Critical Reviews in Food Science and Nutrition

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/bfsn20

Recent perspective on cow’s milk allergy and dairy

nutrition

Lily Jaiswal & Mulumebet Worku

To cite this article: Lily Jaiswal & Mulumebet Worku (2021): Recent perspective on
cow’s milk allergy and dairy nutrition, Critical Reviews in Food Science and Nutrition, DOI:
10.1080/10408398.2021.1915241

To link to this article: https://doi.org/10.1080/10408398.2021.1915241

Published online: 13 May 2021.

Submit your article to this journal

Article views: 137

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=bfsn20
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
https://doi.org/10.1080/10408398.2021.1915241

REVIEW

Recent perspective on cow’s milk allergy and dairy nutrition

Lily Jaiswal and Mulumebet Worku
Department of Animal Sciences, North Carolina Agricultural and Technical State University, Greensboro, North Carolina, USA

ABSTRACT KEYWORDS
Cow’s milk is a highly nutritious biological fluid that provides nourishment and immunity to Cow’s milk allergy; caseins;
infants when breastfeeding declines. However, some infants, children, and adults are allergic to whey proteins; galectin;
cow’s milk because milk contains potential allergens in the form of proteins. Casein and whey pro- pasteurization; dairy
cow nutrition
teins and their coagulated sub-fractions in the milk such as aS1-casein, aS2-casein, b-casein,
j-casein and a-lactalbumin, b-lactoglobulin, bovine serum albumin, immunoglobulins, lactoferrin,
respectively are the major etiological determinant of cow’s milk allergy (CMA). Moreover, milk
processing techniques such as homogenization and pasteurization alter the milk fat and whey pro-
tein’s molecular structure and serve them as allergens to the immune system of allergic individu-
als. Strict exclusion of nutrient-rich milk and other dairy products from diet puts children with
CMA at higher nutritional risk. Thus, regular nutritional monitoring, the inclusion of protein and
mineral-rich supplements as a substitute for cow’s milk, management of animal genetics (sheep,
goats, buffaloes, camel, mare, donkey, yak), and milk processing to produce non-allergenic milk by
inactivating allergic proteins for designer nutrition is essentially required. This review paper details
the prevalence, molecular profiling of milk allergens (proteins), body immune response against
CMA, consequences of milk processing, treatment, and novel role of galectins as potentially allergy
suppressors.

Introduction Milk from domestic dairy mammals has been used in the
human diet for thousands of years except for some ancient
The exceptional feature that differentiates mammals from
tribes who grew up their children only on mother’s milk
other animals in the world is to synthesize and secrete milk without milk from any mammal, for example, the South
from mammary glands. Milk is a nutritious biological fluid American Indians. Around the world, cows (82.4%) and buf-
that is rich in high-quality proteins, lipids, minerals, (cal- faloes (13.6%) contribute significantly to the world’s fresh
cium, magnesium, selenium) and vitamins (riboflavin, vita- milk production while the remaining percentage is shared
min B12, pantothenic acid). The primary biological function by goats, sheep, camels (Villa et al. 2018) and others like the
of milk is to provide nourishment and immunity to infant Tibetan Yak, the North Country reindeer, even horses and
mammals (Bhat, Dar, and Singh 2016). Consequently, milk donkeys (Gall 2013; Park, Haenlein, and Wendorff 2017).
is nutritionally considered to be a complete food. However, the breed, age, species, diet, lactation stage, season,
Colostrum, the very first milk produced after parturition, and the number of parturitions profoundly affect milk com-
contains the mother’s immunoglobulins and either the same position and production. Human milk is the most appropri-
or higher protein and lactose concentration as milk without ate food for infants because of its unique composition for
the fat (Alhussien, Manjari, Mohammed, et al. 2016). Infants their growth and development especially, bones, teeth, hair,
are highly susceptible to infections because they do not have and skin (Do, Williams, and Toomer 2016). However, cow’s
milk and other mammal milk are substituted for human
well-developed innate and adaptive immunity. However,
milk when breastfeeding is discontinued, although some
through milk (colostrum) immunoglobulins that help pro-
individuals, especially infants, can be allergic to milk. Most
vide passive immunity for fighting diseases are passed down
of the affected children outgrow milk allergy by four years
to the infants (Alhussien, Manjari, Sheikh, et al. 2016). In of age; some retain it lifelong, possess allergies to milk and
addition to nutrition, milk provides several biological attrib- exhibit an immediate allergic reaction when consumed (El-
utes such as antimicrobial properties, immune stimulants, Agamy 2007). This review paper details the role of cow’s
enzymes, and antibodies (Park 2009). Moreover, due to neu- milk proteins (CMPs) in cow’s milk allergy (CMA), the
trophils and macrophages as a part of innate immunity, molecular architecture of major milk proteins, CMPs medi-
milk protects the mammary glands from bacterial invasion ated immediate and delayed immune response, the effect of
(Haug, Høstmark, and Harstad 2007). processed and unprocessed milk on CMA, CMPs cross-

CONTACT Mulumebet Worku [email protected] Department of Animal Sciences, North Carolina Agricultural and Technical State University, 1601 East
Market Street, Greensboro, NC 27411-0002, USA
ß 2021 Taylor & Francis Group, LLC
2 L. JAISWAL AND M. WORKU

Table 1. List of cow’s milk bioactive components (Park 2009; Villa et al. 2018).
Major milk protein fractions Milk protein subfractions Bioactive compounds Biological function
Caseins aS1-Casein Isracidin Calcium binding protein, antimicrobial
aS2-Casein Casocidin Calcium binding protein, antimicrobial
a-, b Casein Casomorphins Opioids agonist
a-, b Casein Casokinins Ace inhibitors
a-, b Casein Phosphopeptides Calcium binding protein, increase Ca, P,
Zn absorption
a-, b Casein Immunopeptides Increase immune response, phagocytic activity,
Casomorphins milk stabilization, and coagulation
Casokinins
j-Casein Casoxins Opioid antagonist
j-Casein Casoplatelins Antithrombotic
j-Casein j-Casein glycol-macropeptide Probiotic (bifidobacteria) growth in GI tract
Whey proteins a-Lactalbumin Lactorphins Opioid agonist
b-Lactoglobulin Lactorphins Opioids agonist
Serum albumin Serorphins Opioids agonist
Immunoglobulins IgA, IgE Boost passive immunity
Lactoferrin Lactoferrin Augment humoral immune response, natural killer
cells, IL-6, thymocyte trafficking, antimicrobial
activity, Probiotic (bifidobacteria) growth
promoter in GI tract Decrease TNF-a, reduce
viral attachment
Lactoferrin Lactoferroxins Opioid antagonist
Other Oligosaccharides Oligosaccharides Probiotic (bifidobacteria) growth promoter in
constituents GI tract
Glycolipids Glycolipids Antimicrobial function
Prolactin Prolactin Augment lymphocytes, thymocyte trafficking
Cytokines IL-1, IL-2, IL-6, IL-10, TNF-a, IFN-c, Immune response development
leukotriene,
Growth factors TGF-a, TGF-b, IGF-1, EGF Organ growth and function
Parathromone-P PTHrP Augment calcium metabolism and uptake

