Evaluation of HLA-G immune checkpoint molecule in melanocytic lesions / Avaliação da molécula de checkpoint imunológico HLA-G em lesões melanocíticas

ABSTRACT The human leukocyte antigen-G (HLA-G) is a non-classical molecule of the major histocompatibility complex. HLA-G has been associated with the process of tumorigenesis and tumor escape. In this study, we aim to evaluate the HLA-G expression in melanocytic lesions and in melanoma for determining when melanocytic lesions start its expression. Twenty-two skin biopsies samples were submitted to immunohistochemistry; HLA-G expression was detected in 63.6% of the samples. This expression in melanocytic cells was significantly higher in melanoma than in benign melanocytic lesions (p < 0.002). Our results suggest that HLA-G expression starts late in the process of tumorigenesis.

RESUMEN El antígeno leucocitario humano G (HLA-G) es una molécula no clásica del complejo principal de histocompatibilidad que ha sido asociada al proceso de tumorigénesis y escape tumoral. En este estudio, nuestro objetivo es evaluar la expresión de HLA-G en lesiones melanocíticas y en el melanoma para determinar cuando las lesiones melanocíticas comienzan su expresión. Veintidós muestras de biopsias de piel se estudiaron mediante inmunohistoquímica; se detectó la expresión de HLA-G en el 63,6% de las muestras. Esa expresión en las células melanocíticas fue significativamente mayor en el melanoma que en lesiones melanocíticas benignas (p < 0,002). Nuestros resultados sugieren que la expresión de HLA-G empieza tardíamente en el proceso de tumorigénesis.

RESUMO O antígeno leucocitário humano G (HLA-G) é uma molécula não clássica do complexo principal de histocompatibilidade que tem sido associada ao processo de tumorigênese e escape tumoral. Neste estudo, objetivamos avaliar a expressão de HLA-G em lesões melanocíticas e no melanoma para determinar quando as lesões melanocíticas iniciam sua expressão. Vinte e duas amostras de biópsias de pele foram submetidas à imuno-histoquímica; a expressão de HLA-G foi observada em 63,6% das amostras. Essa expressão nas células melanocíticas foi significativamente maior no melanoma do que em lesões melanocíticas benignas (p < 0,002). Nossos resultados sugerem que a expressão de HLA-G se inicia tardiamente no processo da tumorigênese.

Expression and clinical significance of sHLA-G in plasma exosome in patients with colorectal cancer / 中华检验医学杂志

Objective To detect sHLA-G expression in plasma exosomes in patients with colorectal cancer and evaluate its clinical significance.Methods Retrospective study.Plasma was collected from 52 primary CRC patients,20 colorectal polyps patients,20 inflammatory bowel disease patients and 25 healthy donors in the Taizhou Hospital of Zhejiang Province from May 2017 to August 2018.The exosomes were extracted by exoEasyMaxikit and identified by nanoparticle tracking analysis (NTA) and Western blot.Exosomal sHLA-G was detected by flow cytometry (FCM) and enzyme-linked immunosorbent assay (ELISA).The diagnostic values of exosomal sHLA-G detected by FCM and ELISA were assessed,and their diagnostic performances were compared with carcinoembryonic antigen (CEA) and carbohydrate antigen CA19-9 by ROC curve and Youden index.Results The peak size of exosomes extracted from plasma in CRC patients was 101.1 nm and Western blot showed these exosomes expressed marker CD63,CDS1,and TSG101.Exosomal sHLA-G of CRC patients [28.0(21.5-35.1)U/ml] was significantly higher than that in healthy controls[19.6(16.8-21.3) U/ml,U=143.0,P＜0.001],colorectal polyps patients[19.7(16.2-22.5)U/ml,U=180.0,P＜0.001] as well as inflammatory bowel disease patients[19.9(16.7-25.2)U/ml,U=197,P＜0.001].The postoperative sHLA-G level[19.6(17.8-26.3)U / ml,U=325.5,P=0.015] was significantly lower than that in pre-operation.Exosomal sHLA-G was significantly different in different tumor status(U=64.0,P=0.006),lymph node metastasis (U=81.0,P=0.003) and TNM stage (U=105.0,P=0.015) in patients with CRC.ROC curve showed the area under the curve (AUC) of exosomal sHLA-G detected by FCM and ELISA,CEA and CA19-9 was 0.962±0.019,0.899±0.038,0.786±0.058,0.680±0.068,respectively.The difference of AUC was operated by Z test,and it showed that the exosomal sHLA-G detected by FCM was superior to CEA(Z=2.884,P=0.004)and CA19-9(Z=3.994,P＜0.001),and the exosomal sHLA-G detected by ELISA was superior to CA19-9(Z=2.811,P=0.005).Conclusion Plasma exosomal sHLA-G was associated with the progression of CRC and its diagnostic value was superior to the traditional tumor markers CEA and CA 19-9.

