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Gamze Kabalak,
Rachel M Thomas,
Javier Martin,
Noberto Ortego-Centeno,
Juan Jimenez-Alonso,
Enrique de Ramón, Sabine Buyny,
Sandra Hamsen,
Wolfgang L Gross,
Sebastian Schnarr,
Henning Zeidler,
Erika Gromnica-Ihle,
Reinhold E Schmidt,
Torsten Witte
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ABSTRACT: NKG2D, involved in T-cell activation and viral defense, shows a single-nucleotide polymorphism (SNP) in the transmembrane region, characterized by a substitution of alanine with threonine. We examined the association of systemic lupus erythematosus (SLE) with one of the NKG2D gene variants. We also studied the functional impact of that allele in SLE. Restriction fragment length polymorphism/polymerase chain reaction specific for the SNP rs2255336 G--> A was performed with 247 German SLE patients and 447 controls and with 284 Spanish SLE patients and 180 controls. NKG2D expression on peripheral blood lymphocytes of SLE patients was analyzed via fluorescence activated cell sorter. In addition, proliferation assays were performed. We found that the NKG2D alanine/alanine (G/G) gene variant was significantly associated with SLE in the German cohort (70.4% vs 60.8% controls; p = 0.0027) and almost significantly in the Spanish cohort (66.2% vs 62.2% controls; p = 0.054). In a pooled analysis, the prevalence of G/G was 68.2% in SLE versus 61.2% in the controls (p = 0.0024). There were no significant differences in the expression levels of NKG2D on peripheral blood lymphocytes of the different genotypes. A comparison of the coreceptor activity of the genotypes in response to CD3 and NKG2D antibodies revealed a trend toward higher proliferation in the A/A genotype. In conclusion, based on our study results, SLE is associated with the SNP rs2255336 of NKG2D.
Human immunology 09/2009; 71(1):74-8. · 2.55 Impact Factor
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ABSTRACT: Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by the loss of self-tolerance to nuclear antigens. Aberrant T-cell function plays a central role in lupus pathogenesis. We and others previously demonstrated that peripheral TCRalphabeta+CD3+ T cells express CD8beta either at a high (CD8beta(high)) or low density (CD8beta(low)), thereby defining two functionally distinct subsets. CD8beta(low) T cells express predominantly CD8alphaalpha and less CD8alphabeta as a coreceptor, display a differentiated phenotype and exert effector function. CD8beta(high) T cells appear to be the precursors expressing predominantly the heterodimeric efficient CD8alphabeta coreceptor, exhibiting a naïve phenotype and high proliferative capacity. In the present study, the distribution and functional properties of CD8beta(high) and CD8beta(low) T cells of SLE patients were compared (n = 20) with those of healthy subjects (n = 16). It was found that expansion of CD8beta(low) T-cell subset correlated with disease activity indicating chronic antigenic stimulation leading to a major lack of naïve CD8beta(high) precursor T cells in SLE. Functional characteristics of CD8beta(low) T cells including production of cytokines and cytotoxic granules were not significantly different between patients with SLE and healthy individuals. We speculate that unbalanced CD8beta(high)/CD8beta(low) T-cell relation reflects a skewed homeostasis within the CD8+ T-cell compartment towards fully differentiated effector T cells possibly due to persistent antigen stimulation in SLE.
Scandinavian Journal of Immunology 06/2008; 67(5):501-8. · 2.23 Impact Factor
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ABSTRACT: Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by the loss of self-tolerance to nuclear antigens. Aberrant T-cell function plays a central role in lupus pathogenesis. We and others previously demonstrated that peripheral TCRαβ+CD3+ T cells express CD8β either at a high (CD8βhigh) or low density (CD8βlow), thereby defining two functionally distinct subsets. CD8βlow T cells express predominantly CD8αα and less CD8αβ as a coreceptor, display a differentiated phenotype and exert effector function. CD8βhigh T cells appear to be the precursors expressing predominantly the heterodimeric efficient CD8αβ coreceptor, exhibiting a naïve phenotype and high proliferative capacity. In the present study, the distribution and functional properties of CD8βhigh and CD8βlow T cells of SLE patients were compared (n = 20) with those of healthy subjects (n = 16). It was found that expansion of CD8βlow T-cell subset correlated with disease activity indicating chronic antigenic stimulation leading to a major lack of naïve CD8βhigh precursor T cells in SLE. Functional characteristics of CD8βlow T cells including production of cytokines and cytotoxic granules were not significantly different between patients with SLE and healthy individuals. We speculate that unbalanced CD8βhigh/CD8βlow T-cell relation reflects a skewed homeostasis within the CD8+ T-cell compartment towards fully differentiated effector T cells possibly due to persistent antigen stimulation in SLE.
