90.10.1038/nrd2422Suche in Google Scholar

4. Mogensen KE, Lewerenz M, Reboul J, Lutfalla G, Uzé G. The type I interferon receptor: structure, function, and evolution of a family business. J Interferon Cytokine Res 1999;19:1069–98.10.1089/107999099313019Suche in Google Scholar

5. Jaitin DA, Roisman LC, Jaks E, Gavutis M, Piehler J, Van der Heyden J, et al. Inquiring into the differential action of interferons (IFNs): an IFN-alpha2 mutant with enhanced affinity to IFNAR1 is functionally similar to IFN-beta. Mol Cell Biol 2006;26:1888–97.10.1128/MCB.26.5.1888-1897.2006Suche in Google Scholar

6. Lamken P, Lata S, Gavutis M, Piehler J. Ligand-induced assembling of the type I interferon receptor on supported lipis bilayers. J Mol Biol 2004;341:303–18.10.1016/j.jmb.2004.05.059Suche in Google Scholar

7. Gilli F. Role of differential expression of interferon receptor isoforms on the response of multiple sclerosis patients to therapy with interferon beta. J Interferon Cytokine Res 2010;30:733–41.10.1089/jir.2010.0098Suche in Google Scholar

8. Domanski P, Colamonici OR. The type-I interferon receptor. The long and short of it. Cytokine growth. Factor Rev 1996;7:143–51.10.1016/1359-6101(96)00017-2Suche in Google Scholar

9. Novick D, Cohen B, Rubinstein M. The human interferon alpha/beta receptor: characterization and molecular cloning. Cell 1994;77:391–400.10.1016/0092-8674(94)90154-6Suche in Google Scholar

10. Pfeffer LM, Colamonici OR. Transmembrane signalling by interferon-alpha. Pharmacol Ther 1991;52:149–57.10.1016/0163-7258(91)90005-7Suche in Google Scholar

11. Pfeffer LM, Basu L, Pfeffer SR, Yang CH, Murti A, Russell-Harde D, et al. The short form of the interferon alpha/beta receptor chain 2 acts as a dominant negative for type I interferon action. J Biol Chem 1997;272:11002–5.10.1074/jbc.272.17.11002Suche in Google Scholar PubMed

12. Luftfalla G, Roeckel N, Mogensen KE, Mattei MG, Uzé G. Assignment of the human interferon-alpha receptor gene to chromosome 21q22.1 by in situ hybridization. J Interferon Res 1990;10:515–7.10.1089/jir.1990.10.515Suche in Google Scholar

13. Domanski P, Witte M, Kellum M, Rubinstein M, Hackett R, Pitha P, et al. Cloning and expression of a long form of the beta subunit of the interferon alpha beta receptor that is required for signaling. J Biol Chem 1995;270:21606–11.10.1074/jbc.270.37.21606Suche in Google Scholar

14. Vartanian T, Sorensen PS, Rice G. Impact of neutralizing antibodies on the clinical efficacy of interferon beta in multiple sclerosis. J Neurol 2004;251(Suppl 2):II25–30.10.1007/s00415-004-1205-6Suche in Google Scholar

15. Capra R, Scotti A, Cordioli C, Serana F, Chiarini M, Caimi L, et al. IFNbeta bioavailability in multiple sclerosis patients: MxA versus antibody-detecting assays. J Neuroimmunol 2007;189:102–10.10.1016/j.jneuroim.2007.06.006Suche in Google Scholar

16. Polman CH, Bertolotto A, Deisenhammer F, Giovanni G, Hartung HP, Hemmer B, et al. Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol 2010;9:740–50.10.1016/S1474-4422(10)70103-4Suche in Google Scholar

17. Gilli F, Valentino P, Caldano M, Granieri L, Capobianco M, Malucchi S, et al. Expression and regulation of IFNalpha/beta receptor in IFNbeta-treated patients with multiple sclerosis. Neurology 2008;71:1940–7.10.1212/01.wnl.0000327340.50284.8dSuche in Google Scholar PubMed

18. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–7.10.1002/ana.1032Suche in Google Scholar PubMed

19. Hegen H, Millonig A, Bertolotto A, Comabella M, Giovanni G, Guger M, et al. Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development. Mult Scler J 2014;20:577–87.10.1177/1352458513503597Suche in Google Scholar PubMed

20. Río J, Nos C, Tintoré M, Téllez N, Galán I, Pelayo R, et al. Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients. Ann Neurol 2006;59:344–52.10.1002/ana.20740Suche in Google Scholar PubMed

21. Gneiss C, Tripp P, Reichartseder F, Egg R, Ehling R, Lutterotti A, et al. Differing immunogenic potentials of interferon beta preparations in multiple sclerosis patients. Mult Scler 2006;12:731–7.10.1177/1352458506070941Suche in Google Scholar PubMed

22. Kivisäkk P, Alm GV, Frederikson S, Link H. Neutralizing and binding anti-interferon-beta (IFN-beta) antibodies. A comparison between IFN-beta-1a and IFN-beta-1b treatment in multiple sclerosis. Eur J Neurol 2000;7:27–34.10.1046/j.1468-1331.2000.00002.xSuche in Google Scholar PubMed

23. Rose-John S, Heinrich PC. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J 1994;300:281–90.10.1042/bj3000281Suche in Google Scholar PubMed PubMed Central

