Tick bite induced α‐gal syndrome highlights anticancer effect of allergy

Abstract

Tick bite induced α‐gal syndrome (AGS) following consumption of mammalian meat is a recently described intriguing disease occurring worldwide. Here we argue that AGS and delayed allergy in general is an adaptive defence method against cancer. Our hypothesis synthesizes two lines of supporting evidence. First, allergy has been shown to have direct anti‐cancer effects with unknown mechanism. Second, eating processed meat was shown to be linked to developing cancer. Humans lost their genes encoding molecules α‐gal 30 MYA and Neu5Gc 2 MYA, the latter co‐occurring with the start of using fire. These molecules are acquired from external sources, as tick bite for α‐gal and mammalian meat for Neu5Gc, the latter accumulating in tumors. The resulting specific delayed allergic response is a molecular adaptation to fight cancer. By further testing and applying our hypothesis, new avenues in cancer research and therapy will open that might save lives and decrease human suffering. Tick bite induced α‐gal syndrome (AGS) following consumption of mammalian meat is a recently described intriguing disease occurring worldwide. Here, we argue that AGS and delayed allergy in general is an adaptive defence method against cancer. Our hypothesis might open new avenues in cancer research and therapy.

Full text

Received: 8 June 2021 Revised: 3 November 2021 Accepted: 5 November 2021
DOI: 10.1002/bies.202100142
HYPOTHESIS
Insights & Perspectives
Tick bite induced α-gal syndrome highlights anticancer
effect of allergy
Péter Apari Gábor Földvári
Institute of Evolution, Centre for Ecological
Research, Budapest, Hungary
Correspondence
Gábor Földvári, Institute of Evolution, Centre
for Ecological Research, Konkoly-Thege Miklós
út 29-33, Budapest 1121, Hungary.
Email: FoldvariGabor@gmx.de
Abstract
Tick bite induced α-gal syndrome (AGS) following consumption of mammalian meat
is a recently described intriguing disease occurring worldwide. Here we argue that
AGS and delayed allergy in general is an adaptivedefence method against cancer. Our
hypothesis synthesizes two lines of supporting evidence. First, allergy has been shown
to have direct anti-cancer effects with unknown mechanism. Second, eating processed
meat was shown to be linked to developing cancer. Humans lost their genes encoding
molecules α-gal 30 MYA and Neu5Gc 2 MYA, the latter co-occurring with the start of
using fire. These molecules are acquired from external sources, as tick bite for α-gal and
mammalian meat for Neu5Gc, the latter accumulating in tumors. The resulting specific
delayed allergic response is a molecular adaptation to fight cancer. By further testing
and applying our hypothesis, new avenues in cancer research and therapy will open
that might save lives and decrease human suffering.
KEYWORDS
anticancer effect, delayed allergy, LDL-cholesterol, Neu5Gc, red/mammalian meat allergy, tick,
α-gal syndrome
INTRODUCTION
Ticks (Acari: Ixodidae and Argasidae) are obligate hematophagous
arthropods well known for transmitting a wide spectrum of viruses,
bacteria, and protisits.[1] Besides their important role as vectors of
pathogens of medical and veterinary importance, ticks can also cause
different kinds of toxicoses that probably give selective advantage for
their own survival.[2] Recently, a new type of disease has been associ-
ated with tick bites: a delayed allergic reaction after consumption of
mammalian meat (often referred to as red meat).[3] During the tick-
bite induced α-gal syndrome (AGS) a type of allergy develops that leads
to IgE antibody response against the carbohydrate Galactose-alpha-
1,3-galactose (α-gal). The latter is present in glycoproteins from tick
saliva and tissues of non-catarrhine mammals, with other words, this
molecule is absent in old-world monkeys and apes including humans.
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Repeated tick bites of the same individual induce high levels of anti-
α-gal IgE antibodies that results in a delayed hypersensitivity to con-
sumed mammalian meat products in humans.[3] For the first time, tick
glycoproteins were shown to play an important role in allergy devel-
opment. This newly described condition can potentially cause fatal
delayed anaphylaxis to α-gal-containing foods and drugs and immedi-
ate anaphylaxis to tick bites. The disease has been reported in every
continent where hard ticks occur and it has been associated with sev-
eral tick species and genera. At the time of the first reports, the origin of
tick-derived α-gal was thought either to be blood meal remnants from
mammalian glycoproteins containing α-gal or bacteria present in tick
midgut producing this glycan. Recent studies gave new insights and tick
galactosyltransferases were reported to be responsible for α-gal syn-
thesis that might play substantial roles in the life cycle of both ticks and
tick-borne pathogens.[3]
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The α-gal epitopes are abundantly expressed on cells of nonprimate
mammals and New World monkeys, whereas non-catarrhine mammals
like humans lack this epitope but produce against it a large amounts
of anti-α-gal antibodies. The α-gal molecule has been lost from these
groups nearly 30 million years ago supposedly to protect them from
pathogenic organisms like viruses, bacteria and protists that are
abundantly decorated with this glycan.[4] It is supposed that immuno-
logical reaction against α-gal molecules is an effective evolutionary
solution to protect the hosts from life threating pathogenic organisms.
