Phytother Res. 2012 Aug;26(8):1246-8. doi: 10.1002/ptr.3679. Epub 2011 Dec 12.
Effectiveness of Nigella sativa oil in the management of rheumatoid arthritis patients: a placebo controlled study.
Gheita TA, Kenawy SA.
Faculty of Medicine, Cairo University, Egypt. firstname.lastname@example.org
The constituents of Nigella sativa modulate the immune system. The aim of the present work was to study the effectiveness of Nigella sativa oil in RA patients. Data from 40 female RA patients diagnosed according to the 2010 ACR/EULAR were analysed and discussed. The patients took two placebo (starch filled) capsules daily for 1 month. This was followed by a month of Nigella sativa oil capsules 500 mg twice/day. The disease activity score (DAS-28) significantly decreased after receiving the Nigella sativa capsules (4.55 ± 0.82) compared with before and after placebo (4.98 ± 0.79 and 4.99 ± 0.72, respectively) (p = 0.017). Similarly, the number of swollen joints and the duration of morning stiffness improved. A marked improvement in the disease activity was shown by both the ACR20 and EULAR response criteria in 42.5% and 30% of the patients, respectively, after intake of Nigella. Supplementation with Nigella sativa during DMARD therapy in RA may be considered an affordable potential adjuvant biological therapy.
Copyright © 2011 John Wiley & Sons, Ltd.
Br J Biomed Sci. 2011;68(3):131-7.
Thymoquinone, the active ingredient of Nigella sativa seeds, enhances survival and activity of antigen-specific CD8-positive T cells in vitro.
Salem ML, Alenzi FQ, Attia WY.
Zoology Department, Faculty of Science, Tanta University, Egypt. email@example.com
Recent preclinical and clinical studies provide evidence that adoptive transfer of in vitro activated T cells can results in significant antitumour responses in vivo upon acquisition of certain survival and homing properties during in vitro activation. Based on recent studies showing in vivo antioxidant effects of thymoquinone (TQ), the active ingredient of Nigella sativa seeds, this study aims to determine whether or not TQ can increase survival and sustain the expression of the homing receptor CD62L in antigen-specific T cells in vitro. The results showed that stimulation of OT-1 (transgenic CD+) T cells with OVA antigen resulted in activation, as shown by a decrease in the surface expression of CD62L which coincided with significant apoptosis measured three and five days after antigen stimulation. Addition of low concentrations of TQ during CD85+ T-cell activation resulted in enhanced survival of the activated T cells and sustained expression of CD62L. These effects coincided with enhancement in the capability of CD8+ T cells to produce the effector cytokine interferon-gamma (IFNgamma). These results suggest that TQ has a beneficial effect in conditioning T cells in vitro for adoptive T-cell therapy against cancer and infectious disease.
PMID: 21950205 [PubMed - indexed for MEDLINE]
US National Library of Medicine National Institutes of Health
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BMC Neurol. 2011 Aug 3;11:95. doi: 10.1186/1471-2377-11-95.
Decreased CD8+ T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes.
Pender MP, Csurhes PA, Pfluger CM, Burrows SR.
The University of Queensland, School of Medicine, Health Sciences Building, Royal Brisbane and Women's Hospital, Queensland 4029, Australia. firstname.lastname@example.org
Patients with multiple sclerosis (MS) have a decreased frequency of CD8+ T cells reactive to their own Epstein-Barr virus (EBV) infected B cells. We have proposed that this might predispose to the development of MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. The decreased CD8+ T cell response to EBV results from a general CD8+ T cell deficiency and also a decreased proportion of EBV-specific T cells within the total CD8+ T cell population. Because decreased HLA class I expression on monocytes and B cells has been reported in MS and could influence the generation and effector function of EBV-specific CD8+ T cells, the present study was undertaken to measure the expression of HLA molecules on B cells and monocytes in patients with MS.
We used flow cytometry to determine the proportions of T cells, natural killer cells, B cells and monocytes in peripheral blood mononuclear cells (PBMC) and to quantify the expression of HLA molecules on T cells, B cells and monocytes of 59 healthy subjects and 62 patients with MS who had not received corticosteroids or immunomodulatory therapy in the previous 3 months.
The levels of HLA class I and class II molecules expressed on T cells, B cells and monocytes were normal in patients with MS, with the exception of two patients with secondary progressive MS with very low class II expression on B cells. In confirmation of previous studies we also found that the percentage of CD8+ T cells was significantly decreased whereas the percentage of CD4+ T cells and the CD4:CD8 ratio were significantly increased in patients with MS compared to healthy subjects.
