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ID naloge: 63 Letnik: 1999 Predmet: patologija in histologija
Antigen predstavitvene celice pri lupusnem glomerulonefritisu
Avtor: Nika Babic
Mentor: akad.prof. dr. Dušan Ferluga, dr. med
Somentor: znanst. sod. dr. Alenka Vizjak, dipl. biol
Izhodišce. Antigen predstavitvene celice (APC) igrajo kljucno vlogo v imunskem odgovoru. Antigene predstavljajo v povezavi z molekulami tkivne skladnosti HLA-DR limfocitom T pomagalcem, kar sproži njihovo aktivacijo in omogoci vnetni odziv. Namen raziskave je bil ugotoviti navzocnost APC v glomerulih v normalni ledvici in lupusnem glomerulonefritisu (LGN). Sistemski lupus eritematozus (SLE) je avtoimunska bolezen, pri kateri je osnovni patogenetski mehanizem odlaganje imunskih kompleksov. Vzrok za hude poškodbe glomerula, povezane s kapsulno polmesecasto proliferacijo, bi lahko bila vpletenost celicnega imunskega odziva, ki ga posredujejo APC.
Material in metode. V retrospektivno raziskavo je bilo vkljucenih 10 vzorcev normalnih ledvic, 10 vzorcev z blagim mezangijskim LGN, 10 vzorcev z difuznim proliferacijskim LGN brez ekstrakapilarnih polmesecev in 8 vzorcev z difuznim proliferacijskim LGN s polmeseci v vec kot polovici glomerulov. Celice, pozitivne na oznacevalce za APC (CDla, 5100, HLA-DR), makrofage (CD68), limfocite T (CD3), limfocite T ubijalce (CD8), limfocite B (CD79a), endotelne celice (CD31, F VIII), mezangijske celice (gladkomišicni aktin) in podocite (vimentin), smo ugotavljali z imunoperoksidaznima tehnikama streptavidin-biotin in EnVision. Pozitivne celice smo šteli na veliki mikroskopski povecavi in izracunali njihovo povprecno število na glomerul. Pri obeh skupinah z difuznim proliferacijskim LGN smo izracunali tudi njihovo gostoto na glomerulno površino. Za statisticno vrednotenje izsledkov smo uporabili test analize variance z Bonferonijevim testom, T test, Pearsonov test in Kruskal-Wallissov test s Kolmogorov Smirnovim testom.
Rezultati. CD 1a+ celic v ledvicah nismo ugotovili. V intersticiju normalnih ledvic smo našli posamezne S100+ celice, v ledvicah bolnikov z LGN je njihova gostota narašcala s prizadetostjo glomerulov. Endotelne celice in redke mezangijske celice v glomerulih normalnih ledvic in mezangijskega LGN so na svoji površini izražale HLA-DR molekule. Primerjava HLA-DR z makrofagnim oznacevalcem CD68 je pokazala, da so mezangijske HLA-DR+ celice makrofagi. Število HLA-DR+ celic se je znacilno povecalo pri obeh oblikah difuznega proliferacijskega LGN (p<0,05), ceprav se je izražanje HLA-DR na endotelnih celicah pri difuznem proliferacijskem LGN s polmeseci zmanjšalo. Pri isti obliki LGN smo ugotovili tudi zmanjšano izražanje endotelnega oznacevalca. Makrofagi so bili v normalni ledvci navzoci v mezangiju (povprecno 0,5 na glomerul) in v svetlinah glomerulnih kapilar. Število mezangijskih makrofagov se je povecalo pri mezangijskem LGN (povprecno 2,0 na glomerul). Pri obeh oblikah difuznega LGN lokalizacije makrofagov ni bilo možno opredeliti. Število makrofagov na glomerul je bilo v primerjavi z normalno ledvico znacilno vecje (p<0,05). Makrofage smo našli tudi v ekstrakapilarnem polmesecu, povprecno 2,8 na polmesec. Primerjava števila HLADR+ in CD68+ celic je pokazala, da so HLA-DR+ celice v polmesecih vecinoma makofagi. Limfocite T smo v normalni ledvici našli le v posameznih glomerulih, povprecno 0,16 na glomerul. Njihovo število se je pri obeh oblikah difuznega proliferacijskega LGN v primerjavi z normalno ledvico znacilno povecalo. Mezangijske celice v glomerulu smo prikazali z imunohistokemijsko reakcijo na gladkomišicni aktin (GMA). Število GMA pozitivnih celic se je v primerjavi z normalno ledvico povecalo pri vseh oblikah LGN, statisticno znacilno povecanje smo ugotovili pri difuznem proliferacijskem LGN.
