RESUMEN
AIMS: Endoplasmic reticulum stress followed by the unfolded protein response is one of the cellular mechanisms contributing to the progression of α-synuclein pathology in Parkinson's disease and other Lewy body diseases. We aimed to investigate the activation of endoplasmic reticulum stress and its correlation with α-synuclein pathology in human post-mortem brain tissue. METHODS: We analysed brain tissue from 45 subjects-14 symptomatic patients with Lewy body disease, 19 subjects with incidental Lewy body disease, and 12 healthy controls. The analysed brain regions included the medulla, pons, midbrain, striatum, amygdala and entorhinal, temporal, frontal and occipital cortex. We analysed activation of endoplasmic reticulum stress via levels of the unfolded protein response-related proteins (Grp78, eIF2α) and endoplasmic reticulum stress-regulating neurotrophic factors (MANF, CDNF). RESULTS: We showed that regional levels of two endoplasmic reticulum-localised neurotrophic factors, MANF and CDNF, did not change in response to accumulating α-synuclein pathology. The concentration of MANF negatively correlated with age in specific regions. eIF2α was upregulated in the striatum of Lewy body disease patients and correlated with increased α-synuclein levels. We found the upregulation of chaperone Grp78 in the amygdala and nigral dopaminergic neurons of Lewy body disease patients. Grp78 levels in the amygdala strongly correlated with soluble α-synuclein levels. CONCLUSIONS: Our data suggest a strong but regionally specific change in Grp78 and eIF2α levels, which positively correlates with soluble α-synuclein levels. Additionally, MANF levels decreased in dopaminergic neurons in the substantia nigra. Our research suggests that endoplasmic reticulum stress activation is not associated with Lewy pathology but rather with soluble α-synuclein concentration and disease progression.
Asunto(s)
Chaperón BiP del Retículo Endoplásmico , Factor 2 Eucariótico de Iniciación , Proteínas de Choque Térmico , Enfermedad por Cuerpos de Lewy , Respuesta de Proteína Desplegada , Regulación hacia Arriba , alfa-Sinucleína , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , alfa-Sinucleína/metabolismo , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Chaperón BiP del Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Factor 2 Eucariótico de Iniciación/metabolismo , Proteínas de Choque Térmico/metabolismo , Enfermedad por Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Respuesta de Proteína Desplegada/fisiologíaRESUMEN
PD-L1 is one of the two programmed cell death 1 (PD-1) ligands and a part of an immune checkpoint system (PD-1/PD-L1) with widespread clinical application. The aim of this study was to investigate PD-L1 expression and its association with clinicopathological and prognostic significance in non-clear cell renal cell carcinoma (non-ccRCC) patients. A total of 41 papillary (pRCC) and 20 chromophobe (chRCC) RCC tumors were examined for PD-L1 expression by immunohistochemistry in the cancer cells and tumor-infiltrating mononuclear cells (TIMCs). PD-L1 positivity was detected in 36.6% pRCC and 85.0% chRCC cancer cells, while PD-L1 positivity was observed in 73.2% pRCC and 50.0% chRCC TIMCs. PD-L1 positivity in both pRCC and chRCC tumor cells was not correlated with any of the examined clinicopathological features, while PD-L1 positivity in TIMCs was associated with the age of patients with pRCC. During follow-up, the death was documented among 6 patients with pRCC. Papillary RCC patients with PD-L1-positive tumor cells were significantly associated with an increased risk of death compared with patients with PD-L1-negative cancer cells. A similar trend was observed when comparing PD-L1 expression in TIMCs. However, no differences in overall survival for PD-L1-positive pRCC patients with compared to PD-L1-negative patients were observed in tumor cells or TIMCs.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Antígeno B7-H1/genética , Receptor de Muerte Celular Programada 1 , Leucocitos , Factores de Transcripción , Neoplasias Renales/genéticaRESUMEN
Giant Cell Arteritis (GCA) is an autoimmune mediated systemic vasculitis affecting large arteries - the aorta and its branches. It has the highest incidence of all systemic vasculitides and manifests nearly exclusively in patients aged 50 or older. Amongst its non-specific and specific symptoms are headaches, mastication claudication or signs of rheumatic polymyalgia, a relatively common and immediate treatment requiring condition being acute vision loss due to optic ischemia. A GCA diagnosis is based on clinical and paraclinical findings and imaging techniques including PET/CT; with an important role still being played by histological verification from temporal artery biopsy. Treatment is based on immunosuppressive agents - systemic glucocorticoids, with adjunct therapy options being methotrexate and tocilizumab. Currently, there are also several clinical trials examining the efficacy of other modern biological agents in GCA.
