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Markus Fritzsche
Clinic for Internal Medicine, Soodstrasse 13, 8134 Adliswil, Switzerland
International Journal of Health Geographics 2002 1:5
The electronic version of this article is the complete one and can be found
online at:
http://www.ij-healthgeographics.com/content/1/1/5
Received 28 November 2002
Accepted 20 December 2002
Published 20 December 2002
© 2002 Fritzsche; licensee BioMed Central Ltd. This is an Open Access
article: verbatim copying and redistribution of this article are permitted
in all media for any purpose, provided this notice is preserved along with
the article's original URL.
Abstract
Background
Clusters by season and locality reveal a striking epidemiological overlap
between sporadic schizophrenia and multiple sclerosis (MS). As the birth
excesses of those individuals who later in life develop schizophrenia mirror
the seasonal distribution of Ixodid ticks, a meta analysis has been
performed between all neuropsychiatric birth excesses including MS and the
epidemiology of spirochaetal infectious diseases.
Results
The prevalence of MS and schizophrenic birth excesses entirely spares the
tropical belt where human treponematoses are endemic, whereas in more
temperate climates infection rates of Borrelia garinii in ticks collected
from seabirds match the global geographic distribution of MS. If the
seasonal fluctuations of Lyme borreliosis in Europe are taken into account,
the birth excesses of MS and those of schizophrenia are nine months apart,
reflecting the activity of Ixodes ricinus at the time of embryonic
implantation and birth. In America, this nine months' shift between MS and
schizophrenic births is also reflected by the periodicity of Borrelia
burgdorferi transmitting Ixodes pacificus ticks along the West Coast and the
periodicity of Ixodes scapularis along the East Coast. With respect to
Ixodid tick activity, amongst the neuropsychiatric birth excesses only
amyotrophic lateral sclerosis (ALS) shows a similar seasonal trend.
Conclusion
It cannot be excluded at present that maternal infection by Borrelia
burgdorferi poses a risk to the unborn. The seasonal and geographical
overlap between schizophrenia, MS and neuroborreliosis rather emphasises a
causal relation that derives from exposure to a flagellar virulence factor
at conception and delivery. It is hoped that the pathogenic correlation of
spirochaetal virulence to temperature and heat shock proteins (HSP) might
encourage a new direction of research in molecular epidemiology.
Background
Schizophrenia and multiple sclerosis are distinct neuropsychiatric disorders
of the central nervous system (CNS). Schizophrenia is characterised by
disturbances in multiple domains of brain functioning, few in vivo or
postmortem studies of which find evidence for a particular structural
alteration [1]. MS typically manifests as acute focal inflammatory
demyelination and axonal loss involving the immune system and culminating in
the chronic multifocal sclerotic plaques from which the disease gets its
name [2-4]. MS and schizophrenia, nonetheless, exhibit a striking
epidemiological overlap [5]. Prevailing in the colder parts of the world and
affecting mainly young adults in their most productive years, both run an
irregular, chronic course. Apart from acute infections [6], no other disease
exhibits an equally marked epidemiological cluster by season and locality,
nurturing the hope that solutions might ultimately be attainable [5].
Geographical correlations between MS and schizophrenia prevalence rates
(PRs) have been reported worldwide [5,7-9]. In the north of the USA, the
states with the highest rates of schizophrenia score significantly higher
rates of MS than the states with the lowest schizophrenia rates in the south
[9]. Findings that immigrants from tropical low-risk areas are more likely
to contract schizophrenia or MS than those who stay behind have been widely
replicated and are now considered strong epidemiological risk factors (for
review see [10-12]). Migration away from the hot spots reduces the
probability of developing MS if the move takes place before adolescence.
Regardless of the direction of the move, however, MS death rates for
migrants born in one risk area and dying in another are intermediate between
those of their birthplace and their final residence. These biological
gradients suggest a common environmental component that could be influenced.
If caused by an infectious agent [12] as presupposed by Marie in 1884 [13],
what kind of transmission or virulence would lie at its root?
The earliest lesion seen in MS is a focal infiltration of lymphocytes around
small blood vessels in the brain and spinal cord. This implies that
inflammatory cells are reacting against an antigen located in the central
nervous system (CNS) to which they have become sensitised. In MS patients,
the intrathecal synthesis of immunoglobulins, the appearance of immune
complexes and change in the balance of T cell populations all indicate
immune activity in tissues that are normally quiet (for review see [2,3]).