Zakljucek. V naši raziskavi nismo uspeli dokazati poklicnih APC v glomerulih niti v normalni ledvici niti v ledvici bolnikov z LGN. Ugotovili smo HLA-DR+ glomerulne celice in vnetnice, ki imajo sposobnost predstavljanja antigenov in so skupaj z limfociti T pomagalci najverjetneje vpletene v mehanizem celicne pozne preobcutljivosti pri hudih oblikah LGN.<
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[Abstract / English version]
Antigen presenting cells in lupus glomerulonefritis
Author: Nika Babic
Mentor: akad.prof. dr. Dušan Ferluga, dr. med
Co-mentor: znanst. sod. dr. Alenka Vizjak, dipl. biol
Introduction. Antigen presenting cells (APC) play a key role in immune response. They present antigens together with HLA-DR hystocompatibility molecules to the helper T lymphocytes, inducing their activation and mediating inflammatory reaction. The aim of this study was to establish APC in glomeruli of normal kidney and of lupus glomerulonephritis (LGN). Systemic lupus erythematosus is an autoimmune disease in which the main pathogenetic mechanism is the deposition of immune complexes. However, in severe injury of the glomeruli, associated with capsular crescentic proliferation, cellular immune reaction mediated by APC could be involved.
Material and methods. The retrospective study included 10 specimens of normal kidney, 10 specimens of mild mesangial LGN, 10 specimens of diffuse proliferative LGN without capsular crescents and 8 specimens of diffuse proliferative GN with crescents in more than half of the involved glomeruli. Immunoperoxidase techniques, streptavidin-biotin labelled and EnVision, were applied to demonstrate cells, positive for markers of APC (CD 1a, S 100, HLA-DR), macrophages (CD68), lymphocytes T (CD3), cytotoxic lymphocytes T (CD8), lymphocytes B (CD79a), endothelial cells (CD31, F VIII), mesangial cells (smooth muscle actin) and podocytes (vimentin). The results were statistically assessed by analysis of variance with the Bonferoni test, T test, Pearson test, and Kruskal-Walliss test with Kolmogorov-Smirnov test.
Results. CD 1a+ cells were not demonstrated in the kidney. Rare S 100++ cells were found in the interstitium of normal kidney. In the kidney of LGN patients, their density was increasing in correlation with the glomerular involvement. The HLA-DR molecule was expressed by endothelial cells and rare mesangial cells in the normal kidney. The comparison of HLA-DR with the macrophage marker CD68 showed that mesangial HLA-DR+ cells were macrophages. The number of HLA-DR+ cells was significantly higher in the two forms of LGN (p<0,05). However, the endothelial expression of HLA-DR was decreased in diffuse proliferative LGN with crescents. In this form of LGN, a decreased expression of the endothelial marker was also observed. Macrophages were found to be present in the mesangium (mean 0.5 per glomerul) and glomerular capillary lumen in normal kidney. The number of mesangial macrophages was increased in mesangial LGN (mean 2.0 per glomerul). It was not possible to determine the localization of glomerular macrophages in the two forms of diffuse proliferative LGN. The number of macrophages in relation to the normal kidney was significantly higher (p<0,05). Macrophages were also found to be present in extracapillary crescents, mean 2.8 per crescent. The correlation of HLA-DR+ and CD68+ cells showed that HLA-DR+ cells in crescents were mostly macrophages. Lymphocytes T were found to be present in rare glomeruli in normal kidney, mean 0.16 per glomerul. Their number in the two forms of diffuse proliferative LGN was significantly increased in comparison with normal kidney. Mesangial glomerular cells were demonstrated by immunohistochemical reaction for smooth muscle actin (SMA). The number of SMA+ cells was increased in all forms of LGN, the increase being statistically significant in diffuse proliferative LGN.
Conclusion. In our investigation, professional APC were not demonstrated in the glomeruli of normal kidney nor in the glomeruli of patients with LGN. However, HLA-DR+ glomerular and inflammatory cells were found in LGN. They are capable of presenting antigens and could, together with helper T lymphocytes, be involved in the mechanism of delayed cellular hypersensitivity in severe forms of LGN.
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