Chagas disease, which is caused by the flagellate parasiteTrypanosoma cruzi, affects 8–10 million people in Latin America. The disease is endemic and is characterised by acute and chronic phases that develop in the indeterminate, cardiac, and/or gastrointestinal forms. The immune response during humanT. cruziinfection is not completely understood, despite its role in driving the development of distinct clinical manifestations of chronic infection. Polymorphisms in genes involved in the innate and specific immune response are being widely studied in order to clarify their possible role in the occurrence or severity of disease. Here we review the role of classic and nonclassic MHC,KIR, and cytokine host genetic factors on the infection byT. cruziand the clinical course of Chagas disease.

The human malaria parasite Plasmodium vivax infects red blood cells through a key pathway that requires interaction between Duffy binding protein II (DBPII) and its receptor on reticulocytes, the Duffy antigen/receptor for chemokines (DARC). A high proportion of P. vivax-exposed individuals fail to develop antibodies that inhibit DBPII-DARC interaction, and genetic factors that modulate this humoral immune response are poorly characterized. Here, we investigate if DBPII responsiveness could be HLA class II-linked. A community-based open cohort study was carried out in an agricultural settlement of the Brazilian Amazon, in which 336 unrelated volunteers were genotyped for HLA class II (DRB1, DQA1 and DQB1 loci), and their DBPII immune responses were monitored over time (baseline, 6 and 12 months) by conventional serology (DBPII IgG ELISA-detected) and functional assays (inhibition of DBPII–erythrocyte binding). The results demonstrated an increased susceptibility of the DRB1*13:01 carriers to develop and sustain an anti-DBPII IgG response, while individuals with the haplotype DRB1*14:02-DQA1*05:03-DQB1*03:01 were persistent non-responders. HLA class II gene polymorphisms also influenced the functional properties of DBPII antibodies (BIAbs, binding inhibitory antibodies), with three alleles (DRB1*07:01, DQA1*02:01 and DQB1*02:02) comprising a single haplotype linked with the presence and persistence of the BIAbs response. Modelling the structural effects of the HLA-DRB1 variants revealed a number of differences in the peptide-binding groove, which is likely to lead to altered antigen binding and presentation profiles, and hence may explain the differences in subject responses. The current study confirms the heritability of the DBPII antibody response, with genetic variation in HLA class II genes influencing both the development and persistence of IgG antibody responses. Cellular studies to increase knowledge of the binding affinities of DBPII peptides for class II molecules linked with good or poor antibody responses might lead to the development of strategies for controlling the type of helper T cells activated in response to DBPII. Vaccines are a crucial component of the current efforts to eliminate malaria, and much of the vaccine-related research on P. vivax has been focused on the Duffy binding protein II (DBPII), a ligand for human blood stage infection. A high proportion of individuals who are naturally exposed to P. vivax fail to develop neutralizing antibodies, but the host genetic factors modulating this immune response are poorly characterized. We investigated whether DBPII responsiveness was dependent on the variability of human leucocyte antigen (HLA) class II cell surface proteins involved in the regulation of immune responses. To obtain a reliable estimate of DBPII antibodies, we carried out a longitudinal study, collecting serum from the same individuals over a period of 12-months. The results confirmed the heritability of the DBPII immune response, with genetic variation in HLA class II genes influencing both the development and persistence of the antibody response. HLA class II genotype also influenced the ability of DBPII antibodies to block the ligand-receptor interaction in vitro. Computational approaches identified structural specificity between HLA variants, which we propose as an explanation for differences between a good or poor antibody responder. These results may have implications for vaccine development, and might lead to strategies for controlling the type of immune response activated in response to DBPII.