Hygiene and dysimmunitary disorders: what connection?


OBJECTIF NUTRITION 88 (MAY 2008)
Prof. Jean-François BACH
Permanent Secretary to
The French Academy of Sciences


Could improved hygiene conditions promote the onset of dysimmunitary disorders by reducing stress on the immune system caused by infectious agents?  Such is the basis for the “hygienist theory”.  All observations and available scientific data suggest a protective effect of childhood infections on the development of self-immune/allergic disorders.
However, this apparent protective effect of infectious diseases does not apply to all dysimmunitary pathologies.  Exposure to pathogens is only one of the environmental factors that interact with genetic factors.

EPIDEMIOLOGICAL DATA

Many studies show that the geographic breakdown of dysimmunitary disorders follows a North-South gradient.  This gradient clearly appears in Western Europe for insulin-dependent diabetes and multiple sclerosis, whose incidence is clearly higher in Scandinavia than on the Iberian Peninsula.  It also exists between Europe and Africa and between North and South America.

This observation leads us to consider the weight of genetic and/or ethnic factors.  But their contribution seems low with respect to environmental factors, according to data from several research projects on immigrant populations.  A British study published in 1992 showed that the incidence of insulin-dependent diabetes among Pakistani emigrant children living in Yorkshire was identical to that observed in the local population and about ten times higher than its incidence in Pakistan.  Systemic lupus erythematosus, very rare in Western Africa, is frequent among black Americans who share the same ethnic origins but are exposed to different environments.
Socio-economic status seems to be the most pertinent factor by way of explanation.  A German study published in 1994 thus showed a significantly higher prevalence of asthma and allergic rhinitis in the West (ex FRG) rather than the East (ex GDR).  Other studies on genetically homogenous populations established a link between the frequency of dysimmunitary disorders and various socio-economic indicators.  In Northern Ireland, a study on twenty-six administrative districts demonstrated a significant correlation between low incidence of insulin-dependent diabetes and relatively poor living conditions. In Hanover, a study on a population of children ages 6 and 7 entering school (n = 4 219) showed that incidence of atopic dermatitis rose gradually with the family’s socio-economic level (p < 0.01).  The factors independently associated with high incidence of atopic dermatitis reflected a privileged life style while local environmental factors (air pollution) did not have a significant impact on the frequency of atopic dermatitis.
In addition to the socio-economic level, sanitary conditions were correlated to the risk of dysimmunitary disorders.  With improved food hygiene, the microbiological quality of water helps highly reduce exposure to pathogenic agents.  In a British case-control study published in 1994, two sanitary characteristics of the inhabited residence in the course of childhood (hot water supply and separate bathroom) revealed to be associated with a higher risk of later occurrence of Crohn’s disease.  Finally, various research materials have demonstrated the protective role on allergic diseases played by early interhuman contacts which promote infectious diseases. Three epidemiological studies published in 1999 and 2000 indicated that a child with older siblings or attending a day care center very early in life has a lower risk of subsequently developing asthma, an atopic disease or insulin-dependent diabetes than a child without siblings and not attending a day care.

LOOKING FOR A CAUSAL RELATION

Studies on animal models and human clinical trials can establish a relation of cause and effect between a reduction in infectious diseases and an increase in dysimmunitary disorders.  Offering wide possibilities of experimental interventions, animal studies provide the highest level of proof.

The influence of hygienic conditions on the development of insulin-dependent diabetes was studied on murine models predisposed to diabetes.  In a “conventional” breed, about 40% of the animals develop diabetes.  The frequency of insulin-dependent diabetes goes up to 80% if the animals are isolated and raised in a “decontaminated” environment after cesarean birth.  By contrast, the onset frequency of insulin-dependent diabetes is reduced by a “dirty” breeding environment and early administration of various pathogenic agents (bacteria, viruses or parasites) provides protection against diabetes.  In other murine models, inoculation of various mycobacteria proved to have a protective effect against experimental allergic encephalomyelitis and induced asthma.

A few randomized therapeutic control trials against placebo have been conducted with different probiotic strains on humans.  One of them (published in 2001) studied the preventive effect of Lactobacillus GG administration to pregnant women with a family history of atopy on the onset of atopic dermatitis in their children.
After birth, Lactobacillus GG administration was continued for six months in the children, who were then monitored to age 2.  The 64 children in the Lactobacillus GG group were compared to 68 children in the placebo group.  The frequency of atopic dermatitis at age 2 in the children from the Lactobacillus GG group was two times lower than among the children in the placebo group (23% versus 46% in the placebo group children: relative risk = 0.51 [IC95% = 0.32-0.84]).  Follow-up of the children up to age four suggests a long-lasting preventive effect of perinatal administration of Lactobacillus GG: relative risk of atopic dermatitis = 0.57 [IC95% =0.33-0.97].
Another double blind control trial against placebo (published in 2003) evaluated the clinical effect of six-week supplementation with probiotics (two strains of lactobacilli: L. rhamnosus and L. reuteri) on the severity of atopic dermatitis in children ages 1 to 13.  Improvement in symptoms was observed in 56% of the children receiving probiotics against 15% of those in the placebo group (p = 0.001).  The effect was more pronounced among children with biological allergy symptoms.
The results obtained from these studies are incidental and without clear clinical implications.  A high level of proof would require trials using pathogenic agents, which manifestly could not be envisaged.
By contrast, trials are currently underway with different bacterial extracts administered to young children (starting at 6 months or 1 year of age).  The criterion of study remains the subsequent onset of atopic dermatitis, which is easier to identify than other immuno-allergic symptoms such as asthma.  The preliminary results from these trials are along the same lines as those obtained with probiotics.

MECHANISMS AT PLAY

Their identification remains imperfect and subject to several theories.  One of the formulated hypothesis evokes a competition between two potential stimuli of the immune system, arising either simultaneously or at very short intervals.  In this “antigenic competition”, the “strong” microbial antigen is believed to win over the “weaker” allergic antigen.
The competition is believed to concern more specifically lymphocytic populations consuming homeostatic factors with a low renewal rate.  The frequent presentation of microbial antigens highly stimulating on the immune system is believed to maintain the lymphocytic population specifically directed against them.  The development of other lymphocytic populations may be inhibited by a reduced availability of homeostatic factors.
A second possible mechanism is an “extension” of immune regulation induced by the exogenous bacterial antigen.  Its introduction into the body triggers an anti-infectious response whose extent is controlled thanks to the production of “suppressive” type immune regulation cells.  The immuno-modulating action of these cells could temporarily prevent the onset of an allergic or auto-immune type reaction.
Effects non-mediated by specific antigenic recognition could also be at play.  Some bacterial as well as viral or parasitic components act as ligands for “Toll-like” receptors expressed by immune cells (macrophages and lymphocytes T).  the ligand-receptor bond induces the production of immuno-suppressive cytokines by mononucleic cells.  Stimulation of Toll receptors by microbial components is currently one of the favored research subjects.

LIMITATIONS OF THE HYGIENIST THEORY

The apparent protective effect of infectious diseases does not apply to all dysimmunitary disorders.  The link between the historical decrease in infections and rheumatoid arthritis has not been established and this link seems weak with respect to lupus.  In addition, the protective effect is not conferred by all infections but only by a few pathogens while others are likely to trigger allergic or auto-immune disorders.
In the onset of an immune disorder, exposure to pathogens is only one of the environmental factors interacting with genetic factors.  These are sometimes predisposing and sometimes protective.  In this context, the environment itself will be at time a triggering factor and at other times a protective factor.