The role of MHC- and non-MHC-associated genes in determining the human immune response to malaria antigens

Abstract

SUMMARYIndividual susceptibility to malaria infection, disease and death is influenced by host genotype, parasite virulence and a number of environmental factors including malaria-specific immunity. Immune responses are themselves determined by a combination of host genes and environmental effects. The extent to which host genotype limits the spectrum of possible immune responses may influence the outcome of infection and has consequences for vaccine design. Associations have been observed between human major histocompatibility complex (MHC) genotype and susceptibility to severe malaria, but no similar associations have been observed for mild malarial disease or for specific antibody responses to defined malaria antigens. Epidemiological studies have shown that, in practice, neither T helper cell nor antibody responses to malaria parasites are limited by host MHC genotype, but have revealed that genes lying outside the MHC may influence T cell proliferative responses. These genes have yet to be identified, but possible candidates include T cell receptor (TcR) genes, and genes involved in TcR gene rearrangements. More importantly, perhaps, longitudinal epidemiological studies have shown that the anti-malarial antibody repertoire is selective and becomes fixed in malaria-immune individuals, but is independent of host genotype. These findings suggest that the antibody repertoire may be determined, at least in part, by stochastic events. The first of these is the generation of the T and B cell repertoire, which results from random gene recombinations and somatic mutation and is thus partially independent of germline genes. Secondly, of the profusion of immunogenic peptides which are processed and presented by antigen presenting cells, a few will, by chance, interact with T and B cell surface antigen receptors of particularly high affinity. These T and B cell clones will be selected, will expand and may come to dominate the immune response, preventing the recognition of variant epitopes presented by subsequent infections - a process known as original antigenic sin or clonal imprinting. The immune response of an individual thus reflects the balance between genetic and stochastic effects. This may have important consequences for subunit vaccine development.

Reduced CD3/TCR complex expression leads to immunosuppression during Plasmodium falciparum malaria

“…Most frequently affected are children under 5 years in holoendemic areas of sub-Saharan Africa. The outcome of malaria depends on factors such as parasite virulence, nutrition and host factors (Kern et al 1989;Lyke et al 2004;Shalaby et al 1985;Winkler et al 1999) and genetic background (Hill 1996;Riley 1996).…”

VaccImm: simulating peptide vaccination in cancer therapy

“…The peptide binding characteristics of MHC alleles differ significantly and susceptibility to several diseases has been associated with the MHC-genotype [19,20]. Therefore, we wanted to investigate the influence of the MHC-genotype on the success of peptide vaccination therapy.…”

Mapping the T cell epitopes of the Babesia bovis antigen 12D3: implications for vaccine design

“…These promiscuous epitopes would minimize variability and can also be used to avoid deleterious effects associated with immunization using self‐related antigens (Lou et al . 1996) although challenge infection will not boost vaccine induced immunity produced by irrelevant epitopes (Riley 1996).…”

“…1996). In addition, variation has also been attributed to non‐MHC genes and even nongenetic or stochastic events within the immune response (Riley 1996).…”

“…Polymorphism within MHC loci has been associated with variation in responsiveness to several experimental vaccines including hepatitis B (Alper et al 1989) malaria (Patarroyo et al 1991) and lymphatic filariasis (Chacon et al 1996). In addition, variation has also been attributed to non-MHC genes and even nongenetic or stochastic events within the immune response (Riley 1996).…”