The decreased CD8+ T cell response to EBV-infected B cells in MS patients is not due to decreased HLA class I expression on monocytes or B cells. In a small proportion of patients decreased HLA class II expression on B cells might impair the CD8+ T cell response to EBV by reducing CD4+ T cell help.
J Neuroinflammation. 2013 Jul 27;10:94. doi: 10.1186/1742-2094-10-94.
Increased CD8+ T cell responses to apoptotic T cell-associated antigens in multiple sclerosis.
Lolli F, Martini H, Citro A, Franceschini D, Portaccio E, Amato MP, Mechelli R, Annibali V, Sidney J, Sette A, Salvetti M, Barnaba V.
Dipartimento di Scienze Biomediche, Sperimentali e Cliniche and Neurofarba, Università of Firenze, Azienda Ospedaliera di Careggi, Largo Brambilla 6, 50134 Firenze, Italy.
Here, we evaluated the hypothesis that CD8+ T cell responses to caspase-cleaved antigens derived from effector T cells undergoing apoptosis, may contribute to multiple sclerosis (MS) immunopathology.
The percentage of autoreactive CD8+ T effector cells specific for various apoptotic T cell-associated self-epitopes (apoptotic epitopes) were detected in the peripheral blood and cerebrospinal fluid (CSF) by both enzyme-linked immunospot and dextramers of class I molecules complexed with relevant apoptotic epitopes. Moreover, the capacity of dextramer+ CD8+ T cells to produce interferon (IFN)-γ and/or interleukin (IL)-17 in response to the relevant apoptotic epitopes was evaluated by the intracellular cytokine staining. Cross-presentation assay of apoptotic T cells by dendritic cells was also evaluated ex vivo.
We found that polyfunctional (IFN-γ and/or IL-17 producing) autoreactive CD8+ T cells specific for apoptotic epitopes were represented in MS patients with frequencies significantly higher than in healthy donors. These autoreactive CD8+ T cells with a strong potential to produce IFN-γ or IL-17 in response to the relevant apoptotic epitopes were significantly accumulated in the CSF from the same patients. In addition, the frequencies of these autoreactive CD8+ T cells correlated with the disease disability. Cross-presentation assay revealed that caspase-cleaved cellular proteins are required to activate apoptotic epitope-specific CD8+ T cells ex vivo.
Taken together, these data indicate that apoptotic epitope-specific CD8+ T cells with strong inflammatory potential are recruited at the level of the inflammatory site, where they may be involved in MS immunopathology through the production of high levels of inflammatory cytokines.
PLoS Pathog. 2013 Apr;9(4):e1003220. doi: 10.1371/journal.ppat.1003220. Epub 2013 Apr 11.
Increased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis.
Angelini DF, Serafini B, Piras E, Severa M, Coccia EM, Rosicarelli B, Ruggieri S, Gasperini C, Buttari F, Centonze D, Mechelli R, Salvetti M, Borsellino G, Aloisi F, Battistini L.
Neuroimmunology Unit, Fondazione Santa Lucia-I.R.C.C.S., Rome, Italy.
It has long been known that multiple sclerosis (MS) is associated with an increased Epstein-Barr virus (EBV) seroprevalence and high immune reactivity to EBV and that infectious mononucleosis increases MS risk. This evidence led to postulate that EBV infection plays a role in MS etiopathogenesis, although the mechanisms are debated. This study was designed to assess the prevalence and magnitude of CD8+ T-cell responses to EBV latent (EBNA-3A, LMP-2A) and lytic (BZLF-1, BMLF-1) antigens in relapsing-remitting MS patients (n = 113) and healthy donors (HD) (n = 43) and to investigate whether the EBV-specific CD8+ T cell response correlates with disease activity, as defined by clinical evaluation and gadolinium-enhanced magnetic resonance imaging. Using HLA class I pentamers, lytic antigen-specific CD8+ T cell responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively. In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase. Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS. Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients. Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges. We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse.
J Immunol. 2012 May 1;188(9):4671-80. doi: 10.4049/jimmunol.1103100. Epub 2012 Mar 28.
HLA-B7-restricted EBV-specific CD8+ T cells are dysregulated in multiple sclerosis.
Jilek S, Schluep M, Harari A, Canales M, Lysandropoulos A, Zekeridou A, Pantaleo G, Du Pasquier RA.