reactivity, the role of galectins as allergy suppressor, and Kuitunen 1992). CMP contains 20% whey proteins (b-lacto-
dairy nutrition. globulin, a-lactalbumin, bovine serum albumin, lactoferrins,
transferrins, immunoglobulins) and 80% casein proteins
(alpha-s1-casein, alpha-s2-casein, b-casein, j-casein) shown
The role of cow’s milk proteins in cow’s milk allergy
in Table 1 (Park 2009; Villa et al. 2018).
Although there are some similarities in the composition of
cow’s and human milk proteins, the differences in the type
Molecular architecture of whey proteins
of proteins and their concentration in cow’s milk is suffi- Whey contains primarily a globular protein, b-lactoglobulin
cient to elicit an immune response in humans (Crittenden (10%) is a retinol-binding protein that possesses six genetic
and Bennett 2005). It has been observed that CMPs are the variants and naturally occurs as a dimer of two monomeric
most common cause of food allergy in infants (< two subunits. b-lactoglobulin is a major allergen in milk, and it
years). In healthy individuals, the immune system recognizes has a well-defined globular tertiary structure formed by
milk proteins as innocuous substances, while CMP allergic eight-stranded antiparallel b-barrel and three turn a-helices.
individuals are highly sensitive to milk proteins that initiate Furthermore, b-lactoglobulin has a high resistance to prote-
inflammatory responses that are characteristic of allergies. ase and acid hydrolysis that protects its structural integrity
Epitope mapping of many CMPs, including caseins and by permitting b-lactoglobulin to be absorbed through the
whey proteins, demonstrated that many proteins bear mul- intestinal mucosa, causing allergenicity (Fox 2001). Several
tiple allergenic epitopes that have been implicated in allergic reports have indicated that IgE binding epitopes are located
reactions (Crittenden and Bennett 2005). These epitopes are at the protein surface as a hot spot to react with IgE anti-
sensed by B and T lymphocytes that produce antibodies and bodies that fall mostly at 121 to 135 AA residues (Mici
nski
cell-mediated immune responses, respectively (Crittenden et al. 2013). a-lactalbumin (4%) is a calcium-binding metal-
and Bennett 2005). Milk allergy is often misdiagnosed as lac- loprotein that bears two genetic variants, is classified as a
tose intolerance, but these two phenomena are not the same. major allergen in cow’s milk, and accounts for the second
Many adults experience lactose intolerance, which is mainly copious protein in whey that aids in lactose synthesis via the
caused by a deficiency of lactase enzymes in the intestine transference of galactose to glucose. a-lactalbumin consists
(Haug, Høstmark, and Harstad 2007). of 4 disulfide bridges and has a high calcium-binding ability
that fortifies its secondary structure.
Moreover, a-lactalbumin exhibits high thermal stability,
Composition of unprocessed cow milk
refolding efficiency, and a compact tertiary structure (Villa
Unprocessed cow milk contains a protein concentration et al. 2018). The prevalence of the IgE binding epitope sensi-
three times higher than that of human milk (Savilahti and tization in allergic patients with a-lactalbumin varies from
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 3

27.6% to 62.8%, and the major allergenic site is located at Alpha casein 1 (as1-casein) occurs in a single chain
124 to 135 AA residues. b-lactoglobulin and a-lactalbumin phosphoprotein containing 199 amino acids (AA) rich in
are primarily synthesized in mammary glands, while bovine proline residues. There are seven genetic variants of as1-
serum albumin (1.2%) enters milk through secretory cells casein. Due to the lack of disulfide bonds, as1-casein loosely
from the blood. There are various other fractions present in forms tertiary structures. In addition, as1-casein has a small
small quantities in whey, such as bovine serum albumin percentage of secondary structure with a-helix and b-sheets;
(BSA), orosomucoid, folate binding proteins, fat globules as a result, the majority of molecular structures are unorgan-
(1%), b-microglobulin, and iron-binding proteins (transfer- ized (Goff 2016). The deficiency of conspicuous tertiary
rin & lactoferrin). In contrast to human milk, cow milk pos- structure on as1-casein requires that potential epitopes must
sesses IgG1 immunoglobulin (2.1%) that is passed on to the be present linearly, and their recognition could be a viable
colostrum in a greater amount than in human milk. target for developing therapeutics and diagnostic tools
Moreover, immunoglobulins IgA (2 monomers) and IgM (Matsuo, Yokooji, and Taogoshi 2015). It has been estimated
(pentamers) exist in secretory forms in cow’s milk (Savilahti that in cow’s milk allergic patients, nearly 50% of serum
and Kuitunen 1992). BSA is a major allergen in the milk. samples react with as1-casein (Natale et al. 2004). There is a
The allergenicity of BSA is mainly attributed to its surface difference in opinion among the researchers regarding IgE
IgE binding epitopes that can easily react with the circulat- binding epitopes on as1-casein. Some suggest IgE binding
ing IgE and starts an allergic reaction in the patient. Even epitopes are located at 181–199 AA residues on C-terminal
though the amount of BSA is low in the cow’s milk, this (Nakajima-Adachi et al. 1998), some in the hydrophobic
small amount has binding efficiency up to 50% of the region (Spuergin et al. 1996), while others at 28–50 residues
patient’s serum samples to start a severe allergic response. (Cerecedo et al. 2008; Cong and Li 2012).
BSA has a stable tertiary structure, and the disulfide bond Alpha casein 2 (as2-casein), another family of casein, con-
stabilizes BSA’s major antigenic site (524
598) that is sists of 207 AA, per molecule one disulfide bond, and four
exposed for binding (Hochwallner et al. 2014). genetic variants (A, B, C, and D). It has been found that
90% of serum samples react with as2-casein with six minor
Molecular profile of casein proteins and four major IgE binding epitopes (Cerecedo et al. 2008).
Casein represents the major portion of cow’s milk that upon In terms of as1-casein and as2-casein levels, goat’s milk is
fractionation forms as1 (40%), as2 (12.5%), b (35%), and different from cow’s milk. Goat’s milk has remarkably less
j-casein (12.5%) (Demeulemester, Giovannacci, and Leduc as1-casein and much higher as2-casein content compared to
2006). Casein proteins are a large family that has a hydrated cow’s milk. Moreover, goat’s milk possesses b-casein as the
structure of calcium-binding phosphoproteins whose nega- major casein fractions, while in the case of cow’s milk, it is
tively charged phosphate groups bind firmly with positively as1-casein. It has been reported that the high digestibility of
charged divalent calcium ions. Consequently, charge neutral- goat’s milk is attributed to higher as2-casein content that in
ization causes precipitation of the major subfractions of turn governs micelle conformation and apparently calcium
caseins (as1, as2, b) except j-casein. In contrast, j-casein has availability, hence considered to be less allergenic than cow’s
a low concentration of phosphate groups; thus, fewer cal- milk (Haenlein 2004).
cium ions bind to it. As a result, j-casein is unable to pre- Beta casein (b-casein) has a primary sequence of 209 AA,
cipitate calcium ions. When the calcium concentration in five phosphate groups, and 12 genetic variants. The second
milk is high, casein forms a quaternary structure in the major fraction in cow’s milk is b-casein which has 12 gen-
form of micelles where lactoserum whey and j-casein exist etic variants, including A1, A2, A3, B, C, D, E, F, G, H1,
in the peripheral hydrophilic phase while fat globules, cal- H2, and I (Kami
nski, Cie
sli

nska, and Kostyra 2007). A1 and
cium, and as1, as2, b form a hydrophobic core (Fox 2001). A2 are widespread variants, differs in amino-acid compos-
The principal biological job of casein micelles is the trans- ition particularly at 67 position, which is occupied by histi-
portation and the retention of a considerable amount of cal- dine in A1 while proline in A2 variants (Truswell 2005). B
cium and phosphate in the stomach to be assimilated into b-casein also has histidine at 67 position and is less frequent
the body. Casein micelles are highly susceptible to protei- than A1 and A2 variants. Due to histidine at 67 position in
nases and exopeptidases, but they are insignificantly affected A1 variant, b-casein becomes susceptible to enzymatic cleav-
by urea (denaturing agent) or heating. Casein forms a loose age while proline at 76 position in A2 variants protects it
tertiary and flexible structure, and when it does not form a from enzymatic cleavage (Elliott et al. 1999). In the small
tertiary structure, it exhibits high surface hydrophobicity intestine, under the action of enzymes such as pepsin, elas-
and is hence less immunogenic. Due to different proportions tase and leucine aminopeptidase, A1 b-casein is cleaved into
of hydrophobic, polar, and charged residues, the molecular a seven amino-acid peptide namely b-casomorphin-7 (BCM-
structure of casein is not consistent. As a result, uneven 7). In addition, BCM-4, BCM-5, BCM-6, BCM-8, and BCM-
hydrophilic and hydrophobic patches distributed throughout 11 are also formed (Kami
nski, Cie
sli

