Tag: IL-2

Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a seriously long-term and debilitating illness of unknown cause hallmarked by chronic pain and fatigue, memory and concentration impairment, and inflammation. ME/CFS hypothesis involves impaired Transient receptor potential melastatin 3 (TRPM3) ion channel function, affecting calcium signaling and Natural killer (NK) cell functions.

Currently, substances called opioids, agonists of mu (μ)-opioid receptors (μOR), are the strongest painkillers clinically available for people suffering from strong or long-lasting pain characteristic of ME/CFS. μOR have been reported to specifically inhibit TRPM3 and to be expressed in immune cells where they play an immunomodulatory and immunosuppressive role. Naltrexone hydrochloride (NTX) acts as an antagonist to the μOR thus negating the inhibitory function of this opioid receptor on TRPM3.

Therefore, understanding the mechanism of action for NTX in regulating and modulating TRPM3 channel function in NK cells will provide important information for the development of effective therapeutic interventions for ME/CFS. Whole-cell patch-clamp technique was used to measure TRPM3 activity in Interleukin-2 (IL-2) stimulated and NTX-treated NK cells for 24 h on eight ME/CFS patients and 8 age- and sex-matched healthy controls, after modulation with a TRPM3-agonist, pregnenolone sulfate (PregS), NTX and a TRPM3-antagonist, ononetin. We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in IL-2 stimulated NK cells after modulation with PregS and ononetin.

Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX. Moreover, we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating. The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from ME/CFS patients, resulting in calcium signals remodeling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for ME/CFS. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.

Source: Cabanas H, Muraki K, Staines D and Marshall-Gradisnik S (2019) Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Front. Immunol. 10:2545. doi: 10.3389/fimmu.2019.02545 https://www.frontiersin.org/articles/10.3389/fimmu.2019.02545/full (Full article)

Interferon-γ and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome

Abstract:

Approximately 20% of patients with acute Q fever develop Q fever fatigue syndrome (QFS), a debilitating fatigue syndrome. This study further investigates the role of C. burnetii-specific IFNγ, but also IL-2, CXCL9, CXCL10, and CXLC11 production in QFS patients. C. burnetii-specific IFNy, IL-2, CXCL9, CXCL10, and CXCL11 production were tested in ex vivo stimulated whole blood of QFS patients who recovered from their complaints (n = 8), QFS patients with persisting complaints (n = 27), and asymptomatic Q fever seropositive controls (n = 10).

With the exclusion of one outlier, stimulation with C. burnetii revealed significantly higher IFNy and CXCL10 production in QFS patients with persisting complaints (medians 288.0 and 176.0 pg/mL, respectively) than in QFS patients who recovered from their complaints (medians 93.0 and 85.5 pg/mL, respectively) (p = 0.041 and 0.045, respectively). No significant differences between groups were found for C. burnetii-specific IL-2, CXCL9, and CXCL11 production.

These findings point towards a difference in cell-mediated immunity in QFS patients with persisting complaints compared to those who recovered from their complaints. Such a difference may aid to eventually diagnose QFS more objectively and might serve as an indicator of its underlying etiology.

Source: Raijmakers RPH, Jansen AFM, Keijmel SP, Schoffelen T, Scholzen A, van der Meer JWM, Joosten LAB, Netea MG, van Deuren M, Bleeker-Rovers CP. Interferon-γ and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome. Eur J Clin Microbiol Infect Dis. 2018 Jul;37(7):1385-1391. doi: 10.1007/s10096-018-3265-z. Epub 2018 May 26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015096/ (Full article)

A formal analysis of cytokine networks in chronic fatigue syndrome

Abstract:

Chronic Fatigue Syndrome (CFS) is a complex illness affecting 4 million Americans for which no characteristic lesion has been identified. Instead of searching for a deficiency in any single marker, we propose that CFS is associated with a profound imbalance in the regulation of immune function forcing a departure from standard pre-programmed responses.

To identify these imbalances we apply network analysis to the co-expression of 16 cytokines in CFS subjects and healthy controls. Concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12, 13, 15, 17 and 23, IFN-γ, lymphotoxin-α (LT-α) and TNF-α were measured in the plasma of 40 female CFS and 59 case-matched controls. Cytokine co-expression networks were constructed from the pair-wise mutual information (MI) patterns found within each subject group.

These networks differed in topology significantly more than expected by chance with the CFS network being more hub-like in design. Analysis of local modularity isolated statistically distinct cytokine communities recognizable as pre-programmed immune functional components.

These showed highly attenuated Th1 and Th17 immune responses in CFS. High Th2 marker expression but weak interaction patterns pointed to an established Th2 inflammatory milieu. Similarly, altered associations in CFS provided indirect evidence of diminished NK cell responsiveness to IL-12 and LT-α stimulus.

These observations are consistent with several processes active in latent viral infection and would not have been uncovered by assessing marker expression alone. Furthermore this analysis identifies key sub-networks such as IL-2:IFN-γ:TNF-α that might be targeted in restoring normal immune function.

Copyright © 2010 Elsevier Inc. All rights reserved.

Comment in: Letter to the editor re: “A formal analysis of cytokine networks in chronic fatigue syndrome” by Broderick et al. [Brain Behav Immun. 2010]

 

Source: Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun. 2010 Oct;24(7):1209-17. doi: 10.1016/j.bbi.2010.04.012. Epub 2010 May 4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939140/ (Full article)

 

Chronic fatigue. A prospective clinical and virologic study

Abstract:

To evaluate the clinical and virologic course of patients with chronic fatigue who had elevated Epstein-Barr virus (EBV) titers, we prospectively followed up 26 patients with serial cultures for EBV in blood and saliva and serial EBV serologic and clinical and psychiatric evaluations, and we compared these results with those for healthy controls.

The frequency of isolating EBV in blood or demonstrating EBV infection by in situ hybridization in blood lymphocytes or in saliva was similar in patients and controls. The prevalence and titers of antibody to human herpesvirus type 6 were also similar in the two populations. Patients with chronic fatigue did demonstrate higher in vitro natural killer activity and lower in vitro interleukin 2 production than controls, and patients had a high frequency of DSM-III depressive illness. Over 50% of patients with chronic fatigue improved over the course of follow-up. Improvement was not associated with any discernible change in titers of EBV proteins.

No evidence of ongoing EBV infection with either transforming or nontransforming strains was demonstrated in this population of patients with chronic fatigue. Clinically, most patients gradually improve over time.

 

Source: Gold D, Bowden R, Sixbey J, Riggs R, Katon WJ, Ashley R, Obrigewitch RM, Corey L. Chronic fatigue. A prospective clinical and virologic study. JAMA. 1990 Jul 4;264(1):48-53. http://www.ncbi.nlm.nih.gov/pubmed/2162397

 

Immunotherapy and enhanced antibody-dependent cell-mediated cytotoxicity using virally-infected target cells

Abstract:

We examined the ability of in vitro addition of Interleukin-2 (IL-2) to differentially enhance antibody-dependent cell mediated cytotoxicity (ADCC) utilizing cultured Epstein-Barr virus infected cells and gammaglobulin (Sandoglobulin). We found significant enhancement of ADCC when IL-2 was added. Chronic Epstein-Barr virus or Chronic Fatigue Syndrome patients in a therapeutic gammaglobulin program may benefit from IL-2 given in vivo.

 

Source: Bosse D, Ades EW. Immunotherapy and enhanced antibody-dependent cell-mediated cytotoxicity using virally-infected target cells. J Clin Lab Immunol. 1989 Jul;29(3):109-10. http://www.ncbi.nlm.nih.gov/pubmed/2561291