Division of Immunology and Allergy, Department of Medicine, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
It was hypothesized that the EBV-specific CD8(+) T cell response may be dysregulated in multiple sclerosis (MS) patients, possibly leading to a suboptimal control of this virus. To examine the CD8(+) T cell response in greater detail, we analyzed the HLA-A2-, HLA-B7-, and HLA-B8-restricted EBV- and CMV-specific CD8(+) T cell responses in a high number of MS patients and control subjects using tetramers. Content in cytolytic granules, as well as cytotoxic activity, of EBV- and CMV-specific CD8(+) T cells was assessed. We found that MS patients had a lower or a higher prevalence of HLA-A2 and HLA-B7, respectively. Using HLA class I tetramers in HLA-B7(+) MS patients, there was a higher prevalence of MS patients with HLA-B*0702/EBV(RPP)-specific CD8(+) T cells ex vivo. However, the magnitude of the HLA-B*0702/EBV(RPP)-specific and HLA-B*0702/CMV(TPR)-specific CD8(+) T cell response (i.e., the percentage of tetramer(+) CD8(+) T cells in a study subject harboring CD8(+) T cells specific for the given epitope) was lower in MS patients. No differences were found using other tetramers. After stimulation with the HLA-B*0702/EBV(RPP) peptide, the production of IL-2, perforin, and granzyme B and the cytotoxicity of HLA-B*0702/EBV(RPP)-specific CD8(+) T cells were decreased. Altogether, our findings suggest that the HLA-B*0702-restricted viral (in particular the EBV one)-specific CD8(+) T cell response is dysregulated in MS patients. This observation is particularly interesting knowing that the HLA-B7 allele is more frequently expressed in MS patients and considering that EBV is associated with MS.
1. PLoS One. 2012;7(9):e46120. doi: 10.1371/journal.pone.0046120. Epub 2012 Sep 25.
Epstein-Barr virus peptide presented by HLA-E is predominantly recognized by CD8(bright) cells in multiple sclerosis patients.
Jørgensen PB, Livbjerg AH, Hansen HJ, Petersen T, Höllsberg P.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection, but impaired immune suppression may be part of the disease pathogenesis. CD8(+) T cells that are restricted by HLA-E exert an important immunoregulatory mechanism. To explore how EBV might interfere with immune regulation, we examined the expression of HLA-E and the frequency of CD8(+) cells recognizing HLA-E, presenting either an EBV peptide from the BZLF1 protein or a signal sequence peptide from HLA-A2, in relapsing remitting (MS-RR), primary progressive (MS-PP) MS patients, and healthy controls (HC). Treatment with IFN-α or EBV increased HLA-E expression on CD4(+) cells. However, only MS-PP had increased expression of HLA-E on resting CD4(+) cells when compared with HC (p<0.005). CD8(+) cells were divided into CD8(bright) and CD8(dim) cells by flow cytometry analyses. MS-RR had significantly fewer CD8(dim) cells than HC (p<0.003). Flow cytometry analyses were performed with HLA-E tetramers folded in the presence of the EBV or HLA-A2 peptide to identify HLA-E-interacting cells. MS-RR had increased frequency of CD8(bright) cells recognizing HLA-E/A2 (p=0.006) and HLA-E/BZLF1 (p=0.016). Conversely, MS-RR had fewer CD8(dim) cells that recognized HLA-E/BZLF1 (p=0.001), but this could be attributed to the overall lower number of CD8(dim) cells in MS-RR. Whereas HLA-E/A2 was predominantly recognized by CD8(dim) cells, HLA-E/BZLF1 was predominantly recognized by CD8(bright) cells in MS-RR and MS-PP, but not in HC. As expected, HLA-E/A2 was also recognized by CD8-negative cells in a CD94-dependent manner, whereas HLA-E/BZLF1 was poorly recognized in all groups by CD8-negative cells. These data demonstrate that MS-RR patients have expanded their CD8(bright) cells recognizing HLA-E/BZLF1. Moreover, HLA-E/BZLF1 appears to be recognized by the immune system in a different manner than HLA-E/A2.
1. Iran J Allergy Asthma Immunol. 2013 Jul 13;12(3):276-80.
Low and High CD8 Positive T cells in Multiple Sclerosis Patients.
Izad M, Harirchian MH, Amiri H, Najafi F, Ghaflati Z, Salehi Z.
Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. email@example.com.