nska, and Kostyra
make it water-insoluble (Goff 2016). The genetic poly- 2007). The opioid BCM-7 has agonist activity on m-receptors
morphism of casein that is responsible for its high hetero- and may be implicated as a risk factor in type 1 diabetes,
geneity and the degree of glycosylation, phosphorylation, arteriosclerosis, human ischemic heart disease, and known
and partial hydrolysis greatly affects the allergenic properties to affect gastrointestinal function in milk or lactose intoler-
of caseins (Fox 2001). ant people (Elliott et al. 1999; He et al. 2017). However, the
4 L. JAISWAL AND M. WORKU

other bioactive peptides from bovine b-casein exhibits sev- (Table 2). As food allergy has severe health consequences,
eral attributes such as immunomodulatory, antihypertensive, regulatory bodies in the USA, Canada, European Union,
antimicrobial, antithrombotic, and mineral binding activities Australia, and New Zealand ask food manufacturers to give
nska et al. 2012). b-casein possesses high similarity
(Cie
sli
a piece of precise information about food ingredients to
with as1-casein in terms of loose tertiary and reduced sec- assure food-allergic consumers (Downs et al. 2013).
ondary structure-forming globular hydrophobic domain at
C-terminal and hydrophilic (charged) structure at N-ter-
minal with high proline content and no disulfide bond. CMPs and immune response
Thus, the molecular structural architecture of b-casein advo- It has been observed that when CMP passes through the
cates that IgE binding epitopes (6 major & 3 minor) on gastrointestinal epithelium, it triggers either cell-mediated or
them are linear. Upon cleavage by milk plasmin protease, humoral or both immune responses. Infants ingesting cow’s
b-casein forms a non-immunogenic family of casein such as milk always exhibit an immune response to proteins that
c1-, c2-, and c3 casein (Goff 2016). can be evidenced with the presence of antibodies such as
Kappa casein (j–casein) is composed of 169 AA, has a IgG and IgA isotypes in blood circulation and mucosal
highly hydrophobic N-terminal, and strongly hydrophilic C- layers, respectively. The development of the above-men-
terminal. j–casein possesses eleven genetic variants, and the tioned immune response may be accountable for defensive
variation arises as a result of the difference in the number of anti-inflammatory function and enable the infants to digest
the oligosaccharides attached to j–casein. The opposite CMP smoothly. In contrast, upon CMP ingestion, if the
charges on j–casein creates electrostatic repulsive forces that infant shows any adverse clinical sign and undesirable
prevent micelles aggregation. j–casein is the only glycosy- immune response, the sign represents an allergic reaction
lated casein that consists of galactose, sialic acid, and galact- to milk.
osamine. Depending on glycosylation, j–casein forms 11 As stated above, whey proteins, caseins, and their sub-
isoforms in the milk (Fox 2001). j-casein is unable to pre- fractions are the chief allergens responsible for milk allergy.
cipitate calcium cations because it consists of a low concen- However, in allergic individuals, the pathogenesis of allergic
tration of anionic phosphate groups; as a result, j-casein reactions is chiefly manifested by an imbalance between the
provides stability to other proteins. However, this stability is expressions of T helper type (Th1) and type 2 (Th2) cells.
eliminated upon rennet cleavage that forms para-j-casein Th2 mediated response is allergen-specific, while Th1 medi-
(hydrophobic) and caseinomacropeptide (CMP) (hydro- ated immunity is protective. The therapeutic measure to
philic). CMP plays a crucial role in the overall digestion in curb CMA focuses mainly on the immune response modula-
individuals by augmenting serum gastrin secretion, decreas- tion of the patients by mitigating allergen-specific Th2
ing gastric acid, serotonin secretion, showing anticoagulant response with simultaneous activation of protective Th1
properties, minimizes platelet agglomeration (Goff 2016). It immunity (Sziksz, Vannay, and Haczku 2012). Even though
has been stated that CMP’s glycosylated form is digested in in the chronic phase, IgE antibodies initiate and mediate
a smaller amount and may be responsible for immunoreac- allergic inflammation, the clinical symptoms of pathogenesis
tivity than nonglycosylated forms (Cie
sli
nska et al. 2012). are governed primarily by allergen-specific T lymphocytes.
j-casein bears eight dominant IgE binding epitopes, and This phenomenon evidently reflects that Th2 (allergen-spe-
three of them are implicated with CMA by reacting 93% cific) cells are central to allergic inflammatory reaction
serum samples of patients. The majority of IgE binding epit- maintenance while IgE-independent cell-mediated immunity
opes fall at 9 to 68 AA residues, which cause allergenicity is related to gastrointestinal food allergy (Mercer et al.
(Chatchatee et al. 2001; Han et al. 2008). 2009). In addition, the different genetic variants form differ-
In context to CMA, epitope mapping of many CMPs, ent CMP with different nutritional properties, which in turn
including caseins and whey proteins, demonstrated that have different consequences in human health.
many proteins bear multiple allergenic epitopes that have
been implicated in allergic reactions (Crittenden and
Bennett 2005). In particular, the amino acid sequence align- IgE mediated immediate hypersensitivity to CMPs
ment of bovine and human milk containing a-lactalbumin, IgE-mediated sensitivity to CMPs is well-understood and
b-casein, and j-casein is 78%, 49%, and 52% analogous and easily diagnosed that consists of two crucial phases: sensi-
exhibits 81%, 63%, and 58% homology, respectively tization and reaction elicitation (Table 3). Because the symp-
(Chatchatee et al. 2001 and J€arvinen et al. 2011) (Figures 1 toms appear quickly upon allergen’s exposure, the immune
and 2A and B). Therefore, it is significantly evident that system of an individual responds rapidly; thus, the response
reported IgE binding epitopes on bovine milk show high is termed as immediate hypersensitivity. It is imperative to
resemblances with endogenous human milk proteins. As a have a proper cross-talk between T helper cells and B cells
result, endogenous human milk epitopes are identified by to begin immune response for protein antigen (Savilahti and
cross-reactive IgE antibodies of infants with CMA causing Kuitunen 1992). In particular, T helper cells such as Th1
allergic symptoms. and Th2 cells are major determinants of whether the
In addition to cow’s milk, there are a number of foods immune response would be defensive or allergic. In add-
accountable for 90% of food allergies, such as peanuts, soy- ition, T cells are involved in different secretory roles for
beans, tree nuts, crustacean shellfish, eggs, fishes, and wheat lymphokines secretion. When protein antigen/allergen
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 5

Figure 1. Amino acid sequence alignment of bovine and human (a) a-lactalbumin, (b) b-casein, and (c) j-casein. Dark gray highlighted sequence represents identi-
cal amino acids, light gray for homologous amino acids and underlined for bovine protein bearing known IgE binding epitopes (J€arvinen et al. 2011).

activates Th2 cells, interleukin-4 is produced without inter- Upon attachment of IgE antibodies to allergenic epitopes on
feron-gamma; as a result, B lymphocytes abruptly secrete the milk protein, immediately initiate a series of cascade
IgE antibodies (Figure 3). In mice, IgE has been implicated reactions of hypersensitivity and inflammation leading to
in atopic dermatitis and allergic reactions by cell-mediated allergy (Crittenden and Bennett 2005). IgE-mediated imme-
immunity. Th2 secreting lymphokines trigger the prolifer- diate hypersensitivity to CMP affects the body at cutaneous
ation of mast cells involved in various allergic reactions. IgE (eczema, urticaria, angioderma), respiration (asthma, rhino-
antibodies are attached to the surface of mast cells and baso- conjunctivitis), gastrointestinal level (oral allergy, vomiting,
phils and fortified them with the allergen-specific trigger. nausea, diarrhea), and generalized (anaphylactic shock)
6 L. JAISWAL AND M. WORKU

Figure 2. (A) Amino acid sequence alignment of known IgE epitopes on bovine milk (Bov) (a) a-lactalbumin, (b) b-casein, and (c) j-casein and homologous pepti-
des on human milk (Hum) of breastfeeding infants (Figure 3(B)). Amino acid sequence alignment of known IgE epitopes on bovine milk (Bov) (a) a-lactalbumin, (b)
b-casein, and (c) j-casein and homologous peptides on human milk (Hum) of older children (5-15years). Dark gray highlighted sequence represents identical amino
acids, light gray for homologous amino acids (J€arvinen et al. 2011).

