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- Chiang, S. C. C., et al.
(författare)
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Comparison of primary human cytotoxic T-cell and natural killer cell responses reveal similar molecular requirements for lytic granule exocytosis but differences in cytokine production
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 121:8, s. 1345-1356
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Tidskriftsartikel (refereegranskat)abstract
- Cytotoxic lymphocytes, encompassing cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, kill pathogen-infected, neoplastic, or certain hematopoietic cells through the release of perforin-containing lytic granules. In the present study, we first performed probability-state modeling of differentiation and lytic granule markers on CD8(+) T cells to enable the comparison of bona fide CTLs with NK cells. Analysis identified CD57(bright) expression as a reliable phenotype of granule marker-containing CTLs. We then compared CD3(+)CD8(+)CD57(bright) CTLs with NK cells. Healthy adult peripheral blood CD3(+)CD8(+)CD57(bright) CTLs expressed more granzyme B but less perforin than CD3(-)CD56(dim) NK cells. On stimulation, such CTLs degranulated more readily than other T-cell subsets, but had a propensity to degranulate that was similar to NK cells. Remarkably, the CTLs produced cytokines more rapidly and with greater frequency than NK cells. In patients with biallelic mutations in UNC13D, STX11, or STXBP2 associated with familial hemophagocytic lymphohistiocytosis, CTL and NK cell degranulation were similarly impaired. Therefore, cytotoxic lymphocyte subsets have similar requirements for Munc13-4, syntaxin-11, and Munc18-2 in lytic granule exocytosis. The present results provide a detailed comparison of human CD3(+)CD8(+)CD57(bright) CTLs and NK cells and suggest that analysis of CD57(bright) CTL function may prove useful in the diagnosis of primary immunodeficiencies including familial hemophagocytic lymphohistiocytosis.
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| 2. |
- Meeths, M, et al.
(författare)
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Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 116:15, s. 2635-2643
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Tidskriftsartikel (refereegranskat)abstract
- Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal hyperinflammatory syndrome characterized by fever, hepatosplenomegaly, cytopenia, and in some cases hemophagocytosis. Here, we describe the mutation analysis, clinical presentation, and functional analysis of natural killer (NK) cells in patients with mutations in STXBP2 encoding Munc18-2, recently associated with familial HLH type 5. The disease severity among 11 persons studied here was highly variable and, accordingly, age at diagnosis ranged from 2 months to 17 years. Remarkably, in addition to typical manifestations of familial HLH (FHL), the clinical findings included colitis, bleeding disorders, and hypogammaglobulinemia in approximately one-third of the patients. Laboratory analysis revealed impairment of NK-cell degranulation and cytotoxic capacity. Interleukin-2 stimulation of lymphocytes in vitro rescued the NK cell–associated functional defects. In conclusion, familial HLH type 5 is associated with a spectrum of clinical symptoms, which may be a reflection of impaired expression and function of Munc18-2 also in cells other than cytotoxic lymphocytes. Mutations in STXBP2 should thus also be considered in patients with clinical manifestations other than those typically associated with HLH.
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| 7. |
- Sprafke, Johannes K., et al.
(författare)
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Belt-Shaped π-Systems: Relating Geometry to Electronic Structure in a Six-Porphyrin Nanoring
- 2011
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 133:43, s. 17262-17273
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Tidskriftsartikel (refereegranskat)abstract
- Linear pi-conjugated oligomers have been widely investigated, but the behavior of the corresponding cyclic oligomers is poorly understood, despite the recent synthesis of pi-conjugated macrocycles such as [n]cycloparaphenylenes and cyclo[n]thiophenes. Here we present an efficient template-directed synthesis of a pi-conjugated butadiyne-linked cyclic porphyrin hexamer directly from the monomer. Small-angle X-ray scattering data show that this nanoring is shape-persistent in solution, even without its template, whereas the linear porphyrin hexamer is relatively flexible. The crystal structure of the nanoring-template complex shows that most of the strain is localized in the acetylenes; the porphyrin units are slightly curved, but the zinc coordination sphere is undistorted. The electrochemistry, absorption, and fluorescence spectra indicate that the HOMO-LUMO gap of the nanoring is less than that of the linear hexamer and less than that of the corresponding polymer. The nanoring exhibits six one-electron reductions and six one-electron oxidations, most of which are well resolved. Ultrafast fluorescence anisotropy measurements show that absorption of light generates an excited state that is delocalized over the whole pi-system within a time of less than 0.5 ps. The fluorescence spectrum is amazingly structured and red-shifted. A similar, but less dramatic, red-shift has been reported in the fluorescence spectra of cycloparaphenylenes and was attributed to a high exciton binding energy; however the exciton binding energy of the porphyrin nanoring is similar to those of linear oligomers. Quantum-chemical excited state calculations show that the fluorescence spectrum of the nanoring can be fully explained in terms of vibronic Herzberg-Teller (HT) intensity borrowing.
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