Greater expression of the human leukocyte antigen-G (HLA-G) and interleukin-17 (IL-17) in cervical intraepithelial neoplasia: analytical cross-sectional study / Aumento da expressão do antígeno leucocitário humano-G (HLA-G) e interleucina-17 (IL-17) em neoplasia intraepitelial cervical: estudo transversal analítico

CONTEXT AND OBJECTIVE:Impaired local cell immunity seems to contribute towards the pathogenesis and progression of cervical intraepithelial neoplasia (CIN), but the underlying molecular mechanisms promoting its progression remain unclear. Identification of new molecular markers for prognosis and diagnosis of early-stage CIN may aid in decreasing the numbers of CIN cases. Several novel immunoregulatory molecules have been discovered over the past few years, including the human leukocyte antigen G (HLA-G), which through interaction with its receptors exerts important tolerogenic functions. Several lines of evidence suggest that T-helper interleukin-17 (IL-17)-producing cells (Th17 cells) may play a role in antitumor immunity. However, recent reports have implicated Th17 cells and their cytokines in both pro and anti-tumorigenic processes. The aim of the study was to evaluate the roles of HLA-G and Th17 in the immunopathogenesis of CIN I.DESIGN AND SETTING:Analytical cross-sectional study with a control group using 58 cervical specimens from the files of a public university hospital providing tertiary-level care.METHODS:We examined HLA-G and IL-17 expression in the cervical microenvironment by means of immunohistochemistry, and correlated these findings with clinical and pathological features.RESULTS:There was a greater tendency towards HLA-G and IL-17 expression in specimens that showed CIN I, thus suggesting that these molecules have a contribution towards cervical progression.CONCLUSION:These findings suggest that HLA-G and IL-17 expression may be an early marker for assessing the progression of cervical lesions.

CONTEXTO E OBJETIVO:A deficiência na imunidade celular localizada parece contribuir para a patogênese e progressão das neoplasias intraepiteliais cervicais (NIC), no entanto, ainda não está totalmente esclarecido o mecanismo molecular fundamental nesse processo de progressão. A identificação de novos marcadores moleculares de prognóstico e diagnóstico das NIC em estágios precoces pode ajudar a diminuir a quantidade de casos de NIC. Várias novas moléculas com função imunorregulatória foram descobertas nos últimos anos, inclusive o antígeno leucocitário humano G (HLA-G), que, através de interação com os receptores, tem importantes funções tolerogênicas. Diversas linhas de evidência sugerem que as células T-ajudantes produtoras de interleucina-17 (IL-17, células Th17), podem desempenhar um papel na imunidade antitumoral. Porém, recentes relatos implicaram as células Th17 e suas citocinas tanto em processos pro- quanto anti-tumorigênicos. O objetivo do estudo foi avaliar o papel do HLA-G e Th17 na imunopatogênese das NIC I.TIPO DE ESTUDO E LOCAL:Estudo transversal analítico com grupo controle em 58 espécimes cervicais dos arquivos de um hospital universitário público com assistência prestada no nível terciário.MÉTODOS:Avaliamos a expressão de HLA-G e IL-17 por imunoistoquímica no microambiente cervical, associando esses achados com as características clínico-patológicas.RESULTADOS:Houve tendência aumentada da expressão de HLA-G e IL-17 em espécimes que apresentaram NIC I, sugerindo que essas moléculas têm contribuição na progressão cervical.CONCLUSÃO:Estes resultados sugerem que a expressão do HLA-G e da IL-17 pode ser um marcador precoce para avaliar a progressão das lesões cervicais.

