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


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.

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Available from: David A Hafler, Oct 03, 2015
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    • "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 "
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    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.
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    • "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. "
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    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.
    Developmental & Comparative Immunology 08/2014; 47(2). DOI:10.1016/j.dci.2014.08.002 · 2.82 Impact Factor
    • "Further, it appeared that follicular concentration of CXCL1 showed an overall negative correlation with soluble IL2RA and progesterone and that there were higher progesterone and IL2RA along with relatively lower CXCL1 in GnRH-ant group. The observed correlations along with the relative levels of these cytokines are possibly indicative of insufficient tissue homeostasis and heightened immune activation[5152] in the antagonist treated group. Furthermore, higher levels of CCL11, IL-12 and VEGF in follicular fluid of antagonist treated group were suggestive of higher inflammatory bias in dominant follicels [Figure 1]. "
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    ABSTRACT: Conflicting results were yielded about the superiority of gonadotropin-releasing hormone agonist (GnRH-a) versus gonadotropin-releasing hormone antagonist (GnRH-ant) protocols used in ovarian stimulation in in vitro fertilization (IVF) set-up. Reports also indicate that any single specific individual marker in follicular fluid collected at the time of oocyte retrieval bears inconclusive value as a predictor of oocyte quality. Simultaneous analyses of large numbers of cytokines, chemokines and growth factors in ovarian follicular fluid and perifollicular vascularity in both protocols for ovarian stimulation in IVF program to address the above mentioned lacunae. Normoresponder women (n = 45) were subjected to either GnRH-a (Group 1; n = 23) or GnRH-ant (Group 2; n = 22) for ovarian stimulation in IVF clinics. The fluid samples of dominant follicles collected at oocyte retrieval from women in Group 1 (GnRH-a; n = 20) and Group 2 (GnRH-ant; n = 16) were used for simultaneous quantitative assays of 48 cytokines. Perifollicular vascularity was assessed by Doppler hemodynamics to assess the ovarian vascular response in all participants in Groups 1 and 2. Despite demographic and reproductive parameters studied remained comparable, higher follicular fluid concentration of interleukins, IL-3 (P < 0.01), IL12p70 (P < 0.05) and vascular endothelial growth factor (P < 0.01), P4 (P < 0.05) and pulsatility index (P < 0.04) along with a lower number of oocytes in metaphase II stage (P < 0.03) was observed in Group 2 compared with Group 1. GnRH-a protocol appeared to be superior to GnRH-ant protocol for ovarian stimulation in normoresponder women.
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