INTRODUCTION
The
last three decades have witnessed a dramatic increase in the incidence
of autoimmune inflammatory diseases in developed countries, including
type 1 diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis
(RA), and Crohn's disease, to name but a few (1,2).
Autoimmune disease is characterized by an immune-mediated attack on a
target organ that it is no longer recognized by the immune system as
self. Autoimmune pathology can be caused by both antibody and
cell-mediated components. Predisposition to autoimmunity is under
polygenic control, but studies on identical (monozygotic) twins
demonstrate that environmental factors might be equally important (3,4).
The rising trend in autoimmune diseases looks set to continue and the
projected incidences over the next 30 years are potentially
catastrophic. The countries that have seen the most pronounced rise in
autoimmunity have over the same period seen tremendous improvements in
sanitation and socioeconomic status. Moreover, the steady migration from
rural to urban areas has dramatically reduced childhood exposure to
infectious organisms. Rapid anthropogenic transformation of the
environment and life style has not allowed time for the human immune
system to adjust to these changes. The very characteristics of the
immune system that had previously been so advantageous for combating
infections might now be the principal contributing factor for the
increasing prevalence of autoimmune disease. Improvements in living
conditions and the reduced exposure to childhood infections in
particular, have been suggested to contribute to the increase in atopy
and autoimmunity (5). This so-called Hygiene Hypothesis
has, in recent years, attracted interest and controversy in equal
measure. Epidemiological data from the World Health Organization (WHO)
largely support the hypothesis, indicating that autoimmune inflammatory
diseases like T1D and MS are extremely rare in most African and Asian
populations, yet increase conspicuously when these same populations
migrate to a modern setting (6,7).
In this piece we will review the evidence for the Hygiene Hypothesis
particularly with regard to parasitic worm (helminth) infections and
consider any potential therapeutic avenues that it may prescribe.
INFECTIOUS DISEASE, AUTOIMMUNITY, AND THE HYGIENE HYPOTHESIS
The
Hygiene Hypothesis suggests that parasites and microbes have been
important for shaping and tuning the evolution of the human immune
system (8).
According to this hypothesis, the immune system is in a state of
preparedness, primed to repel the pathogen assaults that characterized
the lot of humanity for most of its existence. In developed countries
industrialization has strongly contributed to human migration from rural
areas to the cities. One of the consequences of resettlement has been
the removal of people from the pathogen-replete ecosystems in which
their immune systems had adapted since prehistory. Sanitation, and
access to clean food and water became a common life standard for most
individuals in the developed world. Additionally, following the Second
World War the use of antibiotics became commonplace, dramatically
altering exposure to bacterial pathogens. The fact that infections were
no longer prevalent has led to the emergence of autoimmune inflammatory
diseases. This suggests that parasites, if not actually preventing
autoimmunity per se, at least divert the immune system to the
more productive cause of limiting tissue pathology. Parasites themselves
wield an astonishing array of mechanisms to evade the ravages of the
host's immune system and in so doing ameliorate the more
self-destructive aspects of a response.
Industrialized
countries are indeed experiencing an increase in autoimmune diseases. A
very different picture is present in developing countries. Because of
limited economic resources, health aid organizations tend to focus more
on the three so-called ‘Big Killer Diseases’; HIV, malaria and
tuberculosis. As a consequence, six neglected infectious diseases with
low mortality rates such as filariasis, leprosy, onchocerciasis,
schistosomiasis, soil-transmitted helminths, and trachoma, are still
widespread yet autoimmune inflammatory diseases are virtually absent
(WHO and International Diabetes Federation databases) (see Figure 1).
Loss of parasite colonization in those individuals living in developed
countries has had a unique impact on our immune response and, together
with genetic predisposition, is probably the pre-eminent factor
contributing to the development of autoimmune disease (9–12).