The human leukocyte antigen G molecule (HLA-G) expression in patients with nasal polyposis / A expressão do antígeno humano leucocitário G (HLA-G) em pacientes com polipose nasossinusal

INTRODUCTION: Sinonasal polyposis (NP) is a chronic inflammatory pathology of the nasal/paranasal cavities which affects from 1%-4% of the population. Although polyps seem to be a manifestation of chronic inflammation in both allergic and non-allergic subjects, the pathogenesis of nasal polyposis remains unknown. HLA-G molecules are a kind of no classic class I antigen with anti-inflammatory and tolerogenic properties. Little attention has been paid to the role of HLA-G chronic inflammatory disorders. OBJECTIVE: The aim of this study is to investigate the expression of HLA-G in the NP. MATERIALS AND METHODS: Prospective study involving samples of patients presenting with nasal polyposis that were subjected to the immunohistochemistry technique. After a skin prick test, all patients were divided into atopic and nonatopic groups and classified as asthmatic or non-asthmatic. RESULTS: Immunohistochemical staining demonstrated a higher expression of the HLA-G molecule in samples from nonatopic than in those from atopic patients, and was significantly lower in the non-asthmatic patients. CONCLUSION: These results indicate that HLA-G may play an important role in the pathology of nasal polyposis. Considering the anti-inflammatory properties of HLA-G, this study suggests that it could reduce susceptibility to atopy and asthma. .

INTRODUÇÃO: Polipose nasossinusal (PNS) é uma patologia inflamatória crônica das cavidades nasais/paranasais que afeta 1%-4% da população. Embora os pólipos pareçam ser uma manifestação de inflamação crônica em ambos os indivíduos alérgicos e não alérgicos, a patogênese da polipose nasal permanece desconhecida. Moléculas HLA-G são antígenos não clássicos da classe I com propriedades anti-inflamatórias e tolerogênicas. Pouca atenção tem sido dada ao papel do HLA-G em doenças inflamatórias crônicas. OBJETIVO: Investigar a expressão de HLA-G na PNS. MATERIAIS E MÉTODOS: Estudo prospectivo de pacientes com polipose nasal que foram submetidas à técnica de imuno-histoquímica. Após realizarem teste cutâneo, os pacientes foram divididos em grupos atópicos e não atópicos e classificados como asmáticos ou não asmáticos. RESULTADO: A coloração imuno-histoquímica mostrou uma maior expressão da molécula HLA-G em pacientes não atópicos do que naqueles atópicos e foi significativamente inferior nos pacientes não asmáticos. CONCLUSÃO: Os resultados indicam que o HLA-G pode ter um papel importante na patologia da polipose nasal. Considerando as propriedades anti-inflamatórias do HLA-G, este estudo sugere que ele poderia reduzir a susceptibilidade a atopia e asma. .

Associação de polimorfismos nas sequências regulatórias dos genes HLA-G, IL-10 e TNF e a sua respectiva expressão gênica em lesões de mucosa em pacientes portadores de doença inflamatória intestinal / Association of HLA-G, IL-10 and TNF regulatory sequence polymorphisms and respective gene expression in biopsies of Brazilian patients with Inflammatory Bowel Disease

Fatores genéticos e imunológicos foram associados à patogenese da doença inflamatória intestinal (DII), ela inclui Retocolite Ulcerativa Idiopática (RCUI) e doença de Crohn (CD). A hiperresponsividade de celulas B e a autoreatividade de células T contribuem para a polarização da resposta imune Th1 em CD e Th2 em RCUI. Sítios polimórficos na região 3'não traduzida do gene HLA-G (completa) e região promotora dos genes IL-10 ( - 1082A/G e - 819C/T) e TNF (completa) foram associados a susceptibilidade a diversas doenças. Estudamos 217 portadores de DII e 249 doadores saudáveis, pareados por sexo e idade. A ascendência africana foi maior em RCUI e caucasiana em DC (p =0,005). Comparados aos controles, o genótipo HLA - G 14bpINS - INS (associado com baixa expressão de HLA - G) (p =0,006) e IL - 10 - 1082G - G (associado com alta expressão de IL - 10) (p =0,030) foram menos frequentes em pacientes com DC, possivelmente contribuindo para a polarização Th1, mas não foram encontradas diferenças nas frequências de TNF. Em RCUI, as frequências do alelo HLA-G +3003C (p =0,015) e genótipo +3003C-T (p =0,003) estavam aumentadas. Apesar da alta frequência do alelo T em africanos, após estratifica rmos por ascendência, o genótipo +3003C - T ainda estava mais frequente em pacientes com ascendência africana (p =0,012)...

