Article

Soluble IL-2RA Levels in Multiple Sclerosis Subjects and the Effect of Soluble IL-2RA on Immune Responses

Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
The Journal of Immunology (Impact Factor: 4.92). 03/2009; 182(3):1541-7. DOI: 10.4049/jimmunol.182.3.1541
Source: PubMed

ABSTRACT

Multiple sclerosis (MS) is an organ-specific autoimmune disorder that is in part genetically determined. The gene encoding the alpha-chain of the IL-2 receptor, IL2RA, harbors alleles associated with risk to MS and other autoimmune diseases. In addition, IL2RA genetic variants correlate with the levels of a soluble form of the IL-2 receptor in subjects with type 1 diabetes and multiple sclerosis. Here, we show that the IL2RA genotypes differentially affects soluble IL-2RA (sIL-2RA) levels in MS cases vs healthy controls; the two variants associated with MS (rs12722489 and rs2104286) account for 15 and 18% of the total variance in log(10)-transformed sIL-2RA concentration in control subjects but less so in subjects with MS (2 and 5%), suggesting that perturbations associated with disease or treatment may influence sIL-2RA levels in subjects with MS. Whereas analyses demonstrate that sIL-2RA serum concentrations are a remarkably stable phenotype in both healthy controls and untreated MS subjects, a difference is observed between benign and malignant MS. These data indicate that, in addition to specific allelic variants at IL2RA, immunological perturbations associated with aggressive forms of the disease can influence sIL-2RA levels in serum of MS subjects. We also demonstrate, functionally, that sIL-2RA can inhibit IL-2 signaling, yet enhance T cell proliferation and expansion. In summary, we propose that before disease onset, strong genetic factors associated with disease risk dictate sIL-2RA levels that may be further modulated with onset of chronic systemic inflammation associated with MS.

Download full-text

Full-text

Available from: David A Hafler
  • Source
    • "In the present study, we found that serum TNF-a levels were low overall in remitting patients and not related to grade on the EDSS or to scores on the functional scales measuring specific neurological impairment. There is some evidence that sIL-2R levels are susceptible to disturbances associated with the RRMS and its treatment (Maier et al., 2009). Therefore, we selected sIL-2Ra as a measure in the present study to test the T-cell-mediated immune "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Although much is known about cytokines and adhesion molecules during an active course of multiple sclerosis (MS), there is limited information about their serum levels during remission. Objective: This study aimed to (1) compare peripheral levels of tumor necrosis factor-a (TNF-a), soluble interleukin-2 receptor a (sIL-2Ra), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble E-selectin (sE-selectin) in MS patients during clinical remission with those of healthy controls and (2) explore possible relationships between the levels of these cytokines and adhesion molecules and neurological impairment. Methods: Initially, 92 patients with relapsing-remitting multiple sclerosis (RRMS) who were in clinical remission and 30 healthy controls were recruited for this study. The severity of neurological impairment was assessed with the Expanded Disability Status Scale (EDSS). Serum concentrations of TNF-a, sIL-2Ra, sICAM-1, and sE-selectin were determined using the sandwich enzyme-linked immunosorbent (ELISA) technique and compared between patients and controls. In a subset of RRMS patients (n ¼ 67), the levels of these cytokines and adhesion molecules were compared between subgroups of patients based on scores on the EDSS subscales, which measure disability level for specific neurological functions. Results: The MS patients’ TNF-a, sICAM-1, and sE-selectin levels were markedly lower than those of the controls, while their sIL-2Ra level was higher. The serum sICAM-1 concentration was positively associated with EDSS total score (r ¼ .291, p ¼ .017) as well as with the EDSS pyramidal (r ¼ .267, p ¼ .029) and cerebellar subscores (r ¼ .303, p ¼ .013). In the patients with cerebellar deficits and severe brain stem dysfunction, sICAM-1 levels were upregulated. Conclusion: Although a decreased sICAM-1 concentration was observed in RRMS patients in remission as compared to healthy controls, sICAM-1 seemed to reflect neurological impairment and clinical disability. These data suggest that increasing serum sICAM-1 levels may be associated with progression of cerebellar or brain stem perturbations. However, further studies are required to confirm these findings in a larger population of RRMS patients.
    Full-text · Article · May 2015 · Biological Research for Nursing
  • Source
    • "It was suggested that sCD25- bound IL-2 is preserved from degradation, since the prolonged survival of sCD25 did enhance serum levels of IL-2 and preserved its bioactivity in mice (Kobayashi et al., 1999). Furthermore sCD25 was reported to inhibit IL-2 signalling to human T cells by competing with surface CD25 for IL-2 binding (Maier et al., 2009), indicating an immunosuppressive role (Cabrera et al., 2010). Also, sCD25 is associated with infection in ducks (Huang et al., 2011) or humans (Saito et al., 2008) as well as immune disorders (Akin and Metcalfe, 2002; Downes et al., 2014; Huefner et al., 1992; Reddy et al., 2014) or malignancies (Bien and Balcerska, 2008; Hashimoto et al., 2013; Yoshida et al., 2013) characterising CD25 as a potential non-specific marker of an activated immune system. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polymorph-nuclear neutrophils (PMN) in cattle exhibit unique features when compared to human or murine PMN and are of particular interest concerning the risk of post-partum mammary gland or extra-mammary infections related to the periparturient suppression of neutrophil functions. Former studies could show that effects of IL-2 on innate immune cells such as PMN were mediated by the Interleukin-2 receptor (IL-2R) β and γ chains. In the current study we could detect IL-2Rα (CD25) expression on bovine PMN using flow-cytometric analysis. CD25 was detected on granulocytes from post-partum and early lactating cows with different inflammatory conditions. The expression of CD25 on PMN in blood and raw milk increased with disease severity. Our results suggest CD25 expression on PMN as a potential biomarker for acute infections in cattle. Furthermore, our data provide a basis to better understanding of the periparturient functional suppressions of PMN what might reveal new molecular targets for therapy or prevention of disease.
    Full-text · Article · Aug 2014 · Developmental & Comparative Immunology
    • "In view of this, studies are in progress to identify the functionally important polymorphisms and to estabb lish their biological roles. For instance, functional sigg nificance was demonstrated for rs6897932, rs2104286, and rs1800693 of the receptor genes IL7RA, IL2RA, and TNFRSF1A, respectively; i.e., different allelic variants of the genes determine different proportions of the membraneebound and soluble receptor forms383940. It is of importance that carriage of the risk allele is always associated with an elevated level of the soluble receptor form. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide association study (GWAS) provides a powerful tool for investigating the genetic architecture of human polygenic diseases and is generally used to identify the genetic factors of disease susceptibility, clinical phenotypes, and treatment response. The differences in allele frequencies of single nucleotide polymorphisms (SNPs) distributed throughout the genome are analyzed with a microarray technique or other technologies that allow simultaneous genotyping at several tens of thousands to several millions of SNPs per sample. Owing to its power to find out highly reliable differences between patients and controls, GWAS became a common approach to identification of the genetic susceptibility factors in complex diseases of a polygenic nature. Using multiple sclerosis (MS) as a prototype complex disease, the review considers the main achievements and challenges of using GWAS to identify the genes involved in the disease and, therefore, to better understand the pathogenetic molecular mechanisms and genetic risk factors.
    No preview · Article · Jul 2014 · Molecular Biology
Show more