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IgE antibodies to
allergen components
The contents of this leaflet are based on the research in the area by
the authors and others, and on their own clinical experiences.

Anna Asarnoj, Susanne Glaumann, Gunnar Lilja, Caroline Nilsson,

Marianne van Hage, Mirja Vetander, Eva Östblom and Magnus Wickman.

Sachs’ Children and Youth Hospital

Karolinska University Hospital. Stockholm 2013
Introduction
The diagnosis of allergy has so far been based on case history, skin prick test results or the
presence of allergen specific IgE antibodies (IgE abs) in serum, elimination of an allergen, and
when possible, oral provocation. The use of quantitative allergen-specific IgE has proved to be
useful for allergy diagnosis. Since 2007 it has furthermore been possible to analyze IgE abs to
single allergenic proteins (allergen components) in allergy-causing substances in Sweden.
This is what the concept Molecular Allergology refers to. The individual proteins have been
given designations based on the Latin name of the allergen source (e.g. peanut = Ara h from
Arachis hypogea) and have been numbered in the order that they have been discovered.

Figure 1. The concept of Molecular Allergology in allergy diagnostics

• To identify the primary specific sensitizing allergen in relation to

the cross-reacting one
• To elucidate the probability that the cross-reactive allergen will
only give rise to mild reactions if any, by
– having knowledge of the degree of homology between the
sensitizing allergen and other related allergens
– acquiring knowledge of the degree of protein stability,
i.e. how heat and acid instable the allergen is
• To have knowledge of how much of the protein there is in the aller­
gy source, i.e. how large the dose will be on a given exposure.

When investigating allergy to milk, egg, fish, pollen, furred animals and mites we now that the
higher the IgE levels, the higher the probability that the patient will suffer symptoms on expos­
ure to the allergen. For a number of allergens from the vegetable kingdom, such as peanut, soy
and wheat, such a clear correlation cannot be seen. This is due to the fact that these foodstuffs
contain allergen components with a similar structure to allergenic proteins in pollens, among
others. This may result in IgE antibodies to these foodstuffs being detected in allergy tests,
even if they do not necessarily cause allergic symptoms to the food.
The main allergen Bet v 1 in birch pollen is the prime example of a type of allergen belonging
to the protein family PR-10 (pathogenesis-related proteins of class 10).
PR-10 allergens are found in many plant-based foodstuffs and exhibit great homology with
Bet v 1. In hazelnut the PR-10 protein is called Cor a 1, in peanut Ara h 8, and in soy Gly m 4.
These proteins are so similar to the main allergen in birch pollen that cross-reactivity between
various IgE antibodies to PR-10 allergens can be expected, especially if the level of IgE to
birch is high. Cross-reactivity between IgE antibodies to structurally similar proteins contain-
ing a greater or smaller share of common epitopes and having the same biological function
means a risk also for clinical cross-reactivity. This is why individuals allergic to birch pollen
experience itching in the mouth and throat when eating plant-based foods containing PR-10
proteins, e.g. apple, peach or hazelnut. These individuals can also react with the same
symptoms if they drink a soy beverage or eat peanuts.
Individuals allergic to birch pollen reacting to hazelnut, peanut or soy as a result of IgE anti-
body cross-reactivity are generally not at any significant risk for suffering severe symptoms on
ingestion of these food allergens. One condition is, however, that they do not have a primary
sensitization to peanut, hazelnut or soy. The reason why serious symptoms do not appear in
birch pollen allergic individuals with IgE cross-reactivity with peanut, hazelnut or soy is that
the PR-10 proteins are present in small amounts and are relatively instable in these foodstuffs.
The instability means that they to a large extent are denatured in food preparation or by the
enzymes and acid of the gastric juice. A prerequisite is however that the intake of the allergen
in question is not too large or too rapid.
The corresponding possibility for IgE cross-reactivity also exists in allergy to e.g. different
pollens (birch, grass and mugwort), various furred animals (cat, dog and horse), insects (bee
and wasp), latex, avocado and chestnut, animals containing tropomyosin (mites, cockroach and
shellfish) and between practically all beans, nuts and seeds, as these foodstuffs contain similar
proteins.
Since 2007 molecular allergology has been used at the pediatric allergy clinic at Sachs’
Children and Youth Hospital, in research and in clinical routine for allergy diagnostics. This
has considerably simplified the management of allergies, above all food allergies, improved
our possibilities to give fact based information to the patient, and increased our knowledge of
when adrenaline in an autoinjector can be prescribed. It is important for us to be able to explain
to the patient that the presence of IgE abs to a specific allergen does not necessarily mean that
you will get an allergic reaction to the allergen in question. Sometimes unpleasant symptoms
may occur in the mouth and throat due to IgE cross-reactivity, but such a reaction is not to be
considered dangerous.
This leaflet is not a complete account of the topic of allergy diagnostics using IgE abs
to allergen components. For further knowledge we refer to review articles published in
recent years (e.g. Hauser et al 2010, Sastre 2010, Borres et al 2011) and to
http//:www.phadia.com/en/Allergen-information/ImmunoCAP-Allergens.