The responsible antigen could be CNS tissue ('self'), in which case we are
dealing with an autoimmune disease. Alternatively, it could be of microbial
('foreign') origin, or both. Analogous to streptococcal infection in
relation to rheumatic fever, the environmental factor in MS may be
accommodated by arguing that exposure to an infection elicits upon
re-exposure an abnormal immune response against a similar antigen in the
CNS.
>From this epidemiological point of view, we are best advised to search for
positive and negative correlation. For general immunity acquired against
endemic infection is supposed to increase the resistance against MS in
developing countries [14]. In the interior of New Guinea, in fact, where
neither MS [15] nor schizophrenia [16] nor Lyme borreliosis [17] appears to
be prevalent, the inhabitants exhibit antibodies possibly induced by endemic
treponemes that cross-react with Borrelia burgdorferi antigens [17].
Since the beginning of the last century it was suggested that MS and
neurosyphilis caused by the spirochaete Treponema pallidum [18] had similar
clinical and histological characteristics. Extremely difficult to find, as
in tabes dorsalis [18], neuropathologists documented the presence of
spirochaetal structures in MS plaques suggesting that the patients were
infected with a spirochaete [19,20], most likely B. burgdorferi [21].
Congenital infection by B. burgdorferi resembles congenital syphilis as
well. Like in humans [22], however, chronic prenatal infections by B.
burgdorferi are rare in mice, and acute prenatal infection of the unborn is
restricted to a narrow time window of transplacental transmission [23].
Henceforth the birth excess of those individuals who later in life develop
sporadic schizophrenia mirrors the seasonal distribution of Ixodes ticks and
Borrelia burgdorferi at the time of conception [16].
If in analogy to chronic hepatitis B infection at birth [24], MS were
induced [25] or exacerbated [26] by exposure to B. burgdorferi antigens
during delivery, we would expect a direct seasonal match between MS birth
excesses and Ixodid tick activity worldwide. Contrasting with the possible
deleterious mutagenic effect of B. burgdorferi at conception [16], a time
difference of nine months is expected between MS births and the
schizophrenic insult to the implanting embryo. Should general immunity
acquired against treponemes [17] increase resistance against Borrelia and
MS, we would furthermore expect a positive geographic correlation of MS to
neuroborreliosis as well as a negative correlation of MS to endemic
treponematoses. Otherwise, the present hypothesis of B. burgdorferi as a
possible major aetiologic factor for both congenital sporadic schizophrenia
and MS would be falsified.
Methods
The different prevalence rates of MS as recently reviewed [15] were compared
to the global distribution of endemic treponematoses [27] and to all
significant schizophrenic birth-excess rates [16] worldwide. For statistical
reasons, only publications encompassing more than 3000 cases of significant
schizophrenic birth excesses compared to the normal population have been
considered [28], including two studies from Denmark and Australia showing
both one significant and one non-significant result each. In a second step
of the investigation, the routes of Borrelia carrying migratory birds were
considered for the following reason. The schizophrenic birth excesses are
limited to exactly those regions that are endemic for B. burgdorferi
transmitting Ixodes tick vectors [16]. This geographical overlap, however,
is less than perfect with respect to MS, particularly in southern latitudes,
and the use of artificial country boundaries is of doubtful biological
value, unless they are given by naturally defined geographical areas [11].
As the rule of MS varying with latitude is violated in central Europe
including Switzerland and its neighbouring countries, areas of high relative
risk were put under closer scrutiny. MS hot spots in central Europe, in
fact, harbour the few remaining nesting sites of the classical passerine
bird, the white stork (Ciconia ciconia), and migratory seabirds following
the rivers and islands spread Ixodes ticks and Borrelia garinii (a
subspecies of Borrelia burgdorferi sensu lato) worldwide [29] (see Figure
1). From the comprehensive literature, the seasonal periodicity of Ixodid
tick activity was then used in this meta analysis and plotted against
numerical data encompassing all neuropsychiatric birth excesses [30] of the
respective macroclimatic regions including MS (Figure 2).
Results
Geographical correlation of MS and sporadic schizophrenia to Ixodes ticks
and migratory birds
The geographical gradient of MS (Figure 1), which sharply declines at the
37° latitude [12,15], entirely spares the tropical belt where human
treponematoses caused by T. carateum, T. pertenue, and endemic T. pallidum
prevail [27]. This negative correlation between areas of endemic
treponematoses on the one hand and MS as well as schizophrenic birth
excesses on the other is striking. With the notable exception of Florida,
Australia and Tunisia (see Figure 1), subtropical areas exhibit neither a
significant schizophrenic birth excess nor a prevalence rate (PR) of MS
higher than 5/100'000 [15].