However, the recently discovered mysterious delayed allergic reaction
to mammalian meat, the tick bite induced AGS, can also lead to deadly
anaphylactic shock in some patients after 3–6 h.[5]
We assume that anti-α-gal immune response not only effects impor-
tant high-virulence acute infections but also low virulence chronic ones
that can have hidden prolonged debilitating consequences. A recent
report has suggested a relationship between anti-α-gal antibodies and
Alzheimer’s disease.[6] Theelevatedlevelofanti-α-gal molecules in
Alzheimer patients is well in line with our hypothesis because there are
studies linking this disease to chronic pathogen activities.[7–9] More-
over, according to some research amyloid plaques themselves have
antimicrobial effects.[10,11 ] Consequently, anti-α-gal response might
be effective against different kinds of cancers if we consider the fre-
quent infectious background of this serious disease group.[12] There
is an inverse relationship between allergy and cancer affecting mouth,
throat, brain glia, colon, rectum, pancreas, skin, and cervix.[13,14 ] One
explanation to this enigmatic phenomenon comes from Margie Pro-
fet who proposed a very attractive hypothesis to solve this mystery.
According to her the immediate symptoms of allergy namely sneezing,
coughing, diarrhea, etc., are preventive reactions activating in seconds
or minutes against potentially deadly toxins even carcinogens.[15] At
first sight the inverse relationship between cancer and allergy is well
explained by this hypothesis. But there is another class of allergic reac-
tions which is manifested only after hours instead of minutes and these
types of allergies could not have the preventive function mentioned by
Profet. How can we resolve this paradox?
Here we propose a hypothesis that in the case of delayed allergy,
the reaction is not prevention but a direct attack against cancer cells
to destroy them. It has been a long-time controversy that allergy
has direct effects against tumor cells but the exact mechanisms are
unknown. Beside the theories that try to explain the negative rela-
tionship between allergy and cancer there is another called immune
surveillance hypothesis. This states that the allergy makes the immune
system hypersensitive but the exact molecular mechanism needs
clarification.[16] In this hypothesis article we argue through the lens of
tick bite induced AGS that allergic reaction can also target cancer tis-
sue and we can propose a plausible molecular mechanism for this.
Allergy, α-gal, pathogens, and tumors are
interconnected
The prophylaxis theory of allergy has gained momentum and become
very popular.[17] It explains well the immediate form of allergy but
struggled to clear the delayed late-phase 1. If a toxin enters into the
host body the immune system must react very quickly because any
delay could be fatal. In the case of tick bite induced AGS developing
after the consumption of mammalian meat, even the life-threating food
allergy reaction manifests only after 3–6 h[18] which is paradoxical in
terms of the prophylaxis theory. We theorize that there is another spe-
cific target for this reaction: to directly attack and destroy tumor cells
inside the host body.
In the mainstream scientific literature most articles mentioned α-gal
as the central molecule in the pathogenesis of the AGS allergic reaction.
However, there are many examples where the suspect is a different
kind of protein instead of the sugar molecule.[5] After mosquito bites,
e.g., a tick α-gal-like molecule can induce hypersensivity reaction in
the host organism. However, not only this molecule can be allergicbut
many proteins play role in the development of the hypersensivity reac-
tions. Interestingly, many of them have delayed allergy-like responses
similarly to the case of tick bite induced AGS developing after the
ingestion of mammalian meat.[19] Moreover, the levels of anti-α-gal
antibodies produced show inconsistent patterns when we try to find
correlation with the severity of symptoms.[20] We hypothesize that
these differences mainly depend on the size and prevalence (metas-
tases) of cancer present in the individual. There are two key molecules
in the anticancer effect of AGS. One of them is α-gal which is a trigger
of the virulence for cancer-causing pathogens by highlighting the
presence of competing tick-transmitted pathogens. As a result, tumor
size can increase. The other key molecule is N-Glycolylneuraminic
acid (Neu5Gc), which is actually responsible for the anti-cancer effect.