T1D occurs equally among males
and females and is more common in whites than in non-whites. Data from
the IDF (International Diabetes Federation) database indicate that T1D
is rare in most African and Asian populations. Conversely, some northern
European (Finland and Sweden) and northern American countries, have
high rates of T1D. Over a million people worldwide have MS and this
incidence also appears to be increasing. Onset of symptoms typically
occurs between the ages of 15 and 40 years, with a peak incidence in
people in their 20s and 30s, and women are affected twice as often as
men. MS occurs worldwide but is most common in Caucasian people of
northern European origin. It is extremely rare among Asians and Africans
(13).
Crohn's disease also occurs most frequently among North Europeans and
North Americans. Although the disorder can begin at any age, its onset
principally occurs between 15 and 30 years of age. There appears to be a
familial aggregation of patients with Crohn's disease such that 20–30%
of patients with Crohn's disease have a family history of inflammatory
bowel disease.
T1D AS AN EXAMPLE OF AN INFLAMMATORY AUTOIMMUNE DISEASE
T1D
is an autoimmune condition characterized by a progressive cellular
infiltration of the pancreas resulting in the destruction of
insulin-producing cells. Since insulin regulates glucose uptake into
cells from the circulation, its deficiency is responsible for glucose
accumulation in the blood and ensuing cell starvation (hyperglycaemia,
coma, etc.). T1D was considered a death sentence until the early 1920s,
when pancreatic extracts were used to correct hyperglycaemia (14).
This discovery led to the availability of an effective treatment –
insulin injections – and the first clinical patient was treated in 1922.
Despite the substantial technological improvement for monitoring
glycaemia, relatively little progress has been made in terms of therapy;
to date, insulin injection remains the only dependable treatment.
T1D
is an autoimmune polygenic disorder, with numerous gene loci
contributing to susceptibility. Historically, the first genes associated
with T1D were the Human Leukocyte Antigens (HLA) on chromosome 6, in
particular the DR and DQ class II regions (15,16).
There remains controversy about the relative contributions of DR and DQ
on T1D susceptibility with some studies supporting a stronger
association for the DQ locus and a secondary role for DR (17).
Recently, other genes outside the HLA complex have been associated with
predisposition to T1D, including cytotoxic T lymphocyte associated
antigen 4 (CTLA-4) and lymphoid tyrosine phosphatase (PTPN22) (18).
As
mentioned above, genetic components affect the propensity for T1D but
the environment appears to play a fundamental role in regulating the
onset of the disease. Many different intercepting factors must be taken
into account. Within the Caucasian population the incidence of T1D
varies between nations. For example Scandinavian countries have the
highest incidence of T1D in Europe, whereas relatively under-developed
countries like Albania and Romania have some of the lowest (see Table 1).
However, these statistics need to be considered in the context of
genetics, i.e. the relatively limited genetic diversity seen in
Scandinavia (particularly Finland) overlaying and possibly synergizing
with the effects of a hygienic environment. Interestingly in Europe,
countries with a more agriculture-based economy have lower incidences of
T1D (19).
This suggests that exposure of the population to a diet containing
fewer processed foods and more direct contact with animal-transmitted
pathogens such as Salmonella could be a relevant factor in
preventing T1D. The North–South gradient also seems to play a role in
diabetes incidence. Indeed in Southern European countries the lower
socio-economic status and higher temperatures might predispose the
inhabitants to infections and contribute to the lower frequency of T1D.
Two of the largest islands in the Mediterranean, Sicily and Sardinia,
present an interesting contrast in T1D incidence and the effects of
genetics. These islands are located at similar latitudes and
bio-geographical zones, yet Sicily has a low incidence of T1D whereas
Sardinia has one of the highest in the world, indicative of a strong
genetic modifier (20).
If we look now at countries outside Europe (and/or North America) we
can see that the inverse correlation between poverty and T1D is even
more pronounced. Poor sanitation and prevalence of infections seem to
protect the inhabitants of developing countries from autoimmune diabetes
(see Table 1). A good example is the interdependence between access to clean water, and diseases such as T1D (Figure 1).