In central Europe, the highest relative risks for MS can be found along the
breeding sites of migratory birds. These hot spots are located along the
north-south axis of the Upper Rhine plain and its tributaries, the Bas Rhin,
Haut Rhin, Moselle regions [31], around Basel [32], in the Swabian Alps
[33], Sardinia, as well as the Aosta Valley [15], the only place in Italy
where the white stork (Ciconia ciconia) still nests (see insert in Figure
1). Tunisia, which is reached by passerine European birds carrying Ixodes
ticks and B. garinii [34], scores the highest rate of MS in Africa [15].
Malta, by contrast (see Figure 1), which compared to Sicily is relatively
free of MS [11,15], hosts a number of endemic lizards, and ticks lose their
infectious potential for humans when feeding on these reptiles. This
so-called zooprophylactic effect also applies to the low-risk areas of MS
and sporadic schizophrenia [9] in the United States, where south of the 37°
latitude infections by B. burgdorferi are poorly maintained in lizards [35].
Although of low prevalence, MS exists in South East Asia: in Japan and
Taiwan [15,36] down to the Philippines [12], where the Wallace Line (see
Figure 1) limits the southward spread of B. burgdorferi harbouring Ixodid
ticks into Austronesia [37]. In Irian Jaya (I.J.) and P.N.G. (see Figure 1),
from where neither the presence of Lyme disease nor MS has been reported,
schizophrenia is non-existent apart from the south-west coast which is
sporadically reached by migratory birds and ticks [16]. In the southern
hemisphere, MS [15]and schizophrenic birth excesses [38] are, compared to
the northern hemisphere, less significant. From the area of Singapore, which
is non-endemic for Ixodes ticks and B. burgdorferi but endemic for
treponematoses (see Figure 1), a schizophrenic birth excess is significantly
absent. This trend parallels the scarcity of MS and relatively recent
upsurge of schizophrenic birth excesses in Japan, where B. garinii
harbouring ticks have been sporadically introduced by migratory birds from
North East Asia (for discussion see [16]). Southern Australia and New
Zealand, by contrast, which can be reached by polar seabirds carrying Ixodes
uriae and B. garinii via the Antarctic [39], score relatively high rates of
schizophrenia [40] and MS [15].
Geographical correlation of MS to Borrelia burgdorferi sensu lato
The infection rates of B. garinii in I. uriae ticks [29] reflect not only
the global distribution of MS, but also its worldwide gradient. The highest
number of spirochaetes detected by microscopy were collected from seabirds
in Iceland, Alaska and the Faroes (see Figure 1) all areas from where
epidemics as well as very high rates of MS have been published [12,41].
Ticks from Sweden yielded lower spirochaetal counts and on an island south
of New Zealand, where MS is reportedly less prevalent compared to the
northern hemisphere [15], the number of detected spirochaetes was the lowest
[29]. Ticks from Cape Sizun (France) yielded negative results, and,
unfortunately, the ticks collected on the Falklands and the Crozet Islands
(South Africa) were dead and thus not examined by microscopy. Regardless of
the geographical origin, B. garinii DNA was isolated and detected by PCR in
all ticks and cultured spirochaetes, with two notable exceptions. The
samples from the Atlantic coast of France and those from the Falklands -
which do not appear as particularly hot spots for MS [31,42] - were all
negative [29].
Seasonal correlation of MS and sporadic schizophrenia to Ixodes tick
activity
If the stochastic annual fluctuations of schizophrenic births [43] and Lyme
disease [44] are taken into account, the birth excesses of MS in Denmark [8]
and those of schizophrenia in Finland [45] are exactly nine months apart. In
northern Europe, the seasonal patterns thereby reflect the activity of
endemic Ixodes ricinus [44,46] at the time of conception and parturition
respectively. Likewise, there exists a nine months' shift between MS birth
excesses in Canada near Vancouver [30,47] and schizophrenic births in the
USA [48]. The respective seasonal distribution exactly mirrors the
periodicity of the adult and juvenile stages of B. burgdorferi transmitting
I. pacificus ticks along the West Coast [49] and that of I. scapularis ticks
along the East Coast (see [37]). Amongst all other neuropsychiatric
disorders, only amyotrophic lateral sclerosis (ALS) [50] shows a similar
seasonal trend [30,51] with respect to Ixodes tick activity in Europe [37]
(see Figure 2).
