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Reduced functional activity of natural killer cells in spondyloarthritis patients may be related to the expression of killer immunoglobulin-like receptor 1 (KIR3DL1)
No full textBackground: Inflammatory mediators in spondyloarthritis (SpA) comprise components of both innate and adaptive immune system (1). In this respect, interesting are the findings that natural killer (NK) cells possess killer immunoglobulin-like receptors (KIRs) that bind HLA-B27 homodimers, abnormal molecules lacking beta2-microglobulin: the interaction between these molecules seems to be relevant in the pathogenesis of SpA in humans.
Objectives: To determine the cytotoxic activity of NK cells bearing the inhibitory receptor KIR3DL1 in SpA patients.
Methods: After informed consent was obtained, we enrolled twenty-one outpatients (14 males, 7 females; mean age 49.2 years, range 39-68; mean disease duration 129 months, range 12-264): among these, eleven fulfilled the modified New York criteria for ankylosing spondylitis and ten were classified as having psoriatic arthritis, characterized predominantly by axial involvement, according to the Moll and Wright criteria modified by Helliwell. All patients showed active disease, as evidenced by BASDAI score (median 6.5, standard deviation ± 2.2). Twenty-one healthy volunteers matched for sex and age were also included. Peripheral blood mononuclear cells (PBMCs) from patients and controls were isolated from heparinized blood by Lymphoprep gradient centrifugation. Immunofluorescence and flow cytometry analysis were used to evaluate the expression of KIR3DL1 on NK and T lymphocytes by sequential gating on forward, side scatter and fluorescence parameters. Flow cytometry was also used to detect NK cell cytotoxicity through a degranulation assay which measures cell-surface expression of the lysosomal protein CD107a (LAMP-1) in PBMCs incubated with either K562, an erythroleukemia cell line, or the mouse mastocytoma cell line P815 pre-incubated with antibodies directed against the NK cell activating receptors CD16 and NKG2D (CD314). The significance of the differences was determined using the nonparametric Mann-Whitney test for unpaired samples and the Wilcoxon's test for matched samples; p values less than 0.05 were deemed statistically significant.
Results: A relevant increase in the expression of KIR3DL1 receptor on peripheral blood NK cells was found in SpA patients respect to healthy controls (p=0.024). Among patients, a significant increase in the KIR3DL1 expression on NK cells was found in respect to CD4+ (p=0.0001) and CD8+ T lymphocytes (p=0.0004). When we evaluated the cytotoxicity through the expression of CD107a on NK cells, no difference between patients and controls was found using either K562 or mAb-coated P815 cells as target, even if controls tended to show higher CD107a expression. In SpA patients a negative correlation between degranulation activity and BASDAI was shown (p=0.016, r=-0.639).
Conclusion: The increased expression of KIR3DL1 on NK cells from SpA patients respect to controls may be responsible for the dampened cytotoxic activity in our patients. Indeed, the NK cell population was largely activated, as indicated by high level of CD69 and HLA-DR expression. This observation supports the ''intrinsic'' reduced activity of NK cells from SpA patients, rather than the possibility that these cells may have exhausted their classical activity in vivo.
References:
Spondyloarthropathy: disease at the crossroads of immunity. FitzGerald O et al. Best Pract Res Clin Rheumatol 2006; 20: 949-67
The CD94/NKG2A killer inhibitory receptor inhibits CD69 receptor-induced mast cell degranulation
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Inactivation of the KIPMR1 gene of Kluyveromyces lactis results in defective cell-wall morphogenesis.
No full textInhibition of intercellular adhesion molecule-1 (ICAM-1) soluble ICAM-1 and Interleukin-4 by Nitric Oxide expression in migraine patients
No full textEvaluation of degranulation and cytokine production in natural killer cells from spondyloarthritis patients at single-cell level.
No full textBackground: A pathogenetic role of natural killer (NK) cells has been hypothesized in spondyloarthritides (SpA), but still conflicting data exist. Aim of this study was to investigate, in a cohort of SpA patients, the peripheral blood NK cell number, the cytokine production (IFNγ and TNFα), and the cytotoxic activity on target cell stimulation. Moreover, we aimed to evaluate the expression of KIR3DL1, an inhibitory receptor binding HLA class I alleles, including HLA B27 strongly associated with SpA, between different NK cell subsets. Methods: We enrolled 21 SpA patients and 21 healthy controls. Multicolor flow cytometry was used to analyze the cytokine levels triggered by activating receptors, the degranulation as CD107a surface expression on target cell stimulation, the number and KIR3DL1 expression on peripheral blood NK cells. Results: When stimulated with P815 cells preincubated with antibodies against activating receptors, NK cells produced IFNγ to a lesser extent respect to healthy controls (P = 0.0012). No differences were found in TNFα production and NK cell degranulation in patients and controls. We observed a higher frequency of KIR3DL1 positive NK cells from SpA patients than in controls (P = 0.02). Similar results were obtained in NK cell subsets. Conclusions: In our SpA patients, we observed a reduced IFNγ production, which may be explained by the elevated frequency of KIR3DL1 expressing NK cells, while the other parameters were similar to those of healthy controls. These results may support the role of NK cells in the pathogenesis of SpA, although more data are needed to substantiate these observations. © 2010 International Clinical Cytometry Society
The genetic regulation of SCN in cluster headache may be affected by Th1/Th2 cytokine derangement
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