NOTE! – A decreased risk for serious allergic reactions only applies provided that
the patient only has a birch pollen-related nut, peanut or soy allergy and not a “true”
allergy.” Mixed forms are common, however, and this can be investigated with IgE testing
for components.
ALLERGY DIAGNOSTICS IN FOOD ALLERGY
FOOD ALLERGENS FROM THE VEGETABLE KINGDOM

Which allergenic proteins from the vegetable kingdom that cause systemic reactions mainly
depends on the amount in which they appear and their degree of stability. In foods from the
vegetable kingdom four different protein families can be identified that may cause sensitization:
storage proteins, lipid transfer proteins (LTPs), PR-10 proteins, and profilins.
The storage proteins and LTPs are stable to heat and digestion and can therefore give rise to
systemic reactions. Allergy to LTPs is relatively uncommon in Sweden, despite the fact that
LTPs are present in most vegetables, fruits and grains. The reason for this is largely unknown,
but may to some extent have to do with the fact that we are not exposed to pollens that contain
LTPs in addition to the main allergen. In addition to LTPs fruits may also contain other stable
allergens, e.g. cysteine protease which can be found in kiwi (Act d 1), among others.

Table 1: The most common protein families in food allergy from the vegetable
kingdom and the risk for systemic reaction on ingestion

Protein group Stability Risk for systemic reaction

on ingestion
Storage proteins belonging High Yes
to various protein families
(2S albumin, 7S globulin,
11S glycin)
Lipid transfer proteins High Yes, but rarely in Sweden
PR-10 proteins Low to moderately low No, but there might
be exceptions
Profilins Low Never

Peanut - Arachis hypogea

Allergen components
Ara h 1 – storage protein, 7S globulin
Ara h 2 – storage protein, 2S albumin
Ara h 3 – storage protein, 11S globulin
Ara h 6 – storage protein, 2S albumin
Ara h 8 – PR-10 allergen, i.e. Bet v 1 (birch) homolog
Ara h 9 – lipid transfer protein, LTP

When investigating peanut allergy, it may seem sufficient to analyze IgE abs to Ara h 2 (“true”)
and Ara h 8 (Bet v 1-homolog) in addition to f13, i.e. peanut allergen extract (for use as a
reference). In cases of IgE sensitization to Ara h 2, and above all if the concentration of IgE abs
to Ara h 2 is high, IgE abs to Ara h 1 and Ara h 3 are most often positive. IgE abs to Ara h 1 and
Ara h 3 demonstrate some cross-reactivity with the corresponding proteins in other seeds, beans/
peas and tree nuts. Analysis of IgE abs also to Ara h 1 and Ara h 3 may therefore be of value.
If there are IgE abs to Ara h 2 and/or Ara h 1/Ara h 3, at a detection limit of 0.35 kUA/L,
the accuracy of a diagnosis that the patient has a “true peanut allergy” is more than 97 %.
On the other hand, if there are IgE abs only to Ara h 8 and to none of the storage proteins,
more than 99 % tolerate peanuts or experience only mild symptoms from the mouth or throat
after ingestion of peanuts.

The majority of patients with IgE abs to Ara h 2 get allergic symptoms when eating peanut,
thus it is not necessary for this patient group to undergo provocation with peanut in order to
confirm the diagnosis. Among patients with IgE abs to Ara h 2 below2 kUA/L there might be
a few individuals who tolerate peanut, but severe reactions to peanut can still occur at such
low IgE-levels to Ara h 2. In cases where it is important to establish the degree of severity of
reactions to peanut provocation may be considered (e.g. teenage problems with denial).

In cases of itching, burning or swelling in the mouth or throat on ingestion of peanuts (like
the reaction to apples in birch pollen allergics) sensitization to Ara h 2 cannot be ruled out.
You should therefore test these patients for IgE abs not only to Ara h 8, but also to Ara h 2,
in addition to peanut.

The presence of IgE abs to Ara h 9 is often linked to allergic systemic reactions and are more
common in the Mediterranean countries, but rare in Scandinavia. In some cases only local
symptoms (OAS) occur. Individuals from southern Europe, living in Scandinavia, may have
IgE abs to Ara h 9.

Even though we can measure IgE abs to many different peanut components there are still
individuals who have clinical reactions despite negative results for all the peanut components
we know today. IgE abs to peanut (f13) is elevated in these cases, but the total amount of IgE
to the components that we can analyze today, does not reach the f13 level.

Children/adolescents who are sensitized and have a clinical allergy to peanut, but are eating
other nuts and/or almond should be able to continue eating these. There is no scientific evid­
ence that avoiding tree nuts should be recommendable as a precautionary measure.

Summary: In cases of suspected peanut allergy you should primarily test for sensitization
to peanut, Ara h 2 and Ara h 8. Analyzing IgE abs to Ara h 1 and Ara h 3 should be considered
if you wish to obtain a complete picture of the sensitization. In some cases also analysis of
IgE abs to Ara h 9 may be motivated. Always analyze for sensitization to birch pollen at
the same time.