(Table 4). Sometimes CMA leads to a life-threatening condi- antigen, Th1 cells stimulate lymphokines mediated B lym-
tion, but its occurrence is infrequent. However, strategies phocytes activation to secrete IgG and IgA (Figure 3).
are made focusing on mitigating CMP’s allergenicity by Delayed allergies to CMP are manifested by crypt hyperpla-
ameliorating protein digestibility. sia, villous atrophy, the augmented density of lymphocytes
in the intestinal epithelium, and the infiltration of mono-
nuclear cells.
Non-IgE mediated delayed hypersensitivity to CMPs
Delayed hypersensitivity is linked to the absence of specific
Raw milk versus commercial/processed milk allergy
milk protein antibodies (IgE) in blood circulation in the
majority of adults and infants. Therefore, non-IgE mediated The history of cow’s milk consumption by humans is thou-
allergic responses tend to be tardy and show symptoms sands of years old. For many years, milk was consumed as
from one hour to several days after milk ingestion. As raw milk until the technique of pasteurization was invented.
delayed reactions are dependent on T-cell response, as a It has been reported that raw milk poses a health risk due
result, the response affects the body at the skin and intes- to its association with several bacterial pathogens that may
tinal level (El-Agamy 2007). Upon interaction with a protein threaten infants and pregnant women. Thus, to alleviate the
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 7

Figure 3. Schematic representation of IgE and non-IgE mediated allergy (Crittenden and Bennett 2005).

Table 2. Common allergenic foods for selected countries (Downs et al. 2013).
objective of processing was to reduce microbial pathogens
from the raw milk, methods opted in the form of homogen-
Allergenic food USA Canada European Union Australia/New Zealand
ization and pasteurization also alter the milk fat and whey
Celery Y
Cow’s milk Y Y Y Y protein molecular structure, respectively, and these poten-
Crustacean shellfish Y Y Y Y tially altered structures present themselves as allergens to the
Egg Y Y Y Y
Fish Y Y Y Y
immune system (Braun-Fahrl€ander and Von Mutius 2011).
Lupine Y Casein is a heat-stable protein; as a result, heating does not
Molluscan shellfish Y Y alter its conformational structure. In contrast, whey proteins,
Mustard Y Y
Peanut Y Y Y Y
particularly b-lactoglobulin and a-lactalbumin are heat sus-
Sesame Seed Y Y Y ceptible. Consequently, the biological functionality of the
Soybean Y Y Y Y abovementioned protein subfractions is lost on heating and
Tree nuts Y Y Y Y
Wheat Y Y Y Y
causes aggregation, denaturation, and insolubilization (Brick
Y stands for yes. et al. 2017). Peyer’s patches (PPs) are small groups of
lymphoid follicles located in the mucosal membrane of the
small intestine. During food allergy, PPs play a pivotal role
above-mentioned risks, industrial milk processing (pasteur-
in immune surveillance. Native whey proteins (unaggregated
ization & homogenization) of raw milk started in the late
form) are usually taken up by enterocytes (intestinal epithe-
19th century. The main purpose of raw milk processing was
lium), and this uptake is comparatively less immunogenic
to extend the shelf life and minimize the risk of milk-borne
than that of PPs. In contrast, upon pasteurization, aggrega-
pathogens such as Mycobacterium tuberculosis, Listeria,
tion of whey proteins takes place that stimulates allergic sen-
Salmonella, Escherichia coli, Campylobacter (Abbring, sitization because the normal intestinal uptake of whey
Kusche et al. 2019). Homogenization works through centri- proteins is skewed from enterocytes to PPs (allergic). This
fugation to remove milk fat globule from raw milk to form abnormal shift in whey protein’s uptake via PPs is observed,
skimmed milk ( 1% fat), semi-skimmed milk (2% fat), and particularly during food allergy, thereby provoking immuno-
whole milk (> 3.25% fat). Although, this process makes genicity (Abbring, Hols et al. 2019). Existing epidemiological
milk emulsion more stable, which in turn increases the sur- evidence has speculated that consumption of organic raw
face area of droplets to which casein micelles adsorb but milk from the farm has beneficial and protective health
augments allergenicity of the processed milk through disrup- effects compared to commercially processed milk because
tion of fat globules and casein micelles (Braun-Fahrl€ander raw milk reduces the risk of asthma, atopic sensitization,
and Von Mutius 2011; Abbring, Hols et al. 2019). Heating is and hay fever (Braun-Fahrl€ander and Von Mutius 2011). It
another procedure of milk processing that includes pasteur- has been found that pasteurization at 72  C denatures part
ization for 15–40 seconds at 71  C and the industrial heat of raw cow’s milk IgG and also changes the structure of
treatment like sterilization for 10–20 min at 110–120  C and lactoferrin. On the contrary, homogenization, and steriliza-
ultra-high temperature (UHT) for 0.5–4 seconds at tion denature IgG fully and reduce lactoferrin content. In
135–145  C (Verhoeckx et al. 2015). Although the sole addition, the concentration of cow’s transforming growth
8 L. JAISWAL AND M. WORKU

Table 3. Classification of allergic reactions to milk (Downs et al. 2013). Table 4. IgE mediated milk allergy symptoms (Downs et al. 2013).
1. True food allergies 1. Gastrointestinal
A. Antibody mediated immediate hypersensitivity (milk allergies) Abdominal cramps
a. IgE facilitated milk allergy including oral allergy syndrome Diarrhea
a. Exercise-associated milk allergy (milk þ exercise) Nausea
A. Cell-mediated food allergies (Delayed hypersensitivity) Oral allergy symptoms
a. Milk protein-induced enterocolitis Vomiting
a. Milk protein-induced enteropathy 2. Cutaneous
a. Milk protein-induced proctitis Angioedema
A. Either antibody-mediated and/or cell-mediated Dermatitis
a. Allergic eosinophilic gastroenteritis Pruritis
a. Allergic eosinophilic esophagitis Urticaria
2. Food intolerances 3. Respiratory
A. Lactose intolerance (a kind of metabolic disorder) Asthma
Heiner’s syndrome
Laryngeal edema
factor (TGF-b1) was noticed to be drastically lower in com- Rhinitis
Rhinoconjunctivitis
mercially processed milk than that of raw milk (Soza
nska 4. Generalized
2019). Several epidemiological studies on the murine model Anaphylactic shock
have suggested that raw milk remarkably diminishes inflam-
matory cells count such as eosinophils, neutrophils, lympho-
Allergic cross-reactivity to cow’s milk
cytes, and macrophages in bronchoalveolar lavage fluid as
well as IL-5 and IL-13 in lung T cells, hence, the abovemen- Allergic cross-reactivity to Cow’s milk is observed in children
tioned attributes consider the raw milk as protective milk with an inability to tolerate goat’s or sheep’s milk (Ah-Leung
and is preferred over processed milk in allergic asthma. et al. 2006). Protein mapping revealed that allergic cross-
However, medical guidelines sharply discourage the con- reactivity between milk proteins, namely caseins and whey
sumption of raw milk as a therapeutic measure for allergic proteins from different dairy species such as goat, sheep,
diseases because raw milk contains a significant amount of camel, buffalo, donkey, and mare is mainly attributed to their
microbial pathogens that could lead to infection common amino-acid sequences and analogous ability to bind
(Soza
nska 2019). specific IgE immunoglobulins (Garc
ıa and Lizaso 2011). Cow
and goat milk have a similar composition (87% water, 3–4%
fat, 3.2% protein, lactose 4.8%, micronutrients), while sheep
Processed CMP in infant formulas
milk accounts for a significantly higher fat, protein, and lac-
Infant formulas contain processed CMP whose casein pro-
tose contents. It suggests that sheep and goat, particularly due
portion is reduced to 40% (6 gm/L), which is equivalent to
to a-casein, have a high allergic potential. However, camel
human milk. However, the amount of casein in formulas
milk also shows high similarity with cow milk but is slightly
varies from 18 to 20 gm/L for preterm infants to 15 gm/L
salty, three times more vitamin C content, unsaturated fatty
for term infants. Commercial formulas are usually heat
acids, and vitamin B than cow milk. Camel and goat milk are
processed in which desired casein concentration is accom-
mostly consumed raw, while due to overall solid content,
plished by mixing an equal proportion of skim milk and
sheep milk is appropriate for the cheese industry (FAO,
whey protein (Savilahti and Kuitunen 1992). Infant formula
2021). It has been reported that 92% and 4% of CMA
is classified into four formulas:
patients demonstrated clinical allergy to goat milk and mare
Partially hydrolyzed formula (PHF): PHF is a cow milk-based milk, respectively (Bellioni-Businco et al. 1999; Businco et al.
formula that has been partially hydrolyzed, containing larger 2000). Donkey and camel milk is considered to be hypoaller-
peptides than EHF. The cow milk proteins are processed in
gic compared to cow milk (El-Agamy 2016). The sera of
such a way that processing techniques wipe out allergenic
epitopes that can cause allergenicity (Crittenden and CMA children are highly likely to identify major parts of
Bennett 2005). casein and whey proteins of goat, sheep, and buffalo, while
feeble cross-reactivity was observed from donkey and mare
Extensively hydrolyzed formula (EHF): EHF is a proteolytic
enzyme-treated cow milk-based formula whose bitter taste and almost no reactivity with camel milk. b-lactoglobulin is
makes EHF unpalatable to consume. The children diagnosed the main whey protein allergen in cow, goat, buffalo, sheep,
with CMA are highly recommended to use EHF as a milk mare, donkey milk, while human and camel milk is devoid of
substitute. In some countries like Italy, EHF is prepared using b-lactoglobulin (El-Agamy, Abou-Shloue, and Abdel-Kader
goat milk (Braun-Fahrl€ander and Von Mutius 2011).
1997). This clearly demonstrated that the low allergenicity of
Soy formula (SF): SF is a soy protein-based formula whose human and camel milk is ascribed to the absence of b-lacto-
nutritional value is analogous to EHF, and SF formula is found globulin (Kappeler 1998). Due to the absence of b-lactoglobu-
more palatable. Fifty-three to eighty-three percent of children
lin and human milk protein similarity, camel milk has
with CMA can well tolerate SF, while 17–47% shows SF
allergenicity (El-Agamy 2016). emerged as hypoallergic milk.
Amino acid-based formula (AAF): AAF is also a cow milk-
based formula and considered to be less allergic. Nearly 10% of Diagnosis of CMA
children who fail to tolerate EHF, comparatively show clinical
benefits against CMA when supplemented with AAF (Hill Owing to the multiplicity of allergic symptoms, the clinical
et al. 2007). diagnosis of CMA varies greatly. The diagnosis can be
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 9

