Analysis of the thiol status of peripheral blood leukocytes in rheumatoid arthritis patients

University of Massachusetts Amherst, Amherst Center, Massachusetts, United States
Journal of Leukocyte Biology (Impact Factor: 4.29). 05/2007; 81(4):934-41. DOI: 10.1189/jlb.0806533
Source: PubMed


Although the exact etiology of rheumatoid arthritis (RA) remains unknown, there is increasing evidence that reactive oxygen species and a pro-oxidant/antioxidant imbalance are an important part of the pathogenesis of joint tissue injury. Flow cytometry was used to evaluate the thiol status [surface-thiols and intracellular glutathione (iGSH)] of leukocytes from RA patients and controls. Levels of surface-thiols and iGSH of leukocytes from RA patients were significantly lower than of leukocytes from controls. CD53, a glycoprotein of the tetraspanin superfamily, which coprecipitates with the GSH recycling enzyme gamma-glutamyl transpeptidase, was elevated significantly on leukocytes from RA patients compared with leukocytes from controls. Surface-thiols and GSH play important roles in redox buffering of cells, providing protection from oxidative stress. The chronic inflammation of RA has been associated with oxidative stress, which is shown to cause a decline in the levels of cellular antioxidant sulfhydryls (R-SH). As antioxidant-protective levels also decline with age, the problem is compounded in older RA patients, who did have fewer R-SH. Chronic stress can also have an effect on telomere lengths, determining cell senescence and longevity. Although telomeres shorten with increasing age, our flow cytometry studies indicate that accelerated shortening in telomere lengths occurs with increasing age of RA patients, suggesting premature cellular aging. The paradox is that lymphocytes from RA patients are believed to resist apoptosis, and we suggest that the elevated expression of CD53, which results from the increased oxidative stress, may protect against apoptosis.

Download full-text


Available from: Robert B Zurier, Feb 07, 2016
  • Source
    • "Increased surface levels of CD53 in response to IL-2 were detected on both NK cells and T cells. Interestingly, up-regulation of CD53 under inflammatory conditions is also observed on macrophages in response to lipopolysaccharide [35], as well as on leukocytes obtained from rheumatoid arthritis patients [36], patients with atopic eczema [37], or in lesions after spinal cord injury [38]. The up-regulation of CD53 under inflammatory conditions is suggested to protect leukocytes from apoptosis during inflammation, underpinned by studies demonstrating that ligation of CD53 protect cells from apoptosis and promote increased cell survival [35], [39]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: NK cells express several tetraspanin proteins, which differentially modulate NK cell activities. The tetraspanin CD53 is expressed by all resting NK cells and was previously shown to decrease NK cell cytotoxicity upon ligation. Here, we show that CD53 ligation reduced degranulation of rat NK cells in response to tumour target cells, evoked redirected inhibition of killing of Fc-bearing targets, and reduced the IFN-γ response induced by plate-bound antibodies towards several activating NK cell receptors (Ly49s3, NKR-P1A, and NKp46). CD53 induced activation of the β2 integrin LFA-1, which was further enhanced upon co-stimulation with activating NK cell receptors. Concordant with a role for CD53 in increasing NK cell adhesiveness, CD53 ligation induced a strong homotypic adhesion between NK cells. Further, the proliferative capacity of NK cells to a suboptimal dose of IL-2 was enhanced by CD53 ligation. Taken together, these data suggest that CD53 may shift NK cell responses from effector functions towards a proliferation phase.
    Full-text · Article · May 2014 · PLoS ONE
  • Source
    • "Although both reduced GSH and Trx1 are able to make SNO-Trx1 denitrosylated, their ability of denitrosylation might be insufficient due to the depletion of GSH in cells induced by severe and/or chronic oxidative stress from RA [52, 70]. For example, levels of surface thiols and GSH of leukocytes from RA patients are significantly lower than those of leukocytes from controls [71]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rheumatoid arthritis is a chronic inflammatory disease characterized by synovial hyperplasia and progressive joint destruction. The impaired apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) is pivotal in this process. However, the molecular mechanisms responsible for the reduced apoptosis are not fully understood. Both nitric oxide and thioredoxin 1 as two important mediators are widely investigated in the pathogenesis of rheumatoid arthritis. Interestingly, studies have showed that thioredoxin 1 may serve as a master regulator of S-nitrosylation of caspase-3 to fine-tune apoptosis in vivo. Thus, it is anticipated that further investigations on the role of thioredoxin 1 in the S-nitrosylation and denitrosylation of caspase-3 in RA-FLS will likely provide a novel understanding of mechanisms implicated in the impaired apoptosis of RA-FLS. In this paper, we will provide an overview on pathways involved in the reduced apoptosis of RA-FLS and then discuss specially the possible roles of nitric oxide and the thioredoxin 1 redox system associated with apoptosis of RA-FLS.
    Full-text · Article · Apr 2013 · Mediators of Inflammation
  • Source
    • "Circulating peripheral blood cells, such as T cells, display oxidative stress due to depletion of glutathione in systemic lupus erythematosus [70]. Levels of surface thiols and intracellular glutathione of leukocytes are significantly lower in RA patients [71]. Excessive production of reactive oxygen species disturbs the redox status and can modulate the expression of inflammatory chemokines, leading to inflammatory processes [72]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In rheumatic and other chronic inflammatory diseases, high amounts of energy for the activated immune system have to be provided and allocated by energy metabolism. In recent time many new insights have been gained into the control of the immune response through metabolic signals. Activation of immune cells as well as reduced nutrient supply and hypoxia in inflamed tissues cause stimulation of glycolysis and other cellular metabolic pathways. However, persistent cellular metabolic signals can promote ongoing chronic inflammation and loss of immune tolerance. On the organism level, the neuroendocrine immune response of the hypothalamic-pituitary adrenal axis and sympathetic nervous system, which is meant to overcome a transient inflammatory episode, can lead to metabolic disease sequelae if chronically activated. We conclude that, on cellular and organism levels, a prolonged energy appeal reaction is an important factor of chronic inflammatory disease etiology.
    Full-text · Article · Jun 2012 · Arthritis research & therapy
Show more