Soy – Glycine max

Allergen components
Gly m 5 – storage protein, 7S globulin
Gly m 6 – storage protein, 11S globulin
Gly m 4 – PR-10, Bet v 1 (birch) homolog

In ”true soy allergy” sensitization to Gly m 5 and Gly m 6 is common and the IgE ab levels to
these components are generally high (>10 kUA/L). In patients with IgE abs to peanut who are
sensitized to Ara h 1 and/or Ara h 3 the majority also have IgE abs to soy protein, without
necessarily suffering reactions to soy. The IgE ab levels to soy are relatively low among patients
who are primarily allergic to peanut. Elevated IgE levels to soy are common in cases of pri-
mary sensitization to grass and birch pollen and other foodstuffs from the plant kingdom.
In these cases IgE to soy is usually at a relatively low level.

Gly m 5 and Ara h 1 are both 7S globulins and Gly m 6 and Ara h 3 are 11S globulins. The
homology between 7S globulins from peanut and soy is just a little over 40%, so strong clinical
cross-reactions are not to be expected. Soy should not be eliminated from these patients’ diets
unless there is also a clinical soy allergy.

Patients with a primary soy allergy often have high levels of IgE abs to soy (f14) compared to
the corresponding level of IgE abs to peanut. Those with a primary peanut allergy often have
IgE abs to Gly m 5 and Gly m 6, but the levels are relatively low. There are however patients
who are primary sensitized to both soy and peanut. They have high IgE ab levels to peanut as
well as soy, but such patients are rare.

One 2S albumin, which is the most important component in peanut and there called Ara h 2, is
also present in soy (Gly m 2S albumin). Studies suggest that Gly m 2S albumin is essential for
triggering allergic reactions to soy together with Gly m 5 and Gly m 6. No test for IgE abs to
Gly m 2S albumin is currently commercially available.

When an allergic reaction to soy is suspected, above all to soy beverage and with concurrent
birch pollen allergy, it is recommended that IgE abs to the soy component Gly m 4 are analyz­
ed. Gly m 4 is a PR-10 allergen and a homolog to Bet v 1 from birch pollen. Note that in these
patients IgE abs to soy (f14) may be negative even if IgE abs to Gly m 4 is positive in testing.
This is due to the fact that there is only a small amount of Gly m 4 in the soy extract.

Strong reactions to soy have been traced to sensitization to Gly m 4. This seems to affect birch
pollen allergic patients when they drink soy beverages fast and especially on an empty stomach
(e.g. long distance runners or instead of breakfast). This has been observed during the birch
pollen season. In some cases systemic reactions have been noted. The explanation may be that
Gly m 4 is probably partly heat and acid/enzyme stable. Another explanation could be that
when soy meal is drunk, this suspension will have considerable contact with the mucosa in
the mouth and throat and Gly m 4 may thus be able to reach the bloodstream without passing
through the stomach. In order for a strong reaction to occur a relatively high dose is probably
also required. Patients with IgE abs to Gly m 4 do not seem to react to soy meal mixed into
other foods. This is probably explained by the fact that the intake of a beverage results in a
much higher mucosa exposures compared to when soy meal is one ingredient among many.

Summary: Analyze IgE abs to soy only on suspicion of soy allergy. If the IgE ab level to soy
is < 0.35 kUA/L, but a strong suspicion that soy is involved in the reaction remains, the patient
should be tested for IgE abs to Gly m 4 (Bet v 1 homolog) and IgE abs to birch pollen.
Hazelnut – Corylus avellana
Allergen components
Cor a 1 - PR-10, Bet v 1 (birch) homolog
Cor a 8 - lipid transfer protein, LTP
Cor a 9 – 11S globulin
Cor a 14 – 2S albumin

Just as we have important allergen components for peanut, we also have such for hazelnut.
This is important in order to distinguish between a probable PR-10 allergen mediated reaction
and a reaction caused by storage proteins. Many birch pollen allergics experience itching in
the mouth and throat when eating hazelnuts due to homology between the two PR-10 allergens
Cor a 1 in hazelnut and Bet v 1 in birch pollen. In systemic reactions in connection with inges-
tion of hazelnut, on the other hand, IgE reactivity to the two storage proteins Cor a 9 (11S
globulin) and/or Cor a 14 (2S albumin) is seen. Cor a 8, which is an LTP allergen, is seldom
elevated in Nordic patients. Always test for birch when investigating suspected hazelnut al-
lergy in order to relate to possible sensitization to Cor 1 a. An IgE ab level to Cor a 1 that is
higher than the corresponding IgE ab level to hazelnut can in most cases be explained by an
even higher IgE ab level to birch pollen. Currently Cor a 11, which is a 7S globulin, is not
commercially available. The scientific literature concerning the storage proteins of the hazelnut
suggests that in most cases it is sufficient to be able to test for IgE to Cor a 9 and Cor a 14.

In patients with a primary sensitization to hazelnut a low grade sensitization to walnut is often
observed, due to the botanical relationship, both being Fagales trees. The clinical relevance of
this cross-reactivity is unknown.