performed by testing either skin or blood or both. Due to Figures 4 and 5. Moreover, the infants with suspected or
the involvement of IgE antibodies in immediate hypersensi- proven CMA should not be given unmodified cow’s, sheep,
tivity, the diagnosis in blood or skin test comes promptly. buffalo, horse, or goat’s milk because they not only pose a
There are 60% cases of CMA in children where the symp- threat of allergenic cross-reactivity but also lack ample
toms are delayed; thus, their instantaneous clinical outcome nutrients to nourish infants as a sole food source (Spuergin
is highly unlikely (El-Agamy 2007). The four reliable clinical et al. 1997). It has been reported that allergy to milk from
diagnostic tests are as follows. other species such as goat, sheep, or camel is less common
(Cases et al. 2011). However, despite some dissimilarity
between human milk proteins and milk from sheep, goat,
Skin prick test (SPT) camel, etc. they can allocate several allergenic epitopes with
SPT is considered to be the most precise test in young kids; CMPs; as a result, they cannot be regarded as generally valid
however, there is no specific age limit for this test. In add- hypoallergenic candidates but only in individual cases as
ition, a strong allergic reaction is a prerequisite for the clin- substitutes for cow milk (Crittenden and Bennett 2005). It
ical reliability of SPT (Majamaa et al. 1999). SPT is a has been observed that CMA patients are also susceptible to
qualitative test that detects IgE antibodies located on the several foods such as soymilk, peanuts, fish, coconuts, etc.;
surface of mast cells that reacts with drops of milk proteins hence, they are not always reliable substitute for cow milk
allergen placed on the forearm of patients. After a few in infants. Accidental exposure and adverse immunological
minutes, wheal and flare reaction start to allergic patients reactions of CMA can be treated with H1- & H2 antihist-
that witness CMA. amines, beta-2-agonists, or glucocorticosteroids; however,
under life-threatening allergic condition, epinephrine is
Blood tests given to the allergic patients (Villa et al. 2018).
RAST and enzyme-linked immunosorbent assays (ELISA)
are the two tests that frequently diagnose the level of IgE in Role of galectins as allergy suppressor
the blood serum of the patients (Garcia-Ara et al. 2004). In
RAST, the serum sample of the patient is incubated with The surface of all mammalian cells consists of glycan struc-
milk allergen, and the latter is already fixed on a solid phase, tures that, under several pathological and physiological body
namely a cellulose disk. This is followed by further incuba- conditions, go through conformational changes and offer
tion with radiolabelled anti-IgE. The antigen-specific binding the best platform to monitor and identify molecular signa-
between anti-IgE and IgE finally corresponds to the amount tures. Galectins are a class of beta-galactoside binding lectins
of IgE in the blood. In the ELISA test, all steps are followed that bears highly conserved carbohydrate recognition
as RAST, but instead of radiolabelled anti-IgE, the enzyme domains (CRDs). Although galectins are known to bind spe-
is linked to anti-IgE to determine the amount of antigen- cifically galactose, they also have a high affinity for oligosac-
specific IgE (Ghosh, Malhotra, and Mathur 1989). charides (Worku et al. 2018; Asiamah et al. 2017). Galectins
and their particular glycan ligands are profusely situated in
the gastrointestinal tract. Recently, galectins have emerged as
Elimination-challenge test novel regulators of several cellular functions such as inflam-
In this test, milk allergy is confirmed in two steps (a) exclu- mation, T-cell activation, cell growth, cell adhesion, migra-
sion of cow milk and its product from the daily diet and tion, and apoptosis (Sziksz, Vannay, and Haczku 2012).
observation of clinical symptoms and improvements, and Among all, migration, T-cell activation, and apoptosis are
(b) re-inclusion of milk-based diet and reappearance of the crucial immunological processes, and they are highly
allergic symptoms (El-Agamy 2007). dependent on the glycosylation of cell surface proteins
(Toscano et al. 2007). Of all, galectins-9 is ‘tandem repeat
Treatment of CMA type’, which has two separate CRDs linked by non-con-
served amino acid sequence, and galectin 3 is characterized
To date, there is no generally valid proven cure and treat- to be a ‘chimera type’ bearing one CRDs and N-terminal,
ment for CMA. The only precautionary measure is avoiding play a pivotal role in modulating allergic reactions
the consumption of CMPs throughout the entire length of (Mulakala et al. 2018). It has been reported in intraepithelial
allergic disease. In addition, for managing CMA in breast- gut lymphocytes of CMA allergic children that the expres-
fed and formula-fed infants, some remarkable recommenda- sion of galectin-3 augments dramatically during cow milk
tions and guidelines have been established for general pedia- intake compared to non-allergic children signifying the
tricians and primary care physicians (Vandenplas et al. potential role in modulating epithelial-immune cells inter-
2007). The above-mentioned recommendations also included action during an allergic reaction (Mercer et al. 2009).
prominence of breastfeeding in healthy infants, emphasis on In particular, galectin-9 has a specific role in immunore-
far-reaching history checks of the family for allergy, meticu- gulation involving suppression of allergic reactions. In the
lous physical examination to rule out other causes, ascertain- murine model of CMA, supplementation of galacto-fructoo-
ing any existing health problems, and categorizing CMA ligosaccharides and Bifidobacterium breve advocated the sup-
into mild, moderate, or severe. The algorithms have been pressive role of galectin 9 in food-induced allergic
summarized exclusively based on the method of feeding in inflammation by reducing IgE mediated mast cell
10 L. JAISWAL AND M. WORKU

