parasites are eukaryotic pathogens , and broadly comprise protozoa , fungi , helminths and arthropods ( figure 1 ) that complete part or all of their life cycle within a host organism . like other pathogens
they succeed in this through a great diversity of strategies for avoiding immune detection , suppressing cellular immunity and deflecting immune attack mechanisms .
it has been suggested that the need to overcome suppressive mechanisms of parasites may have led to compensatory adjustments in immune genes that , in an environment where parasitic infection is not endemic , may increase the likelihood of inappropriate responsiveness to self - antigens ( autoimmunity ) and environmental allergens ( allergy ) .
two recent papers , from jackson et al .   and fumagalli et al .  
an ectoparasite ( a louse of mice ) has recently been found to exert similar immunomodulatory effects to those associated with gastrointestinal helminth infection in a wild wood mouse population . shown
are , clockwise from top left , leishmania mexicana protozoal promastigotes ( l. prieto - lafuente ) ; candida albicans ( from ) ; ixodes hexagonus ( from wikipedia ) ; and heligmosomoides polygyrus adult nematode worms ( c finney ) .
the first line of defense against parasites , as with other pathogens , is the innate immune system , which is ' hardwired ' ( faithful to genomic sequence ) and primed even in the absence of infection .
serum proteins and intracellular and cell - surface receptors  known as pattern recognition receptors ( prrs ) that recognize generic molecular structures associated with different groups of pathogens . among other actions , these receptors mobilize macrophages and granulocytes , unleashing antimicrobial proteins and reactive metabolites .
they also mobilize dendritic cells , which activate the lymphocytes of the adaptive immune system , inducing proliferation of t cells and antibody - producing b cells with variable receptors that specifically recognize the parasite .
the canonical pattern - recognition receptor of the innate immune system is the cell surface toll - like receptor-4 ( tlr-4 ) , which binds to the cell wall lipopolysaccharide ( lps ) of gram - negative bacteria .
detailed phylogenetic analysis of the tlr family indicates strong conservation of sequence and function , but there is significant fine - detail polymorphism across the tlr - related pathway within the human population , linked to differences in immune responsiveness to bacterial infection
it is most likely that they are maintained by variations in tlr ligands among pathogens .
but while the function of the innate receptors is to activate immediate reactions to microbial infection , some eukaryotic parasites can negatively signal through the same receptors , suggesting a complex trade - off for the host , resulting in selection of both ligand - binding and signaling variants which would resist pathogen repression .
innate immunity alone seldom eliminates successful parasites , but it inhibits growth while recruiting the antigen - specific t and b cells of the adaptive immune system to proliferate and differentiate into effector cells competent to attack the infection .
it is therefore the evasion of adaptive immunity that is indispensable to parasite survival , and for rapidly proliferating protozoa an effective evasion strategy is antigenic variation , in which the expression of distinct surface molecules allows new variants to escape immune recognition , quickly replacing those killed by the adaptive immune system .
this type of antigenic variation is not an option for the more long - lived helminth parasites , which survive as individual organisms for months or years . for these creatures ,
a more subtle but no less effective stratagem has been to directly down - modulate the intensity and efficacy of host immune responses .
it has been well established , for example , that patients carrying chronic schistosome or filarial infections lose the ability to mount parasite - specific t cell responses .
this unresponsiveness has been attributed to parasite stimulation of endogenous host immunosuppressive controls both in humans   and animal models .
the best - understood of these suppressive systems is the regulatory t cell ( treg ) , a cellular safety catch on the immune response that normally blocks autoimmunity and reactivity to food antigens and allergens .
indeed , infection with the mouse gut nematode heligmosomoides polygyrus stimulates tregs that are able broadly to suppress responses to allergens . in a recent study on ' real - world ' infections , wild wood mice ( apodemus sylvaticus ) infected with h. polygyrus
were found to mount diminished cytokine responses following tlr stimulation , consistent with the broader immunosuppression seen in laboratory models . by targeting innate immune responses , the parasite is also reducing cytokine - based stimulation of the adaptive immune system .
moreover , similar effects were exerted by ectoparasites , in particular the louse polyplax serrata .
this is the first evidence of systemic down - regulation by arthropod parasites , raising the question of whether ectoparasite infestation could be an important environmental factor in human immune responsiveness .
the need to resist down - regulation of tlr signaling by parasites may explain why some alleles of tlr4 and its co - receptor cd14 are associated with the development of allergic asthma .
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 .
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 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 ; those loci in red italic type are loci encoding cytokines , transcriptional regulators and cell surface molecules that are generally polymorphic in promoter , intronic and 3 ' utr sequences suggesting a regulatory or quantitative effect of polymorphism .
loci above the bifurcation generally determine t cell activation , and those below down - regulation , although the distinction is blurred : for example , il-2 promotes both effector t cell proliferation and treg survival .
clr , c - type lectin receptors , which recognize conserved glycans of pathogens ; nlr , nod - like receptors , intracellular receptors that recognize pathogen products ; tlr , toll - like receptors , which recognize conserved molecular ligands from pathogens ; mhc , major histocompatibility molecules , which bind peptide fragments of pathogen proteins and display them for recognition by t cells ; tcr , t cell receptor , the highly variable receptor through which t cells recognize their targets .
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 .
for example , the il-13 promoter allele -1055 t increases risk of asthma , but decreases schistosome egg load ; 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 ) .
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 .
as with tlr polymorphisms , the presence of allelic forms for many adaptive immune system genes ( in particular , at treg - associated loci ) suggests that there is no certain genetic optimum and that , in an environment with diverse pathogens demanding conflicting response patterns , the fine - tuning effect of multiple allelic variants allows the immune system to be variably calibrated across the population . in the absence of infection , and where genotypes tend to the higher end of reactivity ( for example , where they result in low treg frequencies ) , the immune response is more likely to overshoot , and responses may develop to innocuous targets such as self - antigens and allergens .
although the hygiene hypothesis is couched in very general terms , there is strong evidence that specific gene - environment ( and more specifically , gene - parasite ) interactions can contribute to the development of damaging immune reactions in autoimmunity and allergy .
the identification of precise genetic variants controlling both parasite susceptibility and immunopathology offers the possibility of pinpointing mechanisms that require inhibition or amplification for treatment of disease , identifying genotypes that may be exceptionally susceptible to either infection or pathology , and a deeper understanding of the intimate co - evolution of pathogens and the immune system .
the author 's research is supported by grants from the wellcome trust , the medical research council and the european commission contract inco - ct-2006 - 032436 .
 parasites are accomplished evaders of host immunity . 
 their evasion strategies have shaped every facet of the immune system , driving diversity within gene families and immune gene polymorphisms within populations . 
 new studies published recently in bmc biology and journal of experimental medicine document parasite - associated immunosuppression in natural populations and suggest that host genetic variants favoring resistance to parasites may be detrimental in the absence of infection . 
Parasites
The immune response to parasitic infection
Immunomodulation by parasites
Polymorphism in the immune system
Allelic rheostats
Keeping a balance
Acknowledgements