Discussion
The uneven distribution of MS has been noted in the medical literature for
well over 100 years [52]. Although difficult to assess reliably from one
geographical area to another [11], it has also become clear that the
frequency of the disease varies significantly not only in different parts of
the world, but even within countries. The first epidemiological study by
Davenport (1922) pointed out that MS affected persons of Scandinavian and
Finnish descent more than other ethnic groups, a conclusion confirmed by
Bailey's study of American troops in World War I. Later propositions that
MS, as well as ALS [53,54], relate to latitude and cold climate unleashed a
controversy over nature versus nurture that continues to this day (for
review see [11,12]).
Migratory seabirds spread B. burgdorferi sensu lato (B. garinii) worldwide
Since current opinion favours a genetic/immune process for MS, as well as
ALS, the possibility of spirochaetal infection has not been considered in
depth. The similar global distribution of seabird-borne ticks and
Scandinavians and their descendants, who appear to be at high genetic risk
for MS [55], is not entirely coincidental. One Viking legend claims that the
Faroes were discovered by following marine birds [56]. While seabirds
themselves often follow ships and eat fish offal floating on the water
suface [57], the scandinavians were apparently led by such birds to new
fishing grounds [56].
Little more than 300 of the approximately 9000 known bird species are
seabirds. Yet, these birds occur throughout the world and are the only group
of birds to have successfully colonised Antarctica, the most inhospitable
continent. Although some seabirds breed and winter within comparatively
small areas, many are champions in long distance migration, travelling
thousands of kilometres on journeys from the far north of the northern
hemisphere to the limits of the Antarctic pack ice in the southern
hemisphere [57,58].
The seabirds, which spend most of their lives far out to sea, must procreate
on land. To avoid predators, they often breed on isolated islands and
peninsulas leading to the aggregation of hundreds of thousands, and
sometimes millions of pairs during the breeding season. The presence of such
huge numbers not only depends on the abundance of food in the surrounding
seas, the crowding habit also makes the birds and their offspring vulnerable
to the seabird associated Ixodes uriae tick. No wonder, infestation by I.
uriae has been reported from more than 50 species of seabirds in both
hemispheres (see [29]).
Because seabirds take their food from shallow waters, many coastlines and
islands are prime sites for breeding colonies [57,58], Borrelia transmitting
I. uriae [29], and MS [56]. On the Faroe Islands (see Figure 1), where
Ixodes uriae reportedly transmits Borrelia from seabirds to human bird
catchers [59], the MS scenario apparently unfolded after an annulled ban on
fowling seabirds during a food shortage in World War II [56]. Whatever
speculation be more plausible - transmission by ticks [56] or soldiers
[12,14] - the prevalence of MS subsequently rose from apparently zero to 21
cases heralding the first of four successive epidemics [12].
On Iceland and elsewhere such epidemics have been attributed to increased
awareness, changes in ascertainment or better diagnosis of MS, particularly
of more benign cases in the post-war era [11]. However, a common setting for
MS 'epidemics' is proximity to coastal areas or islands where seabirds nest
[56]. From western Alaska both the presence of Ixodes uriae and B. garinii
have been reported [29], and in Sitka being surrounded by three major
seabird colonies in south-eastern Alaska (see Figure 1) MS was unknown until
its first outbreak occurred in 1965 [41].
Genetic [60,61] as well as epidemiological studies, in which biological
plausibility had been ignored [11], often provided contradictory
information. One of the significant risk factors mentioned in a study from
Key West (Florida), for instance [62], were visits to a local military base,
a finding that the authors noted as a point of similarity to the military
occupation and its reported effect on the Faroe Islanders [12]. In Malta,
however, which was occupied by British troops from 1802 to 1978, the low PR
of MS doubled from 1978 to 1988 (from 4.2 to 8.4), after the British left
[11]. In contrast to Sicily with a relatively high MS PR of 61, however, the
population of Malta (see Figure 1) still enjoys significant protection from
MS that cannot be convincingly explained by geneticists either. It is
noteworthy that since the Arabs were driven out by a band of Scandinavian
adventurers, who had established a kingdom in southern Italy, Malta became a
Norman appendage of Sicily for almost half a millennium. Yet, in addition to
Scandinavian genes [55], Malta also hosts four endemic races of lizards
(Podarcis filfolensis), and ticks lose their infectious potential for human
beings when feeding on these reptiles. This so-called zooprophylactic effect
also applies to the USA [35], where south of the 37° latitude (see Figure 1)
the PR of MS is significantly lower [12,15]. The only notable exception is
Florida [62], where migratory seabirds stop over for nesting [56].