Summary: Test for IgE abs to hazelnut (f17) and birch when investigating hazelnut allergy.
In “true hazelnut allergy” there is IgE reactivity to the storage proteins Cor a 9 and/or Cor a 14.
In exceptional cases there are elevated levels to Cor a 8, which is an LTP allergen. In testing
after a reaction to hazelnut and if IgE abs to Cor a 1 is negative but f 17 positive, there is IgE
either to one of the hazelnut’s storage proteins or to LTP.
Allergen components in other tree nuts,
seeds and leguminous plants (beans/peas)

Homologous allergen components such as storage proteins, LTPs, PR-10 proteins and some
other proteins are found in tree nuts, leguminous plants (peas, beans, lentils) and seeds from
sesame, mustard, pumpkin, sunflower, poppy, etc.). Some degree of IgE ab cross-reactivity
can therefore be expected in allergy to these foods. The greater the homology, the higher is
the like­lihood that clinical cross-reactivity may occur. The homology generally has a botanic­
al link; the closer the relationship, the greater is the likelihood for IgE cross-reactivity and
symptoms due to this reactivity. For example, there exists a strong IgE cross-reactivity in aller­
gy to cashew and pistachio on the one hand and walnut and pecan on the other. Cashew and
pistachio both belong to the family of sumac plants (Anacardiaceae), while walnut and pecan
belongs to the walnut family (Juglandaceae). If allergy/IgE reactivity exists e.g. to cashew
there is no need to analyze IgE abs to pistachio. The level will be approximately the same as
for cashew. The same applies to walnut and pecan nut. If you are allergic to one of these tree
nuts you should also refrain from its close relative.

Table II. Occurrence of 2S albumin, 7S globulin and 11S globulin in peanut

and leguminous plants, tree nuts and seeds, and their designations as
allergen components

Foodstuff PR-10 2S albumin 7S globulin 11S globulin

Peanut Ara h 8 Ara h 2, Ara h 6, Ara h 1 Ara h 3
Ara h 7
Soy Gly m 4 Gly 2S albumin Gly m 5 Gly m 6
Pea Pis s 1
Hazelnut Cor a 1 Cor a 14 Cor a 11 Cor a 9
Cashew Ana o 3 Ana o 1 Ana o 2
Pistachio Pis v 1 Pis v 3 Pis v 2, Pis v 5
Walnut Jug r 1 Jug r 2 Jug r 4
Para nut Ber e 1 Ber e 2
Sesame Ses i 1, Ses i 2 Ses i 3 Ses i 6, Ses i 7
Mustard seed Sin a 1 Sin a 2

Gradually it is becoming possible to analyze allergen components of more tree nuts than just
hazelnut. On the ISAC chip (an allergy test using microarray-immunoassay technology) there
are a number of allergen components of various tree nuts. Now the components Ana o 3 (cash­
ew), Jug r 1, Jug r 3 (walnut) and Ber e 1 (para nut) can also be analyzed with ImmunoCAP
technology. It is a great step forward to be able to analyze IgE to components from various tree
nuts, compared to only analyzing allergen extracts, even if further studies are needed in order
to confirm the full clinical significance of the tree nut components.

Earlier studies have shown that peanut-specific IgE antibodies and IgE for tree nut allergens
may cross-react. This is often seen in the clinic in patients with very high levels of IgE to
peanut. On such occasions also low IgE levels to tree nuts occur. However, studies have shown
that peanuts and tree nuts do not seem to share the same antigen determinant, i.e. epitopes.

In cases with clinical symptoms and IgE abs only to tree nuts but not to peanut there is no
reason to warn against peanut if the child has previously eaten peanut and tolerated it. If a child
has reacted to one kind of tree nut, but tolerates other tree nuts, it can continue to eat these
nuts. This is debated internationally. The same applies to different kinds of leguminous plants,
see Figure 2.

Figure 2. The degree of sequence identity (0-100 %) between 7S globulins

from different leguminous plants and hazelnut

Soy 7S Peanut 7S Pea 7S Hazelnut 7S

Gly m 5 Ara h 1 Pis s 1 Cor a 11
Soy 7S 70-100% 40-49% 51-56% 31-34%
Peanut 7S 40-49% 94-100% 43-52% 33-34%
Pea 7S 51-56% 43-52% 67-100% 35-36%
Hazelnut 7 S 31-34% 33-34% 35-36% 100%

From Kroghsbo S et al Int Arch Allergy Immunol 2011;155:212–224

If an individual has reacted to several kinds of nuts, or if the family has great worries concern­
ing a more general nut allergy, you should analyze IgE abs to all nuts, peanut and possible also
sesame. It is the pattern of IgE abs to tree nuts and peanut and possibly some seeds like sesame
that should be evaluated. In some cases you need to decide if a provocation is needed in order
to clarify which nuts that the child tolerates. In cases of high IgE ab levels to a nut that the
patient gets allergic reactions to, IgE abs to other nuts are often detected, but at considerably
lower levels. This may be a case of IgE cross-reactivity that does not necessarily have clinical
relevance, especially if the difference in IgE concentration is 10 times or more between IgE for
the primary sensitizing allergen and IgE for the secondary allergen. Here component diag-
nostics may facilitate the diagnosis.

