Immune system genes are exceptionally polymorphic, reflecting in part selection by diverse and rapidly varying pathogens, but also the need to balance effective pathogen elimination against the risk of self-destructive reactions. This is well recognized for polymorphisms affecting the structural domains of proteins that function in pathogen recognition. It is less well recognized for the regulation of immune responses. The effect of parasites, for example, has been to dampen, rather than fully ablate, immune responsiveness, and the degree of immunosuppression varies markedly between pathogen species. These graduated effects may, in turn, have driven quantitative polymorphisms in the contemporary immune system that control the strength of the immune response, exemplified by nucleotide variation in regions controlling expression levels rather than variations in amino acid sequence in structural domains (Figure ).
Figure 2 Schematic diagram of the polymorphic elements in immune responsiveness and where pathogen immunomodulation has driven evolution. In black bold type are the immune system families that have diversified primarily at the level of receptor-ligand specificities; (more ...)
This may be the explanation for the link between pathogen richness (number of diverse species) and host genetic diversity that has recently been documented in a report on cytokine gene polymorphism by Fumagalli et al
]. In an analysis of nearly 100 human interleukin genes, they found the highest single nucleotide polymorphism (SNP) frequencies in geographical areas with the highest number of endemic helminth species; those loci showing greatest variability included some encoding cytokines controlling both innate immune responses (such as the IL-1 family) and adaptive Th2 responses (such as IL-4 and IL-4R). Strikingly (in terms of the hygiene hypothesis) 6 out of 9 alleles known to predispose to inflammatory bowel disease (an immunopathology due to reactivity with commensal bacteria) were more frequent in pathogen-rich locations.
Earlier studies have linked noncoding polymorphisms in immune gene variants previously identified as asthma predisposition loci with resistance to parasitic helminths [12
]. For example, the IL-13 promoter allele -1055T increases risk of asthma, but decreases schistosome egg load [13
]; similarly, non-coding variants of the transcriptional regulator STAT-6, which is on the IL-4 pathway, are associated with higher asthma incidence and decreased susceptibility to the roundworm Ascaris
]. Most SNPs associated with both helminth resistance and predisposition to allergy appear to be in non-coding regulatory regions (promoters, intronic regions or 3' untranslated regions (UTRs)), although some structural allelisms are known (for example, in IL-4R [12
]). This suggests that, in the main, parasite-maintained polymorphisms control the intensity of an immune response (or indeed, the strength of a suppressive Treg effect). Such 'allelic rheostats' are also known in autoimmunity-associated loci: for example, in one cohort of systemic lupus erythromatosus patients, the frequency of circulating Tregs was depressed in those carrying a disease-associated 3' UTR SNP allele of CTLA-4, a surface molecule of T cells that acts as a brake on T cell activation [14