Genetic and immunological factors have been associated with inflammatory bowel disease (IBD) pathogenesis, encompassing ulcerative colitis (UC) and Crohn's disease (CD).B cell hyperresponsiveness and T cell auto-reactivity have contributedto a Th1 polarization immune response in CD and a Th2 polarization in UC. Sincepolymorphic sites at the 3’untranslated region (3’UTR)...

Expression of HLA-G in serum and tissue of cancer patients and its function in tumor immune escape / 国际肿瘤学杂志

With depth understanding of the mechanism of human leukocyte antigen G (HLA-G) protein,more and more studies have found that HLA-G is closely related with tumor immune escape.Numerous studies have shown that the expression of HLA-G protein and mRNA could be detected in patients with cancer.

Expression of various subtypes of human leukocyte antigen-G in placenta of patients complicated with severe pre-eclampsia / 中华妇产科杂志

Objective To investigate the different expression of various subtypes of human leukocyte antigen-G(HLA-G)in placenta of patients complicated with severe pre-eclampsia.Methods Ten placental samples from early-onset severe pre-eclamptic pregnancies and ten from late-onset severe preeclamptic pregnancies were collected as study group; ten placental samples from preterm pregnancies and ten from normal pregnancies were collected as control group.The levels of HLA-G protein in the four groups were measured by western blot and immunohistochemistry.Results(1)HLA-G1 protein decreased significantly in both the early-onset(2.4 ± 0.6 versus 2.9 ± 1.1,P ＜ 0.05)and the late-onset pre-eclampsia groups (3.5 ± 2.1 versus 4.2 ± 2.4,P ＜ 0.05).(2)HLA-G5 protein increased in the late-onset pre-eclampsia groups(1.8 ± 1.1 versus 1.1 ± 0.9,P ＜ 0.05); the increase in the early-onset pre-eclampsia group is not obvious(1.6 ± 0.9 versus 1.4 ± 0.7,P ＞ 0.05).(3)The level of HLA-G1 protein in placenta from patients complicated with premature labor is lower(2.9 ± 1.1 versus 4.2 ± 2.4,P ＜ 0.05); HLA-G5 protein does not change significantly(1.4 ± 0.7 versus 1.1 ± 0.9,P ＞ 0.05).(4)HLA-G1 and G5 proteins mainly express in the placenta extravillous cytotrophoblast cells.There is also a high level of expression around the blood vessels and in the extraembryonic mesoderm.Conclusions(1)HLA-G1 decreased significantly in both the early-onset and late-onset pre-eclamptic patients.(2)HLA-G5 increased in both the early-onset and late-onset pre-eclamptic patients,and the increase in the late-onset pre-eclamptic patients is obvious.(3)In late pregnancy,the level of HLA-G1 is lower in patients complicated with premature labor,this may be the result of its earlier pregnancy week; HLA-G5 does not change significantly.(4)HLA-G1 and G5 mainly express in the placenta extravillous cytotrophoblast cells.

Expression of HLA-G mRNA and protein in ectopic and eutopic endometrium in patients with endometriosis / 解放军医学杂志

Objective To investigate the expression of human leucocyte antigen-G (HLA-G) in the endometrium of patients with endometriosis (EM). Methods The expression of HLA-G protein was detected in ovarian endometriosis (OEM) and adenomyosis (AM) using immunohistochemistry method, and the expression of HLA-G mRNA was detected using in situ hybridization technique (ISH), to compare with that in the endometrium of hysteromyoma as the control group. Results The rate of positive HLA-G expression in EM (including AM and OEM) was significantly higher than that in control group (P0.05). The expression of HLA-G protein showed no relation with different clinical phase or different endometrial cycle. Conclusion HLA-G is overexpressed in EM, which may play certain role in the pathogenesis of the disease.