Wheat – Triticum aestivum

Allergen components
rTri a 14 – LTP
Tri a 19 – ω-5 gliadin
Gliadin (α, β, γ and ω )

Clinical allergy to wheat is relatively uncommon, but IgE ab sensitization to wheat without
allergic symptoms from wheat is much more so. The wheat allergen extract contains a large
number of components and the clinical relevance of these components is a hot research area.
In addition to ω-5 gliadin (Tri a 19) wheat also contains LTP and profilin. ω-5 gliadin has so
far proved to be a good marker for clinical wheat allergy. A new test including several of the
gliadins (α, β, γ and ω gliadins) with low solubility is now available for IgE testing and can
complement the picture of the IgE-mediated wheat allergy. In the future we will have access
to more wheat components. There is good correlation between the presence of IgE abs to the
wheat component ω-5 gliadin and the probability of reactions with allergic symptoms to wheat.
We therefore recommend testing for IgE sensitization to ω-5 gliadin if the patient has reacted
to food including wheat, even if a meal containing wheat has been ingested a few hours before
the occurrence of symptoms. This applies especially to the cases where the analysis of IgE
abs to wheat is negative, which can occur in cases of positive IgE reactivity to ω-5 gliadin.
Also remember that ω-5 gliadin may be the triggering agent in exercise-induced anaphylaxis.
IgE abs to wheat extract may be negative in these patients. So far we have limited experience
concerning IgE reactivity to wheat LTP (Tri a 14).

In cases of allergy to grains, including corn and rice, you can expect IgE ab cross-reactivity.
This also applies to grains and grass pollen, due to the fact that allergen extracts from these
foods contain homologous components, profilin among other.

Summary: In cases of IgE sensitization to wheat and/or suspected allergy to wheat, IgE abs
to ω-5 gliadin can be helpful to correctly diagnose wheat allergy. We probably still lack some
important wheat components and our knowledge of correct diagnostics in wheat allergy is
therefore limited.
Allergens in fruits and vegetables

Practically all fruits and vegetables contain LTP and profilin. Many also contain PR-10
aller­gens, i.e. birch pollen homologous allergens. In addition there are enzymatic allergen
components in some fruits that can cause systemic reactions as these allergens are heat and
acid stable. LTP is heat and acid stable, whereas PR-10 allergens and profilins are considered
heat and acid unstable.

Those who react to some fruits and vegetables in raw form but tolerate them in prepared form
usually have a PR-10 allergy due to an underlying birch pollen allergy (e.g. raw potato and
carrot), while patients who react to cooked, oven-prepared, pasteurized juices may be LTP-
allergic. LTP from fruit and vegetables display limited homology. It is uncertain if sensitization
to profilin in foodstuffs cause symptoms at all on ingestion. Mucous contact with inhaled pol-
len profilin, or latex profilin contact via the peritoneum, rectum or vagina, can cause symptoms
as the profilin is not denatured through heating or contact with the gastric juice and its enzymes
in these situations.

The PR-10 allergen from apple (Mal d 1), LTP from peach (Pru p 3) and profilin from birch
(Bet v 2) or peach (Pru p 4) have proved to be good markers for the respective group of aller-
gen components. Mal d 1 and Mal d 3 can only be analyzed with ImmunoCAP.
.

Peach – Prunus persica

Allergen components
Pru p 1 – PR-10, Bet v 1 (birch) homolog
Pru p 3 – LTP
Pru p 4 – profilin

In the Mediterranean area IgE-sensitization to Pru p 3 is common among persons with

systemic reactions to fruit, even if it is ingested in prepared form. Even if certain pollens,
e.g. from parietaria, olive tree or plane tree, contain LTP there is no convincing evidence
that LTP in these pollens are driving Pru p 3-sensitizaton.

If IgE abs to Pru p 3 are analyzed, it is recommended to always simultaneously analyze the
amount of IgE abs to Pru p 1. If IgE abs to Pru p 3 is negative, but there are IgE abs to Pru p
1 the experience of e.g. breathing difficulties at the ingestion of stone fruits and pome fruits
containing PR-10 allergens can probably be explained by a pronounced oral allergy syndrome.
The mild mucosal swelling that may occur in the throat is unpleasant, but not harmful for the
patient.
Kiwi – Actinidia deliciosa
Allergen components
Act d 1 - cysteine protease protein
Act d 8 - Bet v 1 (birch) homolog

It is common that patients with birch pollen allergy react with itching and swelling in the
mouth at the ingestion of kiwi, but there are also those who may react to the food with anaphy­
laxis. In birch pollen allergy IgE abs to Act d 8 are elevated. In “true” kiwi allergy the level of
IgE abs to Act d 1 is often elevated. If IgE abs to Act d 1 is negative, but positive to Act d 8,
the experience of e.g. breathing difficulties at the ingestion of kiwi can probably be explained
by a mild mucosal swelling in the throat.
FOOD ALLERGENS FROM THE ANIMAL KINGDOM

Milk - Bos domesticus

Allergen components
Bos d 4 - α lactalbumin
Bos d 5 - β lactglobulin
Bos d 6 - serum albumin
Bos d 8 - casein
Bos d lactoferrin - transferrin

We have limited knowledge of the clinical usefulness of components as a diagnostic tool in

the investigation of cow’s milk allergy. IgE abs to casein (Bos d 8), followed by IgE abs to
α-lactalbumin and β-lactglobulin (Bos d 4 and d 5) is considered to best reflect clinical milk
allergy. The vast majority of our patients with severe milk allergy have high IgE ab le-
vels to casein. So far we have only seen a few milk allergic persons who have IgE abs to
α-lactalbumin or β-lactglobulin without an elevated IgE level to casein. These are mostly
multi-allergic patients.

