RESUMO
Controlled human infections provide opportunities to study the interaction between the immune system and malaria parasites, which is essential for vaccine development. Here, we compared immune signatures of malaria-naive Europeans and of Africans with lifelong malaria exposure using mass cytometry, RNA sequencing and data integration, before and 5 and 11 days after venous inoculation with Plasmodium falciparum sporozoites. We observed differences in immune cell populations, antigen-specific responses and gene expression profiles between Europeans and Africans and among Africans with differing degrees of immunity. Before inoculation, an activated/differentiated state of both innate and adaptive cells, including elevated CD161+CD4+ T cells and interferon-γ production, predicted Africans capable of controlling parasitemia. After inoculation, the rapidity of the transcriptional response and clusters of CD4+ T cells, plasmacytoid dendritic cells and innate T cells were among the features distinguishing Africans capable of controlling parasitemia from susceptible individuals. These findings can guide the development of a vaccine effective in malaria-endemic regions.
Assuntos
Imunidade Adaptativa/imunologia , Suscetibilidade a Doenças/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Imunidade Adaptativa/genética , Adolescente , Adulto , Anticorpos Antiprotozoários/sangue , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , População Negra/genética , Células Dendríticas/imunologia , Suscetibilidade a Doenças/sangue , Suscetibilidade a Doenças/parasitologia , Feminino , Voluntários Saudáveis , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Interferon gama/metabolismo , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Masculino , RNA-Seq , Análise de Sistemas , Linfócitos T/imunologia , Linfócitos T/metabolismo , População Branca/genética , Adulto JovemRESUMO
De novo expression of HLA-G has been demonstrated in colorectal cancer. HLA-G, amongst others, inhibits natural killer cell function, contributing to host immune defense evasion. Another mechanism to escape anti-tumor immunity is loss of HLA class I. Therefore, we determined HLA-G and HLA class I expression on primary colorectal tumors and associated liver metastases, in order to get insight in the metastasizing process regarding escaping anti-tumor immunity. HLA-G expression was evaluated using three mAbs; 4H84, MEM-G/1 and MEM-G/2. In total 81 colorectal cancer patients were evaluated. Formalin-fixed paraffin-embedded tissue sections of primary tumors and associated liver metastases, were immunohistochemically stained. A concordance between expression or loss/downregulation in the primary tumor and associated liver metastasis regarding HLA class I expression was observed in 80% of the cases. In contrast with the hypothesis of escaping NK cell-killing, we demonstrated for each HLA-G detecting mAbs used in this study, that the majority of the primary tumors that positively stained for HLA-G did not express HLA-G in the associated liver metastasis. Furthermore, we revealed the existence of non-specific binding and in addition we found that the different epitopes of HLA-G detected by 4H84, MEM-G/1 and MEM-G/2 mAbs were expressed differentially in colorectal tumor tissues.