Neu5Gc, that is also absent from humans, is taken up by consuming
mammalian meat. The increased size of tumor leads to an increased
amount of Neu5Gc incorporated. This leads to a more aggressive
anti-Neu5Gc immune reaction targeting cancer cells. We argue that
the α-gal molecule in the tick saliva is a trigger (there could be many
others) which increases the aggressiveness of tumor cells because,
as previously mentioned, most pathogens harbor α-gal[21] and cancer
causing ones might also do so like Human Papilloma virus, Epstein-Barr
virus, Helicobacter pylori, etc. Therefore, in this case these molecules
are indicators of appearance of potential tick-transmitted rival viruses,
bacteria and protists as competitors for carcinogenic pathogens
inside the host body. There is strong evidence that in a lot of cases
multiple infections with different strains or species of pathogens lead
to increase in virulence of all of the participants.[22,23 ] Because many
cancers have infectious etiology,[12] they probably function according
to the previously mentioned rule. Tumors caused by viruses, bacteria,
and parasites are frequent cause of morbidity and mortality in the
reproductive age too.[24–28 ] The most important cause of cervical can-
cer, HPV (Human Papilloma Virus) significantly affects women under
30.[26] The cause adult T-cell leukemia/lymphoma, HTLV (Human
T-lymphotropic Virus), has been reported frequently in patients within
the reproductive age.[27] Epstein–Barr virus- (EBV) is associated with
lymph proliferative diseases such as Burkitt lymphoma which is typical
in children in malaria-endemic parts of Africa.[28] In addition, brain
cancer and leukaemia are also typical tumors during childhood.[24,25 ]
Consequently, pathogen-induced cancers can exert a strong selective

APARI ANDFÖLDVÁRI 3of6
pressure onto the reproductive human population. There are two ways
for reaching higher virulence: the first is increasing the level of free
virions of carcinogenic viruses, the second is increasing the replication
of integrated viruses inside of the dividing cancer cells. Because the
integrated type is invisible for the immune system, only the free virion
type, probably containing α-gal, induces the production of anti-α-gal
antibodies.
We hypothesize that, by introducing pathogens, the tick bite may
increase aggression of tumor cells and this can lead to more severe
allergic symptoms. There are many examples in the medical literature
supporting this notion. The occurrence of Burkitt-lymphoma which
appears on the head and neck of children in Africa strongly correlates
with the geographical distribution of the endemic malaria parasites.
There is a more direct evidence when, after mosquito bite, the Epstein–
Barr virus-infected lymphocytes begin to proliferate extensively.[29]
After tick bite the same reaction has been reported in connection
with transmitted Borrelia infections but in this case the links with
Epstein–Barr virus is unclear.[30] According to a hypothesis, the com-
plex phenomena of tick bite allergy (not the mammalian meat allergy)
are a kind of protection against tick salivary molecules and tick-
transmitted infections. The reactions include epidermal hyperplasia
and increase in thickness of the skin. This can be an alternative of
our pathogen harboring cancer cell argument but the fact that this
allergic reaction is systemic and not a localized one strengthens our
hypothesis.[31]
Anthropogenic evidences show selective advantages
of allergy
N-Glycolylneuraminic acid (Neu5Gc) molecule similarly to α-gal has
been lost from humans but unlike α-gal it exists in our close relatives
like chimpanzees. The α-gal was lost nearly 30 million years ago but
Neu5Gc disappeared only 2 million years ago. In the case of α-gal it
is supposed that reason of loss was a dangerous pathogen[32] but it is
implausible for Neu5Gc. There is a very interesting co-occurrence of an
important event in the history of early human evolution with the loss
of the molecule Neu5Gc namely the control and use of fire.[33] There
is a solid consensus agreement that eating processed meat and devel-
oping cancer are closely linked.[34] We argue that the reason for the
loss of Neu5Gc is to protect humans from various cancers induced by
this dietary shift. To show connection between the loss of Neu5Gc and
cancer we have to find similar patterns in domesticated carnivores like
dogs, cats, and ferrets because humans share the processed meat with
these animals. Interestingly, this is really the case.
