Soluble Receptor Isoform of IFN-Beta (sIFNAR2) in Multiple Sclerosis Patients and Their Association With the Clinical Response to IFN-Beta Treatment

Alternative splicing; Soluble receptors; IFNAR; Interferon beta; Multiple sclerosisEmpalmament alternatiu; Receptors solubles; IFNAR; Interferó beta; Esclerosi múltipleSplicing alternativo; Receptores solubles; IFNAR; Interferón beta; Esclerosis múltiplePurpose: Interferon beta receptor 2 subunit (IFNAR2) can be produced as a transmembrane protein, but also as a soluble form (sIFNAR2) generated by alternative splicing or proteolytic cleavage, which has both agonist and antagonist activities for IFN-β. However, its role regarding the clinical response to IFN-β for relapsing-remitting multiple sclerosis (RRMS) is unknown. We aim to evaluate the in vitro short-term effects and after 6 and 12 months of IFN-β therapy on sIFNAR2 production and their association with the clinical response in MS patients. Methods: Ninety-four RRMS patients were included and evaluated at baseline, 6 and 12 months from treatment onset. A subset of 41 patients were classified as responders and non-responders to IFN-β therapy. sIFNAR2 serum levels were measured by ELISA. mRNA expression for IFNAR1, IFNAR2 splice variants, MxA and proteases were assessed by RT-PCR. The short-term effect was evaluated in PBMC from RRMS patients after IFN-β stimulation in vitro. Results: Protein and mRNA levels of sIFNAR2 increased after IFN-β treatment. According to the clinical response, only non-responders increased sIFNAR2 significantly at both protein and mRNA levels. sIFNAR2 gene expression correlated with the transmembrane isoform expression and was 2.3-fold higher. While MxA gene expression increased significantly after treatment, IFNAR1 and IFNAR2 only slightly increased. After short-term IFN-β in vitro induction of PBMC, 6/7 patients increased the sIFNAR2 expression. Conclusions: IFN-β administration induces the production of sIFNAR2 in RRMS and higher levels might be associated to the reduction of therapeutic response. Thus, levels of sIFNAR2 could be monitored to optimize an effective response to IFN-β therapy.This research was funded by grants from the Instituto de Salud Carlos III and co-funded by European Regional Development Fund (ERDF), Technological Development Project in health DTS/1800045 to BO-M. BO-M holds a contract from Red Andaluza de Investigacion Clínica y Traslacional en Neurología (Neuro-reca) (RIC-0111-2019). PA-G is supported by Promoción de Empleo Joven e Implantación de la Garantía Juvenil 2018 (PEJ2018-002719-A). JR-B is supported by grants from Red Temática de Investigación Cooperativa, Red Española de Esclerosis Multiple REEM (RD16/0015/0010). LL holds a Nicolás Monardes research contract (RC-002-2019) from the Andalusian Ministry of Health and Family. IB-M holds a pFIS contract (FI19/00139) from the Spanish Science and Innovation Ministry

Genetic parameters for social effects on survival in cannibalistic layers: Combining survival analysis and a linear animal model

<p>Abstract</p> <p>Background</p> <p>Mortality due to cannibalism in laying hens is a difficult trait to improve genetically, because censoring is high (animals still alive at the end of the testing period) and it may depend on both the individual itself and the behaviour of its group members, so-called associative effects (social interactions). To analyse survival data, survival analysis can be used. However, it is not possible to include associative effects in the current software for survival analysis. A solution could be to combine survival analysis and a linear animal model including associative effects. This paper presents a two-step approach (2STEP), combining survival analysis and a linear animal model including associative effects (LAM).</p> <p>Methods</p> <p>Data of three purebred White Leghorn layer lines from Institut de Sélection Animale B.V., a Hendrix Genetics company, were used in this study. For the statistical analysis, survival data on 16,780 hens kept in four-bird cages with intact beaks were used. Genetic parameters for direct and associative effects on survival time were estimated using 2STEP. Cross validation was used to compare 2STEP with LAM. LAM was applied directly to estimate genetic parameters for social effects on observed survival days.</p> <p>Results</p> <p>Using 2STEP, total heritable variance, including both direct and associative genetic effects, expressed as the proportion of phenotypic variance, ranged from 32% to 64%. These results were substantially larger than when using LAM. However, cross validation showed that 2STEP gave approximately the same survival curves and rank correlations as LAM. Furthermore, cross validation showed that selection based on both direct and associative genetic effects, using either 2STEP or LAM, gave the best prediction of survival time.</p> <p>Conclusion</p> <p>It can be concluded that 2STEP can be used to estimate genetic parameters for direct and associative effects on survival time in laying hens. Using 2STEP increased the heritable variance in survival time. Cross validation showed that social genetic effects contribute to a large difference in survival days between two extreme groups. Genetic selection targeting both direct and associative effects is expected to reduce mortality due to cannibalism in laying hens.</p