Figure 4. Algorithms showing diagnosis and management of CMA in specifically breast-fed infants (Vandenplas et al. 2007).

granulation (de Kivit et al. 2012). Recently, it has been 1994). Capric and the lauric acid act as antiviral, antibacter-
found that galectins-9 binds firmly with IgE-mediated aller- ial, and COX-I, COX-II inhibitors (Henry et al. 2002). By
gic reaction. Galectins-9, upon binding with highly glycosy- augmenting reverse cholesterol transport, lauric acid, pal-
lated IgE antibodies (galectin9-IgE glycan) minimizes the mitic acid, and myristic acid, which are saturated fatty acids,
chances of the formation of the protein antigen-IgE com- increase high-density lipoproteins (HDL) (Insel, Turner, and
plex, which is responsible for initiating the allergic reaction, Ross 2004). Being a single unsaturated fatty acid, oleic acid
thereby exhibiting an anti-allergic effect (Niki et al. 2009). (8 g/l) reduces plasma cholesterol, triglycerides, and LDL-
So, commercially available galectins could be a viable source cholesterol concentration (Kris-Etherton et al. 1999).
to target glycosylated IgE antibodies to minimize aller- Eicosapentaenoic acid (EPA), which is metabolically pro-
gic reaction. duced by linoleic acid (omega 6 fatty acid) and alpha-lino-
lenic acid (omega 3 fatty acid), decrease cardiovascular risk,
and tumor growth (Bagga et al. 2003). In addition, conju-
The biological role of milk
gated linoleic acid from bovine milk has been found to have
Milk is considered to be a complete food as it is a rich anti-proliferative and pro-apoptotic effects that decrease the
source of all of the following: fats, saturated fatty acids, oleic risk of colon cancer. Phospholipids and glycosphingolipids
acid, lauric acid, myristic acid, palmitic acid, linoleic acid, (1% of total milk lipids) present in milk lipids have a bio-
alpha-linolenic acid, essential amino acids, bioactive proteins active role in emulsion stabilization, cations binding, trans-
and peptides, lactose, magnesium, zinc, selenium, vitamin A, membrane signaling, some hormones, and growth factors
vitamin E, folate, riboflavin, and vitamin B12. Therefore, the receptors, cell-cell interaction, differentiation, proliferation,
daily intake of 500 ml of milk supplies an ample amount of and immune recognition (Keenan and Patton 1995).
nutrients to the body. The major biological attributes of
milk constituents are described below.
Proteins
Bovine milk proteins (32 g/l) are of high significance because
Fats of their prime role as antimicrobials, growth factors,
Fats (33 g/l) supply the body with energy. Among the major enzymes, hormones, antibodies, calcium & phosphate car-
saturated fatty acid (19 g/l), butyric acid helps prevent can- riers, and immune stimulants (Clare and Swaisgood 2000).
cer, while caprylic acid delays tumor growth (Thormar et al. Some milk peptides exhibit antihypertensive effects, while
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 11

Figure 5. Algorithms showing diagnosis and management of CMA in specifically formula-fed infants (Vandenplas et al. 2007).

essential amino acids and branched-chain amino acids pro- governed by Vitamin A (280 ug/l), and milk is a good
mote muscle protein synthesis. Cow’s colostrum contains source of this vitamin (Insel, Turner, and Ross 2004).
taurine (18 mg/l) whose physiological function is related to Selenium (37 ug/l) is the mineral that serves as an antioxi-
neuromodulation, bile acid conjugation, retinal development, dant and is aiding in DNA synthesis, DNA repair, thyroid
parenteral nutrition, and anti-inflammation properties hormone metabolism, and prevention of cancer and asthma
(Lourenco and Camilo 2002). Glutathione, an important 
(Dodig and Cepelak 2004). Bovine milk is also a rich dietary
blend of tripeptides such as sulfur-containing cysteine, gly- source of calcium (1 g/l), which keeps bones and teeth
cine, and glutamic acid, is a master antioxidant that regu- healthy (Insel, Turner, and Ross 2004). In addition, milk
lates hydrogen peroxides production by quenching reactive helps to prevent hypertension, kidney stones, and colon can-
oxygen species (ROS) (Haug, Høstmark, and Harstad 2007). cer. An important element of the thyroid hormone is iodine
In addition, glutathione regulates pancreatic insulin produc- (160 ug/l) in milk, which also regulates the metabolic rate
tion, protects the lungs, and lowers respiratory infections and body temperature (Haug, Høstmark, and Harstad 2007).
(Haug, Høstmark, and Harstad 2007). Glutathione is present Milk is a good source of magnesium (100 mg/l), which has a
in raw milk (9.3 mg), but upon high heat treatment during significant role in reducing asthma and oxidative stress.
pasteurization, the level significantly reduced in pasteurized Moreover, in conjugation with taurine, milk helps to regu-
milk (4.5 mg). The conspicuous reduction in glutathione late calcium release in the cells (Cheuk, Chau, and Lee
content in pasteurized milk is attributed to the breaking of 2005). Zinc (4 mg/l) is present in milk in an adequate
glutamyl-cysteine bonds that itself represents two-third of amount to govern DNA repair, cell growth, gene expression,
glutathione molecule (Masterjohn 2010). lipid metabolism, protein metabolism, immune function,
and DNA replication (Insel, Turner, and Ross 2004). It is
worth noting that even though cow’s milk is a good source
Antioxidants, vitamins, and minerals of vitamin D, very low iron (Fe) content leads to Fe defi-
In bovine milk, Vitamin E (0.6 mg/l) is present in the form ciency in young children. In addition, daily intake of cow’s
of alpha-tocopherol and results in a strengthened immune milk depletes the Fe absorption from other food and causes
system and a reduction in the risk of cancer and coronary gradual loss of Fe in the fecal matter through minor intes-
heart disease (Haug, Høstmark, and Harstad 2007). Proper tinal bleeding. Consuming 400 g/d of fortified milk, rou-
vision, reproduction, growth, and immunity are mainly tinely supplemented with vitamin D and Fe, meets the daily
12 L. JAISWAL AND M. WORKU