There is uncertainty concerning the serum albumin in cow’s milk and its clinical significance
as an allergen. Individuals allergic to furred animals may have IgE abs to serum albumin from
Bos d 6 (i.e. bovine serum albumin) and cross-reacting albumins from other species. The
clinic­al significance of this IgE ab cross-reactivity is in most cases probably limited.

Summary: There is more uncertainty concerning the significance of component diagnostics

relating to milk than concerning allergens from the vegetable kingdom, as the IgE cross-
reactivity is less pronounced. This is probably due to our consumption pattern – practically
all the milk we drink is cow’s milk.

Egg - Gallus domesticus

Allergen components
Gal d 1 - ovomucoid
Gal d 2 - ovalbumin
Gal d 3 - conalbumin
Gal d 4 - lysozyme

In a published study from Japan with a selected patient material it is reported that if the indi­
vidual has an IgE ab level below1.2 kUA/L for ovomucoid (Gal d 1), the probability is 95% or
more that the child tolerates egg in prepared (heated) form. Similar data has now been shown
in the US. It can also be seen that the IgE-levels for egg and ovomucoid largely follow each
other. If these data are transferable to Swedish conditions is not clear. In a situation where pro-
vocation may be considered it may however be of value to check the IgE-level to ovomucoid.
In those cases when egg sensitization can be traced only to Gal d 2 (ovalbumin) egg is often
tolerated in cooked (heated) form.
Summary: Consider analysis of IgE abs to ovomucoid, above all in cases with low IgE-levels
to egg, or when oral provocation is considered and if this provocation could be performed in
the patient’s home. However, it is the previous case history, i.e. the severity of the symptoms at
previous reactions, that is most important to evaluate.



Meat (cattle, lamb, pig and game)
Allergen components
Galactose-α 1.3-galactos (α-Gal)

It has recently been shown that systemic reactions such as anaphylaxis, generalized urticaria
and facial oedema may occur 3 to 6 hours after ingestion of meat. The allergy triggering
component has been the carbohydrate galactose-α-1.3-galactose (α-Gal). The epitope α-Gal
is already well known and is found in tissues in mammals and parasites. According to the
literature these patients have often been bit by a tick a few weeks or months before the reac-
tion to meat. This has been described from the US as well as Europe, including Sweden. It is
primarily adults who are affected, but this form of allergy also occurs among teenagers. The
patient group may be sensitized to meat from various mammals (cattle, pig, lamb, rabbit and
game) but not to poultry. Among these patients also an α-Gal-dependent sensitization to furred
animals (cat, dog, etc.) occurs, which appears to be irrelevant to allergy of the airways. Some
laboratories in Sweden can analyze IgE to α-Gal, but the test is still under development and is
not a regular test.

Fish
Allergen components
Gad c 1 – parvalbumin from cod
Cyp c 1 – parvalbumin from carp

The most commonly used allergen extract for fish is made from cod muscle. Parvalbumin is
the main allergen of cod (Gad c 1, f426) as well as a number of other fish species. There is
cross-reactivity between different fish species, not least among salt water fish. Different fish
have different amounts of parvalbumin. Tuna fish contains small amounts of parvalbumin
compared to cod. Parvalbumin from different fish is very similar and recombinant from carp
parvalbumin contains 70 % of the IgE-binding epitopes present in cod, tuna and salmon.
Therefore the fish extract f3 takes us far in the diagnosis of suspected fish allergy. The exper­
iences of using allergen components in the investigation of fish allergy are so far limited.

Summary: In cases of suspected fish allergy, start testing with standard cod extract, i.e. f3.
Shellfish
Allergen components
Pen a 1 - Tropomyosin from shrimp

Tropomyosin is a muscle protein present in various shellfish, clams, octopus, cockroach, mite,
anisakis, snails and other parasites. There is IgE ab cross-reactivity for tropomyosin in allergy
to any of these animals. Between shrimp, crab and lobster the homology is 90 %. In cases of
primary sensitization to e.g. shrimp the IgE ab levels for crab, lobster and crayfish should be
at almost the same level as IgE for shrimp. The homology between shellfish and clams is only
50-60 %. Between shrimp and mite the homology is 80 %. It is therefore not surprising if per-
sons with a primary mite allergy are also sensitized to shrimp and other shellfish. The clinical
relevance of this cross-reactivity is unclear.

Summary: Tropomyosin is a muscle protein allergen present in shellfish and mollusks,

some arachnea and parasites. Patients allergic to shrimp, crab, lobster or crayfish in most
cases tolerate different kinds of clams or octopus.
Pollen
Birch Betula verrucosa; Timothy Phleum pratense; Mugwort Artemisia vulgaris;
Ambrosia/Ragweed Ambrosia artemisiifolia

Figure 3. The most common allergen components in

birch, timothy, mugwort and ambrosia.