Otherwise, infections by B. burgdorferi are poorly maintained by lizards in
the south of the United States [35]. While seabirds are not common in states
such as North Dakota, Montana, Idaho and Colorado where MS is high, the
inland spread of Ixodes ticks and Lyme disease by land birds is well
documented in the United States [63].
At the expense of a persistent vulnerability to lizards, the tick-borne
pathogen has proven successful in spreading neuroborreliosis including MS
via sub-polar routes [29] across the globe (see Figure 1). European strains
of B. garinii infections have been documented in human cases from the USA
[64] and Australia [39]. The case of Lyme borreliosis in the southern
hemisphere has been confirmed by culture and serotyping [39]. Being of
European origin, this type of B. burgdorferi s.l. was most probably
introduced into Australia by a migratory seabird. Not surprisingly after
all, southern Australia and New Zealand, which polar seabirds carrying
Ixodes uriae [29] reach via the Antarctic, score relatively high risks of
MS. Even the highest PR in these communities, largely originating from the
United Kingdom, is not much more than half the rate in most parts of the
British Isles [15]. This difference in relative risk is hard to understand
from a purely genetic point of view. But there isn't much room for 'pure'
environmentalists either, as Waikato in New Zealand, where the main step in
MS morbidity occurs across the North Island, scores a lower rate than places
in Australia on a comparable southerly latitude [2,15]. For migratory
seabirds introducing Ixodes uriae from the northern hemisphere [29] reach
New Zealand later than Australia (see Figure 1).
In the northern and southern hemispheres, several species are responsible
for this transhemispheric exchange. Great puffins or Manx shearwaters
(Puffini puffini), for example, move around the world in giant loops. They
are abundant off the European continental shelf in July and August, when
they are heading southeast. Between September and December, the puffins
spend their time mainly along the American coast form Rio de Janeiro in the
north to the Rio de la Plata in the south. Along these coasts, the
nutrient-rich water advances during this period with the Falkland Current
producing upwellings on the water surface rich in fish. By March and April
the birds leave their breeding colonies on the Falklands and other islands
in the South Atlantic heading northwest across the equator to the rich
fishing waters off Newfoundland. Then they gradually move back across the
North Atlantic, where they are often seen around Scotland, Ireland and the
Faroes, where the traditional puffin-hunting season starts in the end of
July [57-59].
In the southern oceans, where the winds blow almost continuously eastwards
in the roaring forties and furious fifties, a ringed great puffin has even
been found in south Australia. The distribution of short-tailed puffins, or
short tailed shearwaters (Puffini tenuirostri), is limited to this part of
southern hemisphere, where the birds breed on islands off the coast of New
Zealand and Australia. In Tasmania, as in the Faroes, their so-called
mutton-bird chicks are regularly fowled [58].
Among the most successful and widespread marine birds are the seagulls.
There are some 45 species, which occur in both hemispheres. Colonies may be
tens of thousands strong, particularly if there is a major source of food
thereby. Outside the breeding season most gulls, such as the black headed
gull (Larus ridibundus), undertake migratory movements, sometimes wintering
well out to sea. They move parallel to latitude to avoid cold weather, or
they simply disperse over comparatively short distances along rivers [58,65]
(see Figure 1). Along the tributaries of the upper Rhine [65] they thus
reach the foot of the Swiss Alps where B. garinii has become highly endemic
among other terrestrial passarine birds. These, in turn, may spread
borreliosis to other hosts [66] by regularly migrating to northern [67] and
southern Europe either along the valley of the upper Rhone or directly via
Alpine passes (personal communication 2002, Christian Marti, Swiss
Ornithological Institute, Sempach).
The seasonal correlation of MS to Ixodes ticks may explain hitherto
discrepant findings.
Extending a previous report from the United States, Templer and colleagues
found a high geographical correlation between MS and schizophrenia in Italy
[7]. As a correct temporal relation between cause and effect is essential in
epidemiology [6], correlated birth patterns of MS and schizophrenia were
then studied. In Denmark, a significant birth excess of MS was disclosed in
spring-early summer, but the data on schizophrenia were insignificant
compared to the general population [8]. This negative finding, which can be
explained by stochastic fluctuations (for discussion see [43]), was
unfortunate since accumulating evidence from most other studies [28] did
yield significant schizophrenic birth excesses in winter and spring.