Cumulating evidence points to a key role for CD8+ T cells in the pathogenesis of multiple sclerosis.CD8 expression level was believed to be present constantly on the surface of human peripheral blood T cells. However, it was shown that peripheral blood lymphocytes may be divided by the level of CD8 expression, into CD8+high and CD8+low T cells. Now it is well established that the CD8low population of CD8+ T cells demonstrates an activated effector phenotype while the CD8+high T cells have been reported to have regulatory function. In this report we used a flow cytometric assay to compare the frequency of these two subsets in multiple sclerosis patients (n=31) with healthy age- and gender-matched controls (n=18). We found that CD8+ T cells and CD8+low T cells significantly increased in secondary progressive (SP) and primary progressive multiple sclerosis (PPMS) patients in comparison to controls (p<0.0002 and p<0.004 respectively) and also RRMS (p<0.005 and p<0.017 respectively). These results demonstrated the role of CD8low T cells in progressive form of multiple sclerosis.
PMID: 23893812 [PubMed - in process]
J Autoimmun. 2011 Mar;36(2):115-24. doi: 10.1016/j.jaut.2010.12.003. Epub 2011 Jan 22.
Neuroantigen-specific CD8+ regulatory T-cell function is deficient during acute exacerbation of multiple sclerosis.
Baughman EJ, Mendoza JP, Ortega SB, Ayers CL, Greenberg BM, Frohman EM, Karandikar NJ.
Department of Pathology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). MS is thought to be T-cell-mediated, with prior research predominantly focusing on CD4+ T-cells. There is a high prevalence of CNS-specific CD8+ T-cell responses in MS patients and healthy subjects. However, the role of neuroantigen-specific CD8+ T-cells in MS is poorly understood, with the prevalent notion that these may represent pathogenic T-cells. We show here that healthy subjects and MS patients demonstrate similar magnitudes of CD8+ and CD4+ T-cell responses to various antigenic stimuli. Interestingly, CD8+ T-cells specific for CNS autoantigens, but not those specific for control foreign antigens, exhibit immune regulatory ability, suppressing proliferation of CD4+CD25- T-cells when stimulated by their cognate antigen. While CD8+ T-cell-mediated immune suppression is similar between healthy subjects and clinically quiescent treatment-naïve MS patients, it is significantly deficient during acute exacerbation of MS. Of note, the recovery of neuroantigen-specific CD8+ T-cell suppression correlates with disease recovery post-relapse. These studies reveal a novel immune suppressor function for neuroantigen-specific CD8+ T-cells that is clinically relevant in the maintenance of peripheral tolerance and the intrinsic regulation of MS immune pathology.
Copyright © 2010 Elsevier Ltd. All rights reserve
J Neurol Neurosurg Psychiatry. 2009 May;80(5):498-505. doi: 10.1136/jnnp.2008.161018. Epub 2008 Nov 17.
Decreased T cell reactivity to Epstein-Barr virus infected lymphoblastoid cell lines in multiple sclerosis.
Pender MP, Csurhes PA, Lenarczyk A, Pfluger CM, Burrows SR.
University of Queensland, School of Medicine, Royal Brisbane and Women's Hospital, Queensland, Australia. firstname.lastname@example.org
To investigate T cell and antibody immunity to Epstein-Barr virus (EBV) in multiple sclerosis (MS).
Immunoglobulin G (IgG) immunity to EBV nuclear antigen 1 (EBNA1) and viral capsid antigen was measured by enzyme linked immunosorbent assays, and T cell immunity was assessed using enzyme linked immunospot assays to measure the frequency of peripheral blood mononuclear cells (PBMC) producing interferon gamma in response to autologous EBV infected B cell lymphoblastoid cell lines (LCL) in 34 EBV seropositive healthy subjects and 34 EBV seropositive patients with MS who had not received immunomodulatory therapy in the previous 3 months.
Patients with MS had increased levels of anti-EBNA1 IgG but a decreased frequency of LCL specific T cells compared with healthy subjects. Using purified populations of CD4(+) T cells and CD8(+) T cells, we showed that the LCL specific response resides predominantly in the CD8(+) population, with a frequency 5-7-fold higher than in the CD4(+) population. The decreased CD8(+) T cell response to LCL in MS was not caused by decreased HLA class I expression by LCL, and LCL from MS patients could be killed normally by HLA matched EBV specific cytotoxic CD8(+) T cell clones from healthy subjects. Furthermore, the decreased CD8(+) T cell immunity to EBV was not due to a primary defect in the function of CD8(+) T cells because EBV specific cytotoxic CD8(+) T cell lines could be generated normally from the PBMC of patients with MS.
This quantitative deficiency in CD8(+) T cell immunity to EBV might be responsible for the accumulation of EBV infected B cells in the brains of patients with MS.
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