Phl p 1
Phl p 5 Bet v 1

Polcalcin

Phl p 7 Bet v 4

Phl p 12 Bet v 2
Profilin
Grasspollen Tree pollen
Art v 4
Amb a 8

Art v 5
Amb a 9

Art v 1
Amb a 1
Weed pollen

Allergen components in pollen can be unique, i.e. primary sensitizing, but pollens from differ­
ent species also contain similar allergen components. IgE cross-reactivity in pollen sensitizat­
ion can therefore be expected. The closer the relationship, the greater is the likelihood. Such
IgE cross-reactivity may in certain cases be clinically relevant. In birch allergy in Scandinavia
the PR-10 allergen Bet v 1 is the most important component. For timothy and mugwort the
most important ones are Phl p 1 and Phl p 5 and Art v 1 and Amb a 1, respectively.

Phl p 1 and Phl p 5 belong to groups 1 and 5, respectively, among the grass pollen allergens
and are present in various grass species. IgE to these allergens cross-react between different
grass species within each group and is of great clinical relevance. Art v1(Artemisia/mugwort)
and Amb a 1 (Ambrosia) do not belong to the same protein groups, but mugwort allergics may
still experience symptoms from ambrosia pollen, probably due to pronounced homology be­
tween other allergen components in these weeds, such as profilins and polcalcins. In mugwort
allergy symptoms often appear on ingestion of vegetables and various herbal spices. This may
be due to IgE cross-reactivity of primary sensitization to Art v 1and structurally similar prote-
ins, above all in composite plants and herbal spices. IgE to mugwort LTP can probably
be of importance in reactions to plant-based foods in which LTP is present.
Profilin is found as the components Bet v 2, Phl p 12, Art v 4 and Amb a 8, while polcalcin
is found as Bet v 4, Phl p 7, Art v 5 and Amb a 9. The pollen of most plants can also contain
other components such as isoflavone reductase (Bet v 6), LTP (Art v 3), among others. Even
though profilin and polcalcin are acid unstable and do not withstand heating, the intact proteins
are bioactive, and if they for instance reach the mucosa of the respiratory organs they may
cause symptoms on exposure in individuals with a more pronounced sensitization to these
components.

So what is the usefulness of testing allergen components in pollen allergy? When starting
immunotherapy it is of very great importance. Here component diagnostics can be of value
when making the decision if to offer immunotherapy for birch, grass or both.

Furred animals
Just as in the case of IgE to pollen, IgE to the allergen components of various furred animals
may be cross-reacting, not only serologically, but possibly also clinically. Allergen compon­ents
from furred animals consist of lipocalins, serum albumin, and very species specific com­ponents
like uteroglobin (cat) and prostatic kallikrein (dog). Most of these allergens have been develop­
ed from furred animal epithelia. Recently an allergen in dog saliva which does not occur in
the fur and which appears to have great clinical importance has been identified. Commercial
allergen extracts for dog do not contain this allergen. In connection with allergic symptoms
to furred animals sensitization to lipocalins (Can f 1, Can f 2, Can f 4, Can f 6 and Equ c 1)
is common, and so is uteroglobin (Fel d 1) in cat allergy and prostatic kallikrein (Can f 5) in
dog allergy. It is unclear to which degree IgE to the different lipocalins cross-reacts, not only
serologically but also clinically. With IgE to serum albumin you can expect cross-reactivity,
but in most cases this probably has limited clinical significance.

Figure 4. The most common allergen components from cat, dog and horse.

Protein Cat Dog Horse

Uteroglobin/Secretoglobin Fel d 1 – –
Serum albumin Fel d 2 Can f 3 Equ c 3
Lipocalin Fel d 4 – Equ c 1
Lipocalin Fel d 7 Can f 1 –
Lipocalin – Can f 2 –
Lipocalin – Can f 4 –
Lipocalin – Can f 6 Equ c 2
Prostatic kallikrein – Can f 5 –

Just as in pollen allergy it may be meaningful to investigate sensitization to various allergen

components in allergy to furred animals. This may be important if the patient has furred ani-
mals at home and a multisensitization to furred animals. If the sensitization to the animal you
have at home is only an IgE cross-reactivity to for instance serum albumin the risk is less that
the patient’s allergy will worsen if the animal in question is retained. At the start of immuno­
therapy to furred animals it is also important that you start therapy only to those animals where
primary sensitization is at hand, and not just cross-reactivity without clinical importance.
A patient with a dog at home and with a primary cat allergy may well be sensitized to serum
albumin and therefore positive in testing for cat as well as dog and horse. It is possible that
there is a greater risk to become sensitized to Can f 5 if you are exposed to male dog allergen.
More liopcalin components for more furred animals will probably become available in the
future.

Bee and wasp

Api m 1 Bee
Ves v 1, Ves v 5 Wasp, Paper wasp
MUXF3 (CCD) Bee and wasp

Patients to be investigated serologically are those reacting with a systemic reaction in connect­
ing with a bee or wasp sting and who may be offered immunotherapy. The stung patient may
find it very difficult to tell if he or she was stung by a bee or a wasp. The main allergens for bee
and wasp are totally different and do not cross-react. It is therefore a requirement for starting
immunotherapy that you really know what the patient has reacted to. In addition to species
specific components bee and wasp venom also contain a cross-reacting carbohydrate allergen
(CCD) and hyaluronidase (Api m 2 in bee and Ves v 2 in wasp). This means that an individual
with a primary sensitization and allergic to bee may be sensitized to wasp without this having
any clinical relevance. Only if the patient is sensitized to the unique and species specific aller­
gens, Api m 1, Ves v 1 and Ves v 5, do you know if there is allergy to bee or wasp or both.
These answers you cannot obtain with SPT.