24. Oliver B, Mayorga C, Fernández V, Leyva L, León A, Luque G, et al. Interferon receptor expression in multiple sclerosis patients. J Neuroimmunol 2007;183:225–31.10.1016/j.jneuroim.2006.11.010Suche in Google Scholar PubMed

25. Malucchi S, Gilli F, Caldano M, Marnetto F, Valentino P, Granieri L, et al. Predictive markers for response to interferon therapy in patients with multiple sclerosis. Neurology 2008;70(13Pt2):1119–27.10.1212/01.wnl.0000304040.29080.7bSuche in Google Scholar PubMed

26. Hundeshagen A, Hecker M, Paap BK, Angerstein C, Kandulski O, Fatum C, et al. Elevated type I interferon-like activity in a subset of multiple sclerosis patients: molecular basis and clinical relevance. J Neuroinflammation 2012;9:140.10.1186/1742-2094-9-140Suche in Google Scholar PubMed PubMed Central

27. Comabella M, Lünemann JD, Rio J, Sánchez A, López C, Juliá E, et al. A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis. Brain 2009;132:3353–65.10.1093/brain/awp228Suche in Google Scholar PubMed

28. Bustamante MF, Fissolo N, Rio J, Espejo C, Costa C, Mansilla MJ, et al. Implication of the Toll-like receptor 4 pathway in the response to interferon-β in multiple sclerosis. Ann Neurol 2011;70:634–45.10.1002/ana.22511Suche in Google Scholar PubMed

29. Serana F, Sottini A, Ghidini C, Zanotti C, Capra R, Cordioli C, et al. Modulation of IFNAR1 mRNA expression in multiple sclerosis patients. J Neuroimmunol 2008;197:54–62.10.1016/j.jneuroim.2008.03.019Suche in Google Scholar PubMed

30. Hoffmann S, Cepok S, Grummel V, Lehmann-Horn K, Hackermueller J, Stadler PF, et al. HLA-DRB1*0401 and HLA-DRB1*0408 are strongly associated with the development of antibodies against interferon-β therapy in multiple sclerosis. Am J Hum Genet 2008;83:219–27.10.1016/j.ajhg.2008.07.006Suche in Google Scholar PubMed PubMed Central

Received: 2015-1-25
Accepted: 2015-8-6
Published Online: 2015-10-13
Published in Print: 2016-4-1

©2016 by De Gruyter

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  7. Surrogatmarker der Insulinresistenz bei Studienteilnehmern mit metabolischem Syndrom – Daten der Berliner Altersstudie II
  8. Neurologisches Labor/Neurological Laboratory / Edited by: H. Tumani/U.K. Zettl
  9. Expression of interferon type-I receptor isoforms, clinical response and development of neutralizing antibodies in multiple sclerosis patients – results of a prospective study
  10. Fallbericht/Case Report
  11. Labordiagnostik bei der monoklonalen Gammopathie unklarer Signifikanz (MGUS)
  12. Originalartikel/Original Articles
  13. Comparison between capillary glucose measured with a Contour glucometer and plasma glucose in a population survey
  14. Supplements to a recent proposal for permissible uncertainty of measurements in laboratory medicine
  15. Butyrylcholinesterase as an additional marker in the diagnostic network of acute myocardial infarction
  16. Buchbesprechung/Book Review
  17. Molekulare Allergiediagnostik
https://doi.org/10.1515/labmed-2015-0020
Schlagwörter für diesen Artikel
interferon-β (IFNb); multiple sclerosis (MS); myxovirus protein A (MxA); neutralising antibodies (NAB); polymerase chain reaction (PCR); type-I interferon receptor (IFNAR)
Creative Commons
BY-NC-ND 3.0

Artikel in diesem Heft

  1. Frontmatter
  2. Allergie und Autoimmunität/Allergy and Autoimmunity / Redaktion: U. Sack/K. Conrad
  3. Qualitätskontrolle und Validierung in der diagnostischen Durchflusszytometrie
  4. Quality management in IgE-based allergy diagnostics
  5. Labordiagnostik bei systemischen Autoimmunerkrankungen
  6. Geriatrisches Labor/Geriatrics Laboratory / Redaktion: P. Schuff-Werner
  7. Surrogatmarker der Insulinresistenz bei Studienteilnehmern mit metabolischem Syndrom – Daten der Berliner Altersstudie II
  8. Neurologisches Labor/Neurological Laboratory / Edited by: H. Tumani/U.K. Zettl
  9. Expression of interferon type-I receptor isoforms, clinical response and development of neutralizing antibodies in multiple sclerosis patients – results of a prospective study
  10. Fallbericht/Case Report
  11. Labordiagnostik bei der monoklonalen Gammopathie unklarer Signifikanz (MGUS)
  12. Originalartikel/Original Articles
  13. Comparison between capillary glucose measured with a Contour glucometer and plasma glucose in a population survey
  14. Supplements to a recent proposal for permissible uncertainty of measurements in laboratory medicine
  15. Butyrylcholinesterase as an additional marker in the diagnostic network of acute myocardial infarction
  16. Buchbesprechung/Book Review
  17. Molekulare Allergiediagnostik
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Heruntergeladen am 25.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/labmed-2015-0020/html
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