requirement of children (Sidnell et al. 2016). Folate concen- of PUFA is being secreted in the milk (Givens 2005). Also,
tration in bovine milk is 50ug/l, and folate’s biological role it has been reported that oral probiotic administration in
is to protect the body from hypertension and coronary heart lactating Holstein-Friesian cows boosted immunity and
disease. Milk also contains riboflavin (1.83 mg/l) and vitamin modulated the systemic effect on global gene expression by
B12 (4.4 ug/l), and these vitamins have major roles in meta- upregulating the expression of Toll-like receptor (TLR),
bolic pathways (Haug, Høstmark, and Harstad 2007). inflammation response, and Wnt signaling pathways, which
are involved in immunity and homeostasis (Adjei-Fremah
et al. 2018). TLR are pathogens recognition receptors that
Dairy nutrition and CMA
have the ability to sense highly conserved structural motifs
An adequate amount of nutrients in the diet not only main- of invading pathogens. These motifs are known as the
tains a functional immune system but also protects cows pathogen-associated microbial pattern (PAMP) and are rec-
from metabolic disorders, inflammation, and diseases. ognized efficiently by TLR that triggers a local and systemic
However, the breed, age, species, diet, lactation stage, season, immune response to combat infection (Jaiswal, Ismail, and
and the number of parturitions profoundly affect the milk Worku 2020). Wnt signaling pathways have been linked
compositions and production (Linn 1988). Genetic selection with signal transduction of cellular and biological processes
is an important tool through which milk protein percentage responsible for maintaining homeostasis. In particular, pro-
and composition can be altered (Linn 1988). However, diet- biotic supplements upregulated the genes for cytokines (IL-
ary protein percentage has a less conspicuous effect on milk 1R1, IL-65T, IL-12b, IL-6, IL-12A, IL-13, IL-10), chemokines
protein percentage. Milk immunoglobulins and albumins are (CXCR1, CXCL8, CXCL2), Toll-like receptors (TLR1, TLR2,
not synthesized in the mammary gland; rather, they are TLR3, TLR9), Wnt signaling (WNT6, WNT2B, WNT5B,
transported to them from the blood (Larson 1979). On the WNT3, WNT9A, WNT1) and transcription regulators
other hand, most of the milk proteins are synthesized in the (NFKBIL1) (Adjei-Fremah et al. 2018). The level of lactose,
mammary gland; therefore, it is imperative to have a regular mineral, and vitamin in the milk is almost constant, and
supply of essential and non-essential amino acids to the they get hardly affected through genetic and nutritional
gland for protein synthesis through diet. Increased milk pro- manipulation unless there are mastitic conditions
tein percentages have been reported in the cows grazing in (Linn 1988).
early spring pastures (Linn 1988). It has been reported that Several epidemiological evidence has shown that due to
milk protein percentage and propionic acid in the rumen the exclusion of milk and dairy products, children suffering
are positively correlated with enhancing concentrate feeding from CMA are usually short statured with lower calcium
and decreasing forage size in the diet because high propionic and fat consumption than healthy control groups
acid in the rumen augments milk protein synthesis (Boaventura et al. 2019). In addition, a high prevalence of
(Thomas 1983). micronutrient deficiencies of vitamin A and D was noticed
The consumption of animal-derived fat and saturated in CMA patients. Such deficiencies are possibly linked to
fatty acids (SFA) raised concern because of their implication the development of food allergies and intolerance to dietary
in the risk of cardiovascular diseases, obesity, and type-2 proteins such as casein, whey, and soy protein (Boaventura
diabetes (Givens 2005). Fat is the most variable constituent et al. 2019). During the growth and development of chil-
in milk. The fatty acid composition of milk can be altered dren, an adequate supply of dietary calcium is imperative
through enhanced dairy nutrition, especially introducing because calcium is an important element of bones. Ample
PUFA or MUFA enriched dairy diet. It has been reported dietary calcium intake not only ensures strong and healthy
that cow’s milk quality changes remarkably upon changing bones but also augments bone mineral density (BMD)
the feed ingredients such as camelina meal, which is rich in (Jensen et al. 2004). Some ancient tribes grew up their chil-
PUFA (Toma et al. 2015). Camelina is a flowering plant dren only on mother’s milk without milk from any mam-
which is also known as false flax. Camelina meal is obtained mal, e.g., the South American Indians did not have any
by cold pressing of camelina seed during oil extraction. It is milk-producing animals before the arrival of the Spanish
rich in protein and oil and used as livestock feeding material conquistadores. Because these tribal populations never drank
(Korsrud, Keith, and Bell 1978). When sunflower meal was milk in history and presently, so tribal babies profoundly
substituted with camelina meal (50 to100%) in the com- depend on mothers’ milk for all nutrition. It has been
pound feed (corn, wheat bran & sunflower meal), milk qual- reported the breast milk produced by women who are at a
ity was changed with a higher concentration of low nutritional level produces milk with a consistent level of
polyunsaturated fatty acid (PUFA), n-6 PUFA, and conju- lactose and protein content, but fat contents vary drastically
gated linoleic acid (CLA) with significant decrease in satu- in the milk that dependent on nutritious food intake (Wray
rated fatty acid (SFA) contents (Toma et al. 2015). The 1978). For kids below three years, 700 mg (2–3 servings) of
bovine mammary gland has the unique ability to secrete a dietary calcium intake is recommended require for proper
large amount of short and medium-chain fatty acids from bone development while one cup of mother’s milk provides
the synthetase complex. Under the microbial action, rumi- 79 mg of calcium that is too low than the recommended
nants undergo extensive biohydrogenation; as a result, long- level. Malnutrition and early nutritional deficits are associ-
chain fatty acids are produced and absorbed in the mam- ated with long-term impairment in overall growth and
mary glands. The augmented long-chain fatty acids supply, development. BMD is an important criterion to identify
in turn, obstructs the synthesis of SFA, and a high amount bone health, and a low level of bone health indirectly reflects
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 13

low calcium dietary intake. Milk is a rich source of calcium Acknowledgments

and other nutrients. Due to CMA and lactose intolerance, The authors are grateful to the National Institute of Food and
many children either avoid or limit their milk intake, and Agriculture Evans Allen funds: ‘Molecular Signatures and Regulatory
this adversely affects bone health and attainment of height Checkpoints for Animal Health’ Project NO. NC. X 320-5-19-120.1 for
(Black et al. 2002). As a result, children with CMA are at funding the postdoctoral Scientist. Special thanks also go to the
greater nutritional risk because, as a crucial part of treat- Members of the Laboratory for Animal Genomic Diversity and
Biotechnology (LAGenDB) at North Carolina A&T State University for
ment, they are advised to strictly exclude milk and other assisting with edits. We acknowledge the editorial suggestions from Dr.
dairy products from the diet (Boaventura et al. 2019). A Salam Ibrahim.
dairy product such as cheese, yogurt, and butter is basically
made of milk from the cows, buffaloes, goats, sheep, yak,
zebu, camel, and reindeer. In addition to milk, cheese, and References
yogurt in the diet reduce the cardiometabolic risk in youths. Abbring, S., G. Hols, J. Garssen, and B. C. van Esch. 2019. Raw cow’s
Thus, the inclusion of these products in the daily diet is of milk consumption and allergic diseases—The potential role of bio-
active whey proteins. European Journal of Pharmacology 15:55–65.
paramount importance (Abreu et al. 2014). However, it has
doi: 10.1016/j.ejphar.2018.11.013.
been found that some CMA patients are not allergic to Abbring, S., D. Kusche, T. C. Roos, M. A. Diks, G. Hols, J. Garssen, T.
cheese produced from cow’s milk but show allergenicity to Baars, and B. C. van Esch. 2019. Milk processing increases the aller-
cheese made from goat’s or sheep’s milk (W€ uthrich and genicity of cow’s milk—Preclinical evidence supported by a human
Johansson 1995). proof-of-concept provocation pilot. Clinical & Experimental Allergy
49:1013–25. doi: 10.1111/cea.13399.
Moreover, most children with IgE-mediated CMA can Abreu, S., P. Moreira, C. Moreira, J. Mota, I. Moreira-Silva, P. C.
tolerate yogurt well (Monaco et al. 2019). These findings Santos, and R. Santos. 2014. Intake of milk, but not total dairy, yog-
demonstrate that CMA patients may or may not be allergic urt, or cheese, is negatively associated with the clustering of cardio-
to cheese or yogurt or other milk products, and the degree metabolic risk factors in adolescents. Nutrition Research 34:48–57.
of allergenicity or tolerance vary from cases to cases. doi: 10.1016/j.nutres.2013.10.008.
Adjei-Fremah, S., K. Ekwemalor, E. K. Asiamah, H. Ismail, S. Ibrahim,
Consequently, regular nutritional monitoring is imperative and M. Worku. 2018. Effect of probiotic supplementation on growth
to children with CMA in order to ensure sufficient nutrient and global gene expression in dairy cows. Journal of Applied Animal
intake for normal growth. Research 46:257–63. doi: 10.1080/09712119.2017.1292913.
Ah-Leung, S., H. Bernard, E. Bidat, E. Paty, F. Ranc
e, P. Scheinmann,
and J. M. Wal. 2006. Allergy to goat and sheep milk without allergy
Conclusions to cow’s milk. Allergy 61:1358–65. doi: 10.1111/j.1398-9995.2006.
01193.x.
Casein, whey protein, and some of their sub-fractions in Alhussien, M., P. Manjari, S. Mohammed, A. A. Sheikh, S. Reddi, S.
cow’s milk cause allergies in some infants, children, and Dixit, and A. K. Dang. 2016. Incidence of mastitis and activity of
milk neutrophils in Tharparkar cows reared under semi-arid condi-
adults. Even though pasteurization reduces the risk of
tions. Tropical Animal Health and Production 48:1291–5. doi: 10.
microbial pathogens from raw milk, homogenization, and 1007/s11250-016-1068-8.
other processing techniques alter milk proteins and fat Alhussien, M., P. Manjari, A. A. Sheikh, S. M. Seman, S. Reddi, A. K.
molecular structure and makes them more vulnerable to Mohanty, and A. K. Dang. 2016. Immunological attributes of blood
allergies. Although, there are many different but no available and milk neutrophils isolated from crossbred cows during different
physiological conditions. Czech Journal of Animal Science 61:223–31.
treatments for CMA. For managing CMA in breast-fed and doi: 10.17221/63/2015-CJAS.
formula-fed infants, some great recommendations and Asiamah, E., S. Adjei-Fremah, K. Ekwemalor, B. Osei, H. Ismail, and
guidelines have been established, including the prominence M. Worku. 2017. The effect of stage of lactation and parturition on
of breastfeeding in healthy infants, emphasis on far-reaching galectin expression in cow blood. Journal of Animal Science 95:167.
doi: 10.2527/asasann.2017.338.
history checks of the family for allergy, meticulous physical
Bagga, D., L. Wang, R. Farias-Eisner, J. A. Glaspy, and S. T. Reddy.
examination to rule out other causes, ascertaining any exist- 2003. Differential effects of prostaglandin derived from x-6 and x-3
ing health problems and categorizing CMA into mild, mod- polyunsaturated fatty acids on COX-2 expression and IL-6 secretion.
erate or severe for general pediatricians and primary care Proceedings of the National Academy of Sciences 100:1751–6. doi: 10.
physicians. Recently, galectins have emerged as a possible 1073/pnas.0334211100.
Bellioni-Businco, B., R. Paganelli, P. Lucenti, P. G. Giampietro, H.
novel approach to suppress milk allergies that warrant an Perbornc, and L. Businco. 1999. Allergenicity of goat’s milk in chil-
in-depth study. As a crucial part of treatment, strict exclu- dren with cow’s milk allergy. Journal of Allergy and Clinical
sion of nutrient-rich milk and other dairy products from the Immunology 103:1191–4. doi: 10.1016/S0091-6749(99)70198-3.
diet puts children who have cow’s milk allergy at greater Bhat, M. Y., T. A. Dar, and L. R. Singh. 2016. Casein proteins:
Structural and functional aspects. Milk proteins–from structure to
nutritional risk; thus, regular nutritional monitoring and
biological properties and health aspects. InTech, Rijeka 7:1–7.
inclusion of additional nutrients supplement are imperative Black, R. E., S. M. Williams, I. E. Jones, and A. Goulding. 2002.
for their proper growth. Further investigation is needed on Children who avoid drinking cow milk have low dietary calcium
the use of appropriate nutrition and animal genetics that intakes and poor bone health. The American Journal of Clinical
also looks at the glycome (breeds of sheep, goats, mares, Nutrition 76:675–80. doi: 10.1093/ajcn/76.3.675.
Boaventura, R. M., R. B. Mendonça, F. A. Fonseca, M. Mallozi, F. S.
donkeys, camels, Yak, buffaloes, Zebu, reindeer) as well as Souza, and R. O. Sarni. 2019. Nutritional status and food intake of
improved milk processing to produce non-allergenic milk by children with cow’s milk allergy. Allergologia et Immunopathologia
inactivating allergic proteins for designer nutrition. 47:544–50. doi: 10.1016/j.aller.2019.03.003.
14 L. JAISWAL AND M. WORKU