In dogs there are regional differences. In Europe, where processed
meat is common, dogs lost their Neu5Gc universally but in Asia, where
the dietary habits are mixed, the genetic composition of Neu5Gc posi-
tiveandnegativedogsismixedtoo.Inthecaseofferretsthepurelywild
type has Neu5Gc but in the derived domesticated one it is missing.[35]
Furthermore, when we artificially knock out the Neu5Gc gene in labo-
ratory mice we experience similar targeted accumulation of Neu5Gc
molecules inside the cancer cells of these animals as in the case of
humans.[32] Tumors were induced by a mouse mammary tumor virus
oncogene.[36] Based on our hypothesis, this trait could be used for
tumor localization in the future. This experiment confirms that the
function of Neu5Gc is universal and its loss is not a by-product but a
case of adaptation in all of the participants probably for the same rea-
son: to fight cancer. The fact that mice as independent model organ-
isms physiologically behave like humans after knocking out Neu5Gc
strengthens the suspicion that the same had happened to humans
and domesticated carnivores for similar evolutionary reasons in
the past.
Neu5Gc pathogenesis of allergy: An anticancer
mechanism
The 3–6 h delay in the tick bite induced mammalian meat allergy
is hard to explain mechanistically. We suggest that after eating
mammalian meat the process is slow because the prolonged pro-
cess of digestion, absorption, and intake of Neu5Gc and its expres-
sion on the surface of cancer cells takes a lot of time. Interest-
ingly, mainly placenta and tumors accumulate Neu5Gc and express
them on the cell surface.[37] These two tissues are not as dissimi-
lar as we think at first sight because placental cells structurally and
behaviorally are essentially cancerous.[38] We hypothesize that after
cancer cells express Neu5Gc on their surface the produced anti-
Neu5Gc antibodies bind to them and destroy them very effectively
in a form of allergic reaction (Figure 1). According to some specu-
lations, the resulting inflammation would not stop but help the pro-
gression of tumors.[37] We find many contradicting evidence for this.
First, we know that pathogenic microorganisms incorporate Neu5Gc
on their surface and anti-Neu5Gc kills them effectively on many
occasions.[37] Second, many tumors have infectious etiology.[12] More-
over, there is an observed negative correlation between many can-
cers and allergy.[13,14] There is general consensus that mammalian
meat consumption leads to development of cancer, however, there are
three cancers that, as an exception, are negatively connected to mam-
malian meat consumption, namely lymphoma, melanoma, and endome-
trial cancer.[39] Further clinical and experimental data need to be avail-
able to find out which specific cancers are negatively connected to
mammalian meat allergy and why.
Besides mammalian meat allergy, tick bite can induce anaphy-
laxis in cancer patients treated with the drug called Cetuximab.[40]
This medicine is a human-murine hybrid monoclonal antibody con-
taining both α-gal and Neu5Gc.[41,42 ] The originally planned mecha-
nism of action of these antibodies is to bind and block the epider-
mal growth factor receptors and stop the progress of cancer. How-
ever, it seems that the drug is primarily working because of its sec-
ondary cytotoxic effect not by the direct inhibition of the epider-
mal growth factor molecules. Interestingly, the other monoclonal anti-
body drug, the purely human Panitumumab, is weaker because of
the poor cancer cell killer effect.[43] In the case of mammalian meat
allergy the anaphylaxis appears after 3–6 h but for Cetuximab it is
only 15 min.[40] The reason for this could be the fact that Cetux-

4of6 APARI AND FÖLDVÁRI
FIGURE 1 Putative anticancer mechanism of the delayed allergic reaction after consumption of mammalian meat. Red arrows indicate the
processes triggered by Neu5Gc molecule. Blue arrows indicate the processes triggered by α-gal molecule. Green arrows show the alternation of
cancer-causing pathogens between the states of free virions and the integrated form inside the cancer cell genome. Created with BioRender.com
imab is an intravenous drug and this direct route speeds up the
manifestation of Neu5Gc and α-gal induced allergic symptoms and
reaction.
LDL cholesterol parallels with Neu5Gc
The anti-cancer effect of tick bite induced AGS can probably be
extrapolated to other types of delayed late-phase allergies. If our
reasoning is correct, we have to find other molecules that have
very similar characteristics to Neu5Gc. LDL-cholesterol was shown
to induce the production of anti-cholesterol antibodies and is linked
to allergic reactions.[44] Moreover, microorganisms cannot synthesize
LDL-cholesterol but can incorporate it into the cell wall in case of
bacteria.[45] The higher blood level of cholesterol is inversely con-
nected to infection level[46] and many microorganisms are directly
linked to cancer.[12] There are widespread data that statins (molecules
that lower blood cholesterol) increase the severity of infections and
boost tumor.[47] Tumors can accumulate significant amounts of LDL-
cholesterol and express it on their cell membrane.[48] There is experi-
mental evidence that higher levels of cholesterol decrease the sever-
ity and extension of hepatocarcinoma[49] but there is no explana-
tion for the phenomenon. We expect a similar molecular mecha-
nism here as in the case of Neu5Gc-mediated anti-tumor reaction.