Scandinavian Journal of Immunology 04/2008; 67(5):501 - 508. · 2.23 Impact Factor
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ABSTRACT: Thrombomodulin is an endothelial cell membrane glycoprotein and is detected in plasma and serum after endothelial injury. In our study comprising 311 patients with systemic lupus erythematosus (SLE) clinical and laboratory associations of elevated thrombomodulin serum concentrations were examined. Elevated thrombomodulin concentrations were detected in 7.1% of the SLE patients and were associated with nephritis including the laboratory parameters proteinuria and erythrocyte casts, vasculitis and neurological involvement of the central nervous system. These correlations remained significant after consideration of the influence of renal function. In SLE, the serum thrombomodulin concentration may become a marker to monitor damage of endothelial cells and involvement of the central nervous system.
Rheumatology International 02/1999; 19(1-2):15-8. · 1.88 Impact Factor
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ABSTRACT: Recent findings underline the role of NK cell subsets in regulating adaptive immunity. To define characteristics of NK cell subpopulations, purified CD56(dim) and CD56(bright) NK cells were analyzed by using gene chip arrays covering more than 39,000 transcripts. Gene profiling revealed resting NK cells to differ in respect to 473 transcripts with 176 exclusively expressed in CD56(dim) and 130 solely in CD56bright NK cells. Results were compared with array analyses using mRNA obtained from activated CD56(bright) and CD56 bright NK cells. In this approach, NK cell receptors, cytolytic molecules, adhesion structures, and chemokine ligands showed differential expression patterns in the two subpopulations. These data were validated using FACS, RT-qPCR, or cytokine bead array (CBA) techniques. Cytokines produced by CD56(dim) and CD56(bright) NK cells were determined using a protein array covering 79 different hioactive mediators. GDNF, IGFBP-1, EGF, and TIMP-2 were detected in both subsets. In contrast, IGFBP-3 and IGF-1 were mainly produced by CD56, while GM-CSF, TARC, and TGF beta 3 were expressed by CD56 bright NK cells. In summary, we report new characteristic features of CD56(dim) and CD56(bright) NK cells, further underscoring that they represent independent populations with functionally diverse capabilities. The information on NK cells generated in this study will help to define corresponding NK cell populations in other species that lack CD56 expression on NK cells, such as mice. This will subsequently lead to the establishment of suitable animal models for detailed analysis of NK cell populations in vivo.
Journal of Leukocyte Biology. 80(6):1529-1541.
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ABSTRACT: Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by the loss of self-tolerance to nuclear antigens. Aberrant T-cell function plays a central role in lupus pathogenesis. We and others previously demonstrated that peripheral TCR alpha beta(+)CD3(+) T cells express CD8 beta either at a high (CD8 beta(high)) or low density (CD8 beta(low)), thereby defining two functionally distinct subsets. CD8 beta(low) T cells express predominantly CD8 alpha alpha and less CD8 alpha beta as a coreceptor, display a differentiated phenotype and exert effector function. CD8 beta(high) T cells appear to be the precursors expressing predominantly the heterodimeric efficient CD8 alpha beta coreceptor, exhibiting a naive phenotype and high proliferative capacity. In the present study, the distribution and functional properties of CD8 beta(high) and CD8 beta(low) T cells of SLE patients were compared (n = 20) with those of healthy subjects (n = 16). It was found that expansion of CD8 beta(low) T-cell subset correlated with disease activity indicating chronic antigenic stimulation leading to a major lack of naive CD8 beta(high) precursor T cells in SLE. Functional characteristics of CD8 beta(low) T cells including production of cytokines and cytotoxic granules were not significantly different between patients with SLE and healthy individuals. We speculate that unbalanced CD8 beta(high)/CD8 beta(low) T-cell relation reflects a skewed homeostasis within the CD8(+) T-cell compartment towards fully differentiated effector T cells possibly due to persistent antigen stimulation in SLE.
Scandinavian Journal of Immunology. 67(5):501-508.
