Systems analysis and controlled malaria infection in Europeans and Africans elucidate naturally acquired immunity.

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.

Multi-dimensional analysis of B cells reveals the expansion of memory and regulatory B cell clusters in humans living in rural tropical areas.

B-cells play a critical role in the formation of immune responses against pathogens by acting as antigen-presenting cells, by modulating immune responses and by generating immune memory and antibody responses. Here, we studied B-cell subset distributions between regions with higher and lower microbial exposure, i.e. by comparing peripheral blood B-cells from people living in Indonesia or Ghana to those from healthy Dutch residents using a 36-marker mass cytometry panel. By applying an unbiased multidimensional approach, we observed differences in the balance between the naïve and memory compartments, with higher CD11c+ and double negative (DN-IgDnegCD27neg) memory (M)B-cells in individuals from rural tropical areas, and conversely lower naïve B-cells compared to residents from an area with less pathogen exposure. Furthermore, characterization of total B-cell populations, CD11c+, DN and Breg cells showed the emergence of specific memory clusters in individuals living in rural tropical areas. Some of these differences were more pronounced in children compared to adults and suggest that a higher microbial exposure accelerates memory B cell formation, which 'normalizes' with age.

Early symptom-associated inflammatory responses shift to type 2 responses in controlled human schistosome infection.

Schistosomiasis is an infection caused by contact with Schistosoma-contaminated water and affects more than 230 million people worldwide with varying morbidity. The roles of T helper 2 (TH2) cells and regulatory immune responses in chronic infection are well documented, but less is known about human immune responses during acute infection. Here, we comprehensively map immune responses during controlled human Schistosoma mansoni infection using male or female cercariae. Immune responses to male or female parasite single-sex infection were comparable. An early TH1-biased inflammatory response was observed at week 4 after infection, which was particularly apparent in individuals experiencing symptoms of acute schistosomiasis. By week 8 after infection, inflammatory responses were followed by an expansion of TH2 and regulatory cell subsets. This study demonstrates the shift from TH1 to both TH2 and regulatory responses, typical of chronic schistosomiasis, in the absence of egg production and provides immunological insight into the clinical manifestations of acute schistosomiasis.

HLA-G and classical HLA class I expression in primary colorectal cancer and associated liver metastases.

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.