In Sicily, interestingly enough, MS birth excesses being shifted towards the
end of the year [68] show a seasonal trend reminiscent of the seasonal
Ixodes tick activity in neighbouring North Africa [37]. And in Tunisia,
where Ixodes ticks harbour B. garinii and B. lusitaniae [34] - species known
to be scattered geographically by birds from Europe - MS scores the highest
rates in Africa [15].
Temperature and spirochaetal virulence: the genetic interface between
immunity and environment
MS has never been reported in ethnically pure Eskimos, Inuit, Lapps,
Amerindians, Australian aborigines, New Zealand Maoris or Pacific Islanders
[11]. Yet, most of these natives either live near the polar circle, where
tick activity abates due to low ambient temperature, or they live in
tropical climates where Treponema [27] but not Borrelia spirochaetes prevail
(see Figure 1).
The most convincing evidence for the importance of genetic or acquired
resistance is the extreme rarity of MS in native Africans. In the Cape
Province of South Africa, the disease is recognised among the so-called
coloured, but neurologists in Johannesburg are extremely reluctant to make
the diagnosis in a black person [11]. Hawkes [14] maintains that in
developing countries a general immunity is acquired against infection, which
might also spread "in utero or during parturition" and possibly increases
the resistance against MS and sexually transmitted disease. Until the early
nineties, I was working as a medical delegate in southern Africa and cannot
share Hawkes's opinion on the isolation of 'black' Africans from 'white'
sexual permissiveness. Venereal diseases including syphilis were highly
prevalent among natives of South Africa, Angola and Mozambique, and in that
part of the world it is the incidence of AIDS, but not MS, which has
substantially risen. The "infrequency of MS and AIDS in the same patient"
[14] rather favours the hypothesis of a hyperergic immune process [2,3]
which is suppressed in a state of immunodeficiency such as AIDS.
Whilst it is always more prudent to await the discovery of new facts [69],
long-held [25] hypotheses [14] often raise testable questions if taken
together and dissected with Occam's razor. The MS gradient, which sharply
declines at the 37° latitude, suggests a temperature-related environmental
factor that cannot be ignored (see Figure 1). The geographical distribution
of endemic treponematoses, by contrast, as well as blood group 0 antigens
which appear to convey resistance against Treponema pallidum [70], are
restricted to exactly those parts of the tropics that are free of MS. This
contrast is of evolutionary importance with regard to the adaptation of
intracellular pathogenic spirochaetes. Like the AB0 blood group system [71],
the evolutionary conserved heat shock proteins (HSPs) do not only induce
heat resistance, but also activate host immune defences that are detrimental
for pathogens (see for example [72-78]).
Molecular evidence reveals that Treponema pallidum - the agent of syphilis
being an exclusively human pathogen and B. burgdorferi s. l. - the human and
animal pathogens of Lyme borreliosis - have circumvented this immunological
impasse differently. Whilst in the course of evolution Treponema pallidum,
being directly transmissible from human to human, lost its capacity to
induce HSPs [79], heat resistance [80] and thus vector-borne transmission,
B. garinii has adapted to a broad temperature range [81]. To survive heat
shocks during vector-borne transmission, the gram-negative Borrelia pathogen
therefore expresses HSP-60 and HSP-70 [82], which are members of the
evolutionary conserved HSP family. This form of vector adaptation is
essential during rapid changes in temperature, in particular when
transmitted from ticks to their warm-blooded hosts [83] including birds.
In the absence of other vertebrate hosts on certain islands, the presence of
Borrelia in I. uriae ticks suggests seabirds to be competent reservoirs and
amplifying hosts. In contrast to B. burgdorferi sensu stricto being cleared
from the respective Ixodes vectors at 37°C [84], a temperature of 38°C is
permissive for the transmission of B. garinii [81]. The relatively low body
temperature of 38°C in marine birds, compared to the body temperature of
terrestrial birds of 40°C, explains why these B. burgdorferi s.l.
spirochaetes are particularly adapted to seabirds [29].
But the pathogen's success of transmission also depends on its ability to
replicate and survive within a host for long periods. One option is to
remain latent inside the long-lived cells of the CNS whose temperature is
about 38° in humans. This coincidence elucidates the characteristic spread
and neurotropism of B. garinii, which is frequently associated with
neurological manifestations [85]. In vitro evidence suggests early invasion
of the CNS by B. burgdorferi sensu lato by adherence of this organism to
sphingolipids [86]. Functionally linked to a flagellar protein, HSP-60 is
thereby involved in binding to the neural cell surface for intrusion into
the CNS [87,88]. As HSP-60 is a major immunodominant antigen of B.
burgdorferi [89], it comes as no surprise that antibodies to HSP-60 were
also detected in the synovial fluid of Lyme arthritis patients [90].