Indeed many parasitic diseases such as Schistosomiasis require a
freshwater environment for transmission. Overall these considerations
strongly suggest that the continuous improvement in sanitation and
living standards in developed countries is a key factor for the increase
of T1D.
According to the IDF database the global incidence of T1D in children
and adolescents is increasing, with an estimated overall annual rate of
about 3%. Before the 1920s childhood diabetes, although uncommon, was
rapid and fatal, therefore it could be argued that the introduction of
insulin treatment contributed to a subtle increase in the frequency of
T1D susceptibility genes. That said, the dramatic rise of T1D in
children under 14 years of age in developed countries cannot be
explained by genetic factors alone. The T1D epidemic observed over the
last 50 years in Western Europe and North America is predicted to
plateau. For example, Norway showed no increase over the last decade (21).
The high T1D-incidence areas (with the exception of Finland) in Europe
appear to have reached a plateau, but the overall trend is still rising
in ex-Eastern Bloc countries and in the Middle East, particularly in
Kuwait (22–24).
Since changes in the environment seem to play a more significant role,
predications are that childhood diabetes will not increase exponentially
in the high incidence areas but will rather take place in those
countries that are gradually seeing an improvement in their living
standards and hygiene. For instance, the projections for diabetes
incidence in the year 2025 predict a sharp increment in diabetes in the
Middle East, South America, Mexico, and South Ea
ANIMAL MODELS OF HUMAN AUTOIMMUNE DISEASE: THE NOD MOUSE AND SCHISTOSOMA MANSONI INFECTION
Since
the 1970s the NOD (Non-Obese Diabetic) mouse has provided a good model
for the study of T1D. Initially generated in Japan by Makino and
co-workers, the NOD mouse has became one of the most popular models to
study T1D (25).
NOD mice spontaneously develop T1D, with features similar to the human
disease. NOD T1D is under polygenic control and, much like the human
disease, associates with particular Class II major histocompatibility
(MHC) polymorphisms (26).
The pancreas of NOD mice become infiltrated with mononuclear cells
around 6 weeks of age, with cells appearing chiefly around the islets
and pancreatic ducts. By 8–12 weeks of age the infiltrate progresses to
the islets, causing destruction of the β cell mass. Pathology is
primarily cell-mediated, with dendritic cells (DC), macrophages (MΦ) and
B cells responsible for the initiation of the autoimmune process by
presentation of pancreatic antigen and secretion of inflammatory
mediators (27,28).
Subsequently, CD8+ and CD4+ T cells enter the pancreas, infiltrate the
islet area and β cell destruction arises through a Th1-mediated immune
response (29) (Figure 2).
After 12 weeks of age the clinical signs of disease start to manifest
with polydypsia and glycosuria and by the age of 30 weeks 80–100% of
female mice are diabetic. NOD mice show a distinct gender difference
with female NOD mice developing T1D at a much higher incidence than the
males (10–20%). There are variations between colonies and the conditions
under which NOD mice are kept appear to greatly influence the rate and
frequency of onset of diabetes. It rapidly became clear that NOD mice
kept under germ-free conditions developed diabetes at a much faster rate
and higher incidence than mice kept under conventional conditions (30).
This observation, made independently in many different laboratories,
provoked immunologists to consider the possibility that infection and/or
exposure to microbial products was responsible for the reduction of T1D
incidence in some animal colonies. Experiments designed to test this
hypothesis and elucidate the mechanisms of T1D prevention, revealed that
infections triggering both Th1- and Th2-like responses could delay or
abolish autoimmune pathology in NOD mice (see Table 3).
st Asia (see Table 2).
The NOD mouse appears to be a
good model for testing the predictions of the Hygiene Hypothesis,
therefore we have used it to study the effects of bacterial and helminth
infection on the onset of T1D. Schistosoma mansoni infection,
or even exposure to antigens derived from this helminth, results in
long-lasting prevention of diabetes characterized by a strong Th2
response (31,32). S. mansoni
protection appears to stem largely from a shift to a non-pathological
Th2 response, although there is also evidence for the generation of
immunosuppressive regulatory cells (Treg) (32). Essentially similar results have been observed using two other species of helminth, Heligmosomoides polygyrus and Trichinella spiralis (C. Lawrence, unpublished data). Similarly, infection of NOD mice with live attenuated Salmonella bacteria induces a long-lasting protection from T1D (35).