Braun-Fahrl€ander, C., and E. Von Mutius. 2011. Can farm milk con- Elliott, R. B., D. P. Harris, J. P. Hill, N. J. Bibby, and H. E. Wasmuth.
sumption prevent allergic diseases? Clinical & Experimental Allergy 1999. Type I (insulin-dependent) diabetes mellitus and cow milk:
41:29–35. doi: 10.1111/j.1365-2222.2010.03665.x. Casein variant consumption. Diabetologia 42:292–6. doi: 10.1007/
Brick, T., M. Ege, S. Boeren, A. B€ ock, E. Von Mutius, J. Vervoort, and s001250051153.
K. Hettinga. 2017. Effect of processing intensity on immunologically FAO (2021). Milk composition, http://www.fao.org/dairy-production-
active bovine milk serum proteins. Nutrients 9:963. doi: 10.3390/ products/products/milk-composition/en/.
nu9090963. Fox, P. F. 2001. Milk proteins as food ingredients. International
Businco, L., P. G. Giampietro, P. Lucenti, F. Lucaroni, C. Pini, G. Di Journal of Dairy Technology 54:41–55. doi: 10.1046/j.1471-0307.2001.
Felice, P. Iacovacci, C. Curadi, and M. Orlandi. 2000. Allergenicity 00014.x.
of mare’s milk in children with cow’s milk allergy. Journal of Allergy Gall, C. F. 2013. Production systems around the world. In Milk and
and Clinical Immunology 105:1031–4. doi: 10.1067/mai.2000.106377. dairy products in human nutrition, ed. Y. W. Park and G. F. W.
Cases, B., C. Garc
ıa-Ara, M. T. Boyano, M. P
erez-Gordo, M. Pedrosa, Haenlein, 1–30. Oxford, UK: Wiley-Blackwell Publiser.
F. Vivanco, S. Quirce, and C. Pastor-Vargas. 2011. Phosphorylation Garc
ıa, B. E., and M. T. Lizaso. 2011. Cross-reactivity syndromes in
reduces the allergenicity of cow casein in children with selective food allergy. Journal of Investigational Allergology and Clinical
allergy to goat and sheep milk. Journal of Investigational Allergology Immunology 21:162–170.
and Clinical Immunology 21:398–400. Garcia-Ara, M. C., M. T. Boyano-Martinez, J. M. Diaz-Pena, M. F.
Cerecedo, I., J. Zamora, W. G. Shreffler, J. Lin, L. Bardina, M. C. Martin-Munoz, and M. Martin-Esteban. 2004. Cow’s milk-specific
Dieguez, J. Wang, A. Muriel, B. D. L. Hoz, and H. A. Sampson. immunoglobulin E levels as predictors of clinical reactivity in the
2008. Mapping of the IgE and IgG4 sequential epitopes of milk follow-up of the cow’s milk allergy infants. Clinical & Experimental
allergens with a peptide microarray–based immunoassay. Journal of Allergy 34:866–70.
Allergy and Clinical Immunology 122:589–94. doi: 10.1016/j.jaci. Ghosh, J., G. S. Malhotra, and B. N. Mathur. 1989. Hypersensitivity of
2008.06.040. human subjects to bovine milk proteins: A review. Indian Journal of
Chatchatee, P., K. M. J€arvinen, L. Bardina, L. Vila, K. Beyer, and H. A. Dairy Science 42:744–9.
Sampson. 2001. Identification of IgE and IgG binding epitopes on Givens, D. I. 2005. The role of animal nutrition in improving the
b-and j-casein in cow’s milk allergic patients. Clinical & nutritive value of animal-derived foods in relation to chronic dis-
Experimental Allergy 31:1256–62. doi: 10.1046/j.1365-2222.2001. ease. Proceedings of the Nutrition Society 64:395–402. doi: 10.1079/
01167.x. pns2005448.
Cheuk, D. K., T. C. Chau, and S. L. Lee. 2005. A meta-analysis on Goff, H. I. 2016. Introduction to dairy science and technology: Milk
intravenous magnesium sulphate for treating acute asthma. Archives history, consumption, production and composition. In The dairy sci-
of Disease in Childhood 90:74–7. doi: 10.1136/adc.2004.050005.
ence and technology eBook. Guelph, Canada: University of Guelph.
Cie
sli

nska, A., E. Kostyra, H. Kostyra, K. Ole

nski, E. Fiedorowicz, and S.
Haenlein, G. F. 2004. Goat milk in human nutrition. Small Ruminant
Kami
nski. 2012. Milk from cows of different b-casein genotypes as a
Research 51:155–63. doi: 10.1016/j.smallrumres.2003.08.010.
source of b-casomorphin-7. International Journal of Food Sciences
Han, N., K. M. J€arvinen, R. R. Cocco, P. J. Busse, H. A. Sampson, and
and Nutrition 63:426–30. doi: 10.3109/