As cancer cells accumulate cholesterol and express it on their cell
surface the production of anti-cholesterol antibodies will be induced
leading to an anti-tumor immune reaction as detailed above for
Neu5Gc.
Interestingly, many cancers have an inverse relationship with
atherosclerosis[50] which is the result of inflammatory reaction to the
LDL-cholesterol stucking on the cell membrane. Atherosclerosis is
solely a human disease and we cannot find it in our closest relatives,
chimpanzees.[51] Moreover, there is an intriguing synergistic effect
between the amount of fat in mammalian meat and the tick-bite
induced AGS. The higher fat content leads to more severe allergic
symptoms.[52] There is published evidence indicating that allergy can
promote the development of atherosclerosis.[53] This is in line with
our above hypothesis concerning the Neu5Gc-mediated anti-tumor
reaction.
How to test our hypotheses?
The proposed negative correlation between allergy and cancer should
be reflected in clinical data. We predict a significantly lower occur-
rence of tumors among individuals with allergic conditions, especially
among those who have mammalian meat-related allergies. This could
be tested by quantifying allergic diseases in large clinical datasets of
patients with diagnosis of cancer in comparison to the healthy popula-
tion. Large-scale retrospective studies of this kind could help to shed
light on other candidate molecules with anti-cancer effects that are
currently unknown.
In the case of allergy to the cancer drug Cetuximab we need to focus
on cases with the most radical symptoms. We predict that in patients
with high occurrence of anaphylaxis the prognosis of cancer is very
good compared to those who do not develop any symptoms. The other

APARI ANDFÖLDVÁRI 5of6
option is to experimentally observe ferrets where the purely wild type
has Neu5Gc but in the derived domesticated one it is missing.[35] The
susceptibility to cancer after consuming processed meat could be
compared under laboratory conditions between the wild type ferrets
and the domesticated ones that do not harbour Neu5Gc.
CONCLUSIONS AND PROSPECTS
Published evidence summarized above convincingly support our
hypothesis that the delayed late phase allergy is an adaptive and effec-
tive defence mechanism against cancer. We used an interdisciplinary
approach to prove our concept. First, we found anthropogenic data
that humans lost their innate Neu5Gc but, after consumption of mam-
malian meat as an external source, this molecule accumulates inside
cancer cells. Surprisingly, the situation can be experimentally repro-
duced in a non-human host. When we knock out the Neu5Gc gene
in laboratory mice targeted accumulation of Neu5Gc molecules inside
the cancer cells occurs which indicates that this is a universal phe-
nomenon. Moreover, in domesticated carnivores this gene has been
lost too because, we suppose, humans share processed meat with their
pets. Interestingly the time of the first use of fire by humans is very
close to loss of Neu5Gc, approximately 2 MYA.[33] Secondly, the cancer
drug Cetuximab harbors both α-gal and Neu5Gc and binds to the epi-
dermal growth factor receptors. It can destroy cancer cells while the
purely human Panitumumab cannot. This highlights the possibility that
Neu5Gc directs an allergic immune attack against cancer cells. Thirdly,
Neu5Gc induced anti-cancer effect is probably not unique but part of
a more general mechanism. For this reason, scientific efforts need to
be directed to find other molecules with similar behavior. A probable
next suspect is LDL cholesterol which is as immunogenic as Neu5Gc
and shares many similarities with this molecule. In the future we need
to search for more candidates in these classes of molecules which
open a new way to not only treat but cure different kinds of deadly
cancers.
In conclusion we highlighted a new kind of natural anticancer adap-
tation, namely the loss of some genes encoding α-gal and Neu5Gc from
our genome to protect us from cancer. Probably we have been losing
a lot of innate molecules for this reason during human evolution. We
acquire these molecules from external sources like tick bite in case of
α-gal and mammalian meat consumption in case of Neu5Gc, the latter
accumulating in tumor tissues, that induces antibody production. By
this specific immune response humans have developed a new molecu-
lar weapon to fight against deadly tumors. By further testing and prac-
tical application of our hypothesis new avenues in cancer research and
therapy will open that might save lives and decrease human suffering.
ACKNOWLEDGEMENTS
This work was supported by the grant “In the light of evolution:theories
and solutions” (GINOP-2.3.2-15-2016-00057).
CONFLICT OF INTEREST
The author declares no conflict of interest.
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How to cite this article: Apari, P., & Földvári, G. (2021). Tick
bite induced α-gal syndrome highlights anticancer effect of
allergy. BioEssays, e2100142.
https://doi.org/10.1002/bies.202100142