Prevention of a Th1-mediated autoimmune disease such as T1D by
infection with a classic Th1-stimulating pathogen appears rather
paradoxical. Potentially a generalized Salmonella-induced IFN-γ
release may mediate suppression through its effects on the innate
immune system, particularly DC, but the mechanism awaits full
characterization (our unpublished observations). At any rate, the
invocation of a simple Th1 to Th2 shift is unable to explain all the
immunomodulatory effects of microbial infection that lead to prevention
of T1D, and may instead require a more complex paradigm incorporating,
for example, the action of Treg.
HELMINTH MODULATION OF THE IMMUNE SYSTEM
Amongst
the various infectious agents, helminth parasites are regarded as
master manipulators of the host immune system, often inducing a
long-lasting asymptomatic form of infection (37,38).
Parasitic worms can establish and reproduce in mammalian hosts,
switching off the inflammatory immune response and inducing a tolerant
response to parasite antigens. Following encounter with S. mansoni
antigens, profound changes are observed in the innate immune system of
the host, including modification of DC, MΦ, and NKT cells, phenotype and
cytokine secretion (39,40). S. mansoni antigens can induce the secretion of regulatory cytokines from these cells as well as B1 B cells (41), resulting in the expansion of Th2 and Treg populations that might be responsible for maintaining self-tolerance (42–45) (see Figure 3).
DC and MΦ are fundamental to directing immune responses along either a
tolerating or activating pathway, therefore it is not surprising that
helminths have evolved strategies targeting receptors on these cells.
Toll like receptors (TLRs) and C-type lectin receptors (CLRs), broadly
expressed on DCs and MΦs, are the main parasite targets for evading
immuno-surveillance (46). More specifically, glycosylated molecules (expressed and secreted by S. mansoni) bind to the CLR and antagonize a TLR pro-inflammatory pathway (47). Numerous studies have shown that S. mansoni
products induce IL-10 production by DCs and have a direct
anti-inflammatory effect on DCs by controlling TLR ligand-induced DC
maturation (48). S. mansoni
has also been shown to induce alternatively activated MΦ, which secrete
small amounts of inflammatory mediators and inhibit T cell
proliferation (49).
The influence of helminth products on the innate immune
system is not just restricted to DCs. Depending on the nature of the
pathogen, NKT cells can direct the immune response in an appropriate
direction by secreting a wide variety of pro- and anti-inflammatory
cytokines (50).
Schistosomes are rich in glycosylated molecules, which heavily decorate
their integument or are actively secreted, and glycolipids presented by
CD1d (a non-classical MHC molecule) on antigen presenting cells (APCs)
may thus be able to activate regulatory NKT cells (51).
One of the most obvious and well-documented responses to S. mansoni
is the Th2 dominance in the T cell population. Any initial Th1 response
to the parasite is quickly redirected to a state of quiescence (52).
The cytokine environment is fundamental for this purpose: large amounts
of IL-4, IL-5 and IL-13 are secreted from the T cell pool, reinforcing
not just T cell polarization, but also the anti-inflammatory loop on DC
and MΦ (32).
The parasite is also capable of containing the side-effects of such a
strong Th2 response, inducing the secretion of IL-10 and TGF-β by other T
cell subtypes (53,54). For example, animals and humans infected or exposed to S. mansoni antigens do not automatically develop allergies at a higher incidence (see Figure 3). The de novo
induction and/or the expansion/recruitment of Treg almost certainly
underlies the ability of many parasites to both evade a sterilizing
immune response and also suppress both Th1 and Th2 arms of the adaptive
immune system (55,56).
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