Exploring the role of IFNs λ3 and λ4 polymorphism rs12979860 in Systemic lupus erythematosus
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1
Instituto Nacional de Cardiología Ignacio Chávez, Immunology, Mexico
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2
Instituto Nacional de Cardiología Ignacio Chávez, Nephrology, Mexico
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3
Instituto Nacional de Ciencias Médicas y la Nutrición Salvador Zubirán, Gastroenterology, Mexico
Systemic lupus erythematosus (SLE) is a multisystem disease that results from an abnormal immune response; it is characterized by a wide variety of clinical manifestations and multiple cellular abnormalities. SLE affects skin, kidneys, heart, central nervous system and joints (Tsokos, 2011). SLE has incidence rates that vary from about 1 to 10 cases per 100,000 people per year and the prevalence rate varies from 20-70 per 100,000 per year (Pons-Estel et al., 2010). The incidence of SLE in Mexico is unknown, but the point prevalence in 2011 was 0.07% (Alvarez-Nemegyei et al., 2011).
The development of SLE is heterogeneous and the major pathogenic mechanism is given by the polyclonal B cell activation, autoantibodies synthesis (i.e. antinuclear and anti-DNA), immune complex formation, T lymphocytes dysfunction of various subpopulations that affect production and function of various cytokine circuits (Wong et al., 2000). One of the best studied abnormalities in the etiopathogenesis of SLE occurs with the participation of different systems cytokines in the initiation and progression of the disease (Yap et al., 2013). Among these, the role of Type I Interferons (IFNs) in the pathogenesis of SLE has been extensively studied, and has an strong involvement, so that, type I IFNs pathway is currently a promissory therapeutic target in patients with SLE (Niewold et al, 2010; Crow et al., 2015). In particular the participation of type I IFNs in SLE has been established in various studies in animals and humans (Crow, 2014). In this sense, the type I IFNs concentration and / or activity in plasma, the elevation of a broad range of transcripts (IFN signature) in peripheral cells and genetic polymorphisms of the IFN pathway, IFN-α activity is involved in a high number of SLE patients, although the involvement of IFN-β is not discarded (Crow, 2014). In this regard, the infection is Epstein Barr virus present in most SLE patients (Hanlon et al., 2014). Furthermore, treatment with IFN-α in some individuals with HCV induced LES syndromes type with production of multiple autoantibodies (Niewold et al., 2005).
In 2003 Sheppard and collaborators determined the location of the genes coding for a new family of IFN called type III or λ, these genes are located on human chromosome 19 (19q13) different from the IFN genes type location I that located on chromosome 9 (Sheppard et al, 2003). It has been extensively studied that single nucleotide polymorphisms (SNPs) in the locus encompassing the IFNs λ3 also and the recently described IFN-λ4 and strongly determine the response to IFN-α endogenous (self-limiting viral infection) and exogenous peg-IFN-α plus Ribavirn therapy. Added to this, Lalle and colleagues evaluated the effect of this SNP may be the expression of the receptor 1 IFN-α (IFNR1) infected with Hepatitis C virus (HCV) patients and healthy subjects. Thus this study concluded that the SNP rs12979860 modulates the response to IFN-α in samples from healthy donors, being higher levels of mRNA expression in individuals carrying IFNR1 CC genotype (Lalle et al, 2013).
Because the rs12979860 polymorphism rare allele T has a high frequency in Mexican Mestizo (> 40 %), and modulates IFN-α, the aim of this study was to assess the involvement of rs12979860 polymorphysm in SLE patients and healthy individuals.
A total of 92 samples from patients with SLE and 22 samples from healthy donors (control group) were included. The genotypic variants of rs12979860 were determined by hybridization probes in a Roche LightCycler 2.0; Mononuclear peripheral blood cells (PBMC; 36 samples of SLE patients and 22 samples from healthy controls) were cultured and stimulated 24 h. with 1000 U of recombinant IFN-α, mRNA expression of IP-10, ISG15 and LY6E was determined by qRT-PCR. Also, the concentration of IP-10 secreted by PBMCs stimulated by IFN-α and serum concentration of IP-10 in SLE patients and healthy donors was determined by ELISA. We found that the TT genotype was associated with a lower frequency of anti-DNA antibodies positivity (p = 0.038), and a higher frequency of systemic hypertension (p = 0.016). As previously reported, serum levels of IP-10 were higher in patients with SLE compared to the control group (p <0.0001), and the IP-10 levels in serum correlated positively with SLEDAI (p = 0.004). Serum levels of IP-10 in the control group were higher in individuals with the CC genotypes presence, compared to CT TT individuals (p = 0.0054) but in patients with SLE serum levels of IP-10 were higher in patients with TT genotype compared to CC, CT patients (p = 0.015). In the in vitro experiments secretion levels of IP-10 were significantly induce by the treatment of 1000 U of IFN-α compared with RPMI both the control group and SLE patients (p <0.0001 respectively). Interestingly, the secretion of IP-10 was higher in both the control group and patients with SLE with presence of the C allele compared to T allele (p = 0.032 and p = 0.037, respectively). Also in culture, the mRNA expression levels of IP-10 mRNA were higher in the 1000 U treating IFN-α treatment compared to both RPMI control group and SLE patients (p <0.0001), and the levels of mRNA expression of ISGs (IP-10, ISG15 and LY6E) were higher in the treatment of 1000 U of IFN-α treatment compared with RPMI (p = 0.048, p = 0.019 and p = 0.010 respectively), however, no significant differences were found in the mRNA expression levels of the studied ISGs and IP-10 according to the genetic variants of rs12979860.
In conclusion, in our study the rs12979860 TT genotype was associated with a higher frequency of systemic hypertension and a lower presence of anti-DNA antibodies. The TT genotype was associated with higher levels of IP-10 in serum of patients with SLE, more interestingly; this genotype is associated with the production of IP-10 in PBMCs culture in both the control group and patients with SLE. However, more studies are necessary to clarify the participation of this and other polymorphisms in the locus of IFN-λ3 and λ4 involved in the modulation of responses associated with IFN-α in SLE.
Keywords:
IFNs λ3 and λ4,
Rs12979860,
systemic lupus erythematosus,
IFN-α,
Mexico
Conference:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015.
Presentation Type:
Oral Presentation
Topic:
Autoimmunity
Citation:
Sanchez-Munoz
F,
Juarez-Vicuña
Y,
Amezcua-Guerra
LM,
Villaseñor-Jasso
J,
Sixtos-Alonso
S,
Ballinas-Verdugo
MA,
MARQUEZ VELASCO
R and
Bojalil
R
(2015). Exploring the role of IFNs λ3 and λ4 polymorphism rs12979860 in Systemic lupus erythematosus.
Front. Immunol.
Conference Abstract:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología.
doi: 10.3389/conf.fimmu.2015.05.00319
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Received:
01 Jun 2015;
Published Online:
15 Sep 2015.
*
Correspondence:
PhD. Fausto Sanchez-Munoz, Instituto Nacional de Cardiología Ignacio Chávez, Immunology, Mexico, Mexico, fausto22@yahoo.com