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Arteritis de Células Gigantes , Humanos , Arteritis de Células Gigantes/complicaciones , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/tratamiento farmacológico , Metotrexato/uso terapéutico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Glucocorticoides/uso terapéutico , Inmunosupresores/uso terapéutico , Factores Biológicos/uso terapéuticoRESUMEN
Supraphysiological levels of IL-7 induce increase counts of pre-B cells, naive T cells and memory phenotype CD8+ T cells. Immunocomplexes of IL-7 and αIL-7 mAb M25 (IL-7/M25) were described as IL-7 superagonist in vivo. Thus, treatment of mice with IL-7/M25 remarkably increases the size of the T cell pool. We decided to use IL-7/M25 in order to expand the T cell population prior to the administration of αCTLA-4 and αPD-1 mAbs in tumor-bearing mice and in turn boost the immunotherapy based on a combination of CTLA-4 and PD-1 blockage. We found that just four doses of IL-7/M25 increased the absolute numbers of splenocytes approximately fivefold and significantly shifted the CD4+:CD8+ T cell ratio in favor of CD8+ T cells. There was also a substantive increase in relative counts of memory phenotype CD8+ T cells (approximately threefold) within CD8+ T cells but a significant decrease (approximately 30%) in relative counts of Treg cells within CD4+ T cells. All these data suggest that IL-7/M25 offer a suitable approach to potentiate tumor immunotherapy through CTLA-4 and PD-1 blockage. Unexpectedly, IL-7/M25 significantly abrogated the antitumor activity of αCTLA-4 plus αPD-1 mAbs in the following mouse tumor models: MC-38 and CT26 colon carcinoma and B16F10 melanoma. This paradoxical effect of IL-7/M25 on the antitumor activity of CTLA-4 and PD-1 blockage was not mediated via either increased levels of IL-10 or TGF-ß in the sera or increased counts of IL-10-producing B or T cells in the spleen of mice injected with IL-7/M25. Thus, our work shows that caution should be exercised when combining two immunotherapy approaches together.
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Anticuerpos Monoclonales/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Antígeno CTLA-4/inmunología , Interleucina-7/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Animales , Antineoplásicos/inmunología , Línea Celular Tumoral , Neoplasias del Colon/inmunología , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoterapia/métodos , Interleucina-10/inmunología , Masculino , Melanoma/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Persona de Mediana Edad , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
The term 'endemic parkinsonism' refers to diseases that manifest with a dominant parkinsonian syndrome, which can be typical or atypical, and are present only in a particular geographically defined location or population. Ten phenotypes of endemic parkinsonism are currently known: three in the Western Pacific region; two in the Asian-Oceanic region; one in the Caribbean islands of Guadeloupe and Martinique; and four in Europe. Some of these disease entities seem to be disappearing over time and therefore are probably triggered by unique environmental factors. By contrast, other types persist because they are exclusively genetically determined. Given the geographical clustering and potential overlap in biological and clinical features of these exceptionally interesting diseases, this Review provides a historical reference text and offers current perspectives on each of the 10 phenotypes of endemic parkinsonism. Knowledge obtained from the study of these disease entities supports the hypothesis that both genetic and environmental factors contribute to the development of neurodegenerative diseases, not only in endemic parkinsonism but also in general. At the same time, this understanding suggests useful directions for further research in this area.
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Trastornos Parkinsonianos , Humanos , Trastornos Parkinsonianos/epidemiología , Trastornos Parkinsonianos/genética , Guadalupe/epidemiología , Europa (Continente) , Fenotipo , BiologíaRESUMEN
The current nosological concept of α-synucleinopathies characterized by the presence of Lewy bodies (LBs) includes Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB), for which the term "Lewy body disease" (LBD) has recently been proposed due to their considerable clinical and pathological overlap. However, even this term does not seem to describe the true nature of this group of diseases. The subsequent discoveries of α-synuclein (αSyn), SNCA gene, and the introduction of new immunohistochemical methods have started intensive research into the molecular-biological aspects of these diseases. In light of today's knowledge, the role of LBs in the pathogenesis and classification of these nosological entities remains somewhat uncertain. An increasingly more important role is attributed to other factors as the presence of various LBs precursors, post-translational αSyn modifications, various αSyn strains, the deposition of other pathological proteins (particularly ß-amyloid), and the discovery of selective vulnerability of specific cells due to anatomical configuration or synaptic dysfunction. Resulting genetic inputs can undoubtedly be considered as the main essence of these factors. Molecular-genetic data indicate that not only in PD but also in DLB, a unique genetic architecture can be ascertained, predisposing to the development of specific disease phenotypes. The presence of LBs thus remains only a kind of link between these disorders, and the term "diseases with Lewy bodies" therefore results somewhat more accurate.