Although still a controversial issue [91-93], molecular mimicry of flagellar
epitopes, which are highly antigenic [94], may misdirect antibodies against
host tissues as well [95,96]. For pathogens must avoid being destroyed by
the immune response while maintaining access to a new host, and protracted
antigenic exposure destabilises the immune system.
Molecular, pathologic and microbiological evidence for an involvement of
Borrelia burgdorferi
Epidemiology cannot replace molecular, experimental and pathological
investigation including case reports, despite the fact that these are often
dismissed as 'anecdotal'.
Is it possible that the Borrelia flagellar basal rod protein (fbrp),
implicated in the pathogenesis of sporadic schizophrenia at conception
[16,97,98], also plays a pathogenic role in MS following transmission at
birth? As fbrp shares an epitope with the human interleukin-1 receptor
antagonist IL-1ra (see Table 1 an [99]), it is plausible to assume that such
amino acid homology between B. burgdorferi and its human host potentially
induces and misdirects anti-IL-1ra antibodies. Might re-exposure to the same
[100] or similar antigens [101,102] subsequently trigger MS later in life?
Conversely, may cross-reacting antibodies acquired against Treponema
spirochaetes protect migrants from tropical countries against infection by
Borrelia spirochaetes and thus antigenic exposure to fbrp?
Not only tropical spastic paraplegia [14] mimics the clinical pattern of MS.
In several respects, MS is more reminiscent of neuroborreliosis [102-105],
which in its chronic form is supposed to be an autoimmune disease triggered
by these spirochaetes [95,105]. MS plaque-derived DNA [106] shows an
abundance of transcripts for several heat shock proteins (HSPs), including
HSP-70 and anti-HSP-70 antibodies, but apparently not for interleukin-1
(IL-1ß), the underlying pro-inflammatory cytokine (see also [107-110]). This
contrasts with other common gram-negative infection, in which HSP-70
induction correlates with elevated levels of IL-1ß transcripts [111]. A
putative anti-IL-1ra immune response against IL-1 receptor antagonists
(IL-1ra) might therefore explain this specific post-transcriptional
dysbalance at the level of the IL-1 receptor unleashing a cascade of ruinous
inflammatory cytokines. There are three arguments in support of such a role:
reduced genetic expression of IL-1ra versus IL-1ß has been associated with
disease severity in MS [112]. IL-1ra can be increased by interferon beta
[113], the first neuromodulatory drug approved for the treatment of MS [4].
Conversely, lower IL-1ra versus higher IL-1 activity enhances inflammation,
whereas a dysbalance in favour of IL-1ra versus IL-1 reportedly mitigates
this reaction in MS, experimental allergic encephalomyelitis (EAE) and B.
burgdorferi induced Lyme disease [114,115].
When in 1925 Adams et al. [116] inoculated rhesus monkeys with material from
MS plaques, spirochaetes emerged in their ventricular fluid after several
months. More recently, cystic structures originating from B. burgdorferi
were found in eight of ten MS patients by immunofluorescence and in all the
MS patients by use of transmission electron microscopy and staining after
culture [21]. The patients originated from a well-defined coastal area of
southern Norway, where Lyme borreliosis [117,118] as well as MS [12,15] is
highly endemic. No such cysts could be observed in the five controls with
either method, but the investigators noted a similarity between those found
in the MS patients and the cystic forms characteristic of spirochaetes and
chronic B. burgdorferi infection. More importantly, the cysts of the MS
patients exhibited positive reactions to antispirochaetal antiserum [21].
In analogy to the induction of heptocellular carcinomas upon chronic
hepatitis B infection acquired during delivery [24] and in analogy to
lymphomas of the skin induced by chronic B. burgdorferi s.l. infection
[117,118], we would expect an association of MS and ALS with neoplastic
transformations of the lymphatic system. A significant correlation between
non-Hodgkin's lymphomas and MS appears to exist [119], and in a review of
neurolymphomatosis a case was documented with schizophrenia and anterior
horn involvement, a hallmark of ALS [120]. As the cause could not be
identified, a virally mediated autoimmune pathogenesis was proposed.
Whatever the pathogenic link between schizophrenia and MS - an infection
followed by an altered immunologic response [5] or a continuum of chronic
inflammatory CNS disorders including neuroborreliosis, syphilis, or viral
encephalitis [121] - we would expect an analogous link between schizophrenia
and ALS in terms of latitude [53,54], season (see Figure 2) and causality
[122].
Among relatives of Ashkenazi immigrants to metropolitan New York suffering
from schizophrenia [123], the prevalence of ALS compared to the expected
population rate in the USA, where B. garinii is non-endemic, was more than a
hundred times higher. Not surprisingly after all, the countries of ancestral
origin included eastern Europe and Russia [123] areas where B. garinii is
endemic [117,118].
Up to ten percent of patients initially diagnosed as having ALS are
re-diagnosed as having a disease other than ALS [124]. Although it seems
unlikely that infection by B. burgdorferi is a frequent cause of ALS [117],
a discrete subset of patients living in hyperendemic areas appears to be
significantly more likely to have immunologic evidence of exposure to B.
burgdorferi than do controls, and some of these patients do appear to
improve if treated with antibiotics [125].
Is the epidemiological association biologically plausible?
Although the nosological criteria for MS and schizophrenia have high
diagnostic reliability, affected individuals may differ substantially in the
specific profile of signs and symptoms, as well as in the severity and
course of their illness. What we recognise clinically as 'schizophrenia' or
'MS', is likely to encompass a complex set of disorders. A major task of
future studies will thus be to resolve the question of heterogeneity in MS
[2] as well as its aetiologic overlap with other disease processes.
Seroepidemiological studies relating B. burgdorferi to MS [126-128] and ALS
[125,129,130] have produced conflicting results. However, when entering the
CNS, microorganisms can undergo antigenic [131] and extensive metabolic
changes, which prevent them from being recognised by the current serologic
test methods. These changes protect B. burgdorferi from the host's immune
system and reduce the effect of antibiotics [21,132]. Although infections
all induce specific antibodies and cell-mediated immunity, microbial
virulence factors have not often been individually defined or even
identified [133]. There are hundreds or thousands of antigens, and immune
responses develop to many of these. Resistance to infection, however,
depends on the reaction against a few antigens on the surface of the
microorganism [133]. The flagellar basal rod protein of B. burgdorferi
(fbrp) responsible for locomotion, adherence and host cell penetration is
part of such a virulence factor. Influencing parasite-host interaction,
gram-negative bacteria use this type of basal ring assembly to secrete and
translocate flagellar and virulence proteins directly into the cytoplasm of
their host cell [134]. While temperature is a key environmental cue for the
switch between motility and plasmid-encoded gene expression of virulence,
stress-related degradation of the secreted substrates is accordingly
prevented by the chaperonising function of HSPs [135]. The coincidence of
both genetic and antigenic exposure to Borrelia fbrp is therefore not
casual, but a highly specific pathogenic event. Mutations by homologous
recombination affecting the implanting blastocyst at conception [16] and
chronic infection afflicting the immunologically immature newborn upon
delivery [24], it is conjectured, will subsequently trigger sporadic
congenital schizophrenia and MS respectively.
Conclusion
That maternal infection by B. burgdorferi s. l. poses a risk to the neonate
cannot be excluded. The global epidemiological clustering by season and
locality rather emphasises a causal relation between MS and sporadic
schizophrenia, which derives from both genetic and antigenic exposure to a
spirochaetal virulence factor at conception and birth. The identification of
flagellar Borrelia DNA on human CB1 and its relation to IL-1 receptor
dysfunction reminds us of Virchow's postulate in 1849: "In searching for
pathological systems one must clearly not construct nosological but only
etiological ones" [136]. It is hoped that this correlation might encourage a
new direction of neuropsychiatric research in molecular epidemiology.
List of abbreviations used
AIDS: acquired immunodeficiency syndrome
ALS: amyotrophic lateral sclerosis
B. burgdorferi s.l.: Borrelia burgdorferi sensu lato
CB1: central cannabinoid receptor gene
CNS: central nervous system
DNA: desoxyribonucleicacid
EAE: experimental autoimmune encephalomyelitis
fbrp: flagellar basal rod protein
HLA: major histocompatibility complex
HSP: heat shock protein
IL-1: interleukin-1
IL-1ra: interleukin-1 receptor antagonist
MS: multiple sclerosis
PR: prevalence rate
Acknowledgement
To RP re-diagnosed as having a birth defect, MS, ALS, and ultimately
atypical neuroborreliosis many thanks for her trust and patience.
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