Allergy diagnostics of foods in connection

with exercise-induced or idiopathic anaphylaxis

In cases of anaphylaxis with or without exercise where the cause is unknown an analysis of
IgE abs to allergen components from wheat and soy should be made, even if the IgE-levels for
the whole allergen for wheat or soy is below 0.35 kUA/L. Also investigate the possibility of an
underlying allergy to celery or meat (α-Gal):

Analysis of IgE abs to

1. ω-5 gliadin (wheat component), especially if specific IgE abs to wheat is
< 0.35 kUA/L and wheat cannot be ruled out as the allergy-causing agent.
2. Gly m 4 (soy component), even if specific IgE abs to soy is < 0.35 kUA/L,
simultaneously analyze also IgE abs to birch pollen.
3. Celery, also analyze IgE abs to mugwort pollen.
4. IgE abs to α-Gal.
Summary and some “good to know” facts

IgE ab cross-reactivity of various degrees is common. IgE antibodies to various tree nuts, seeds,
peas and beans can occur simultaneously due to homology, as the allergen extract contains
structurally similar proteins (7S globulin, 11S globulin, LTP and profilin), but it is considerably
less usual that this causes clinical cross-reactivity. Ara h 1 exhibits weak IgE cross-reactivity with
Gly m 5 and a number of peas/beans, tree nuts and seeds. Similarly, Ara h 3 only to a small extent
exhibits IgE cross-reactivity with Gly m 6 and a number of peas/beans, tree nuts and seeds. 2S
albumin is the clinically most important allergen component in the peanut and it is present also in
all nuts, beans and seeds. However, cross-reactivity in IgE reactivity to 2S albumin only occurs
between botanically very closely related species, e.g. walnut and pecan nut.
Do not test with peanut, hazelnut, soy or wheat in an SPT panel as screening. This only
causes problems due to IgE ab cross-reactivity at sensitization for homologous components in
pollens and foods. Only test for the food allergen(s) that are suspected based on the case history.
If a child eats certain nuts but reacts to another nut, it may be valuable to analyze IgE for
all nuts, i.e. almond, hazelnut, para nut, walnut and cashew. Primary sensitization to several nuts
may exist at the same time. You can possibly refrain from testing for pistachio in cashew nut
allergy, as the main allergens in these two nuts are particularly homologous. The same applies to
walnut and pecan nut. There is no scientific basis for “forbidding” all nuts just because of allergy
to peanut or one or two tree nuts.
If the sum of IgE abs to the components analyzed is lower than the IgE abs to the allergen
extract you should be careful, as some components are then probably missing in the analysis.
The IgE-levels to pistachio and cashew nut correlate, i.e. the content of IgE abs is often at
the same level. If sensitization and clinical reaction is present to one of these two nuts you should
be careful with the other one. The same applies to walnut and pecan nut.
In children < 3 years also low IgE-levels (0.1 – 0.35 kUA/L) to tree nuts and peanut can be
associated with anaphylaxis.
When the patient is no longer exposed to peanut/tree nuts the IgE ab levels may decrease,
sometimes by 50 % or more. Values below 0.35 kUA/L can therefore be seen at follow-up if the
child has not been exposed to the allergen for a time. These children should not be provoked
until school age and at least 5 years after the latest symptom-causing exposure (not scientifically
proven). Great caution with provocation should be observed if the patient has previously reacted
to the food with anaphylaxis of degree 2 or more.
Even though the risk for a reaction is linked to the IgE ab level, a food reaction in a patient
with a negative test result cannot be totally ruled out. Always take previous reactions into con­
sideration before a possible provocation.
Coconut, sunflower seed, pine nuts and sesame are not related to tree nuts and can in
most cases be eaten despite nut allergy. There are exceptions, however, as these foods have
some allergen components in common.
Many children tolerate almond despite allergy to peanut or other tree nuts. They can there-
fore eat marzipan or almond paste.
Our knowledge of allergy to macadamia nut is limited, but it should be treated as other nuts
and it can be tested for.
IgE cross-reactivity occurs in pollen allergy, but this may lack clinical relevance. You should
therefore test in order to find out what is primary sensitizing, this can be of great value when
starting immunotherapy. The same applies to furred animals and bee and wasp.
All the authors work at the Sachs’ Children and Youth Hospital, Stockholm
South General Hospital, except Anna Asarnoj who works at Astrid Lindgren
Children’s Hospital, Karolinska University Hospital, Solna and Marianne van
Hage, Karolinska Institutet and Karolinska University Hospital, Solna.

Contact: magnus.wickman@ki.se

Copyright © November 2013

Anna Asarnoj, Susanne Glaumann, Gunnar Lilja, Caroline Nilsson,
Marianne van Hage, Mirja Vetander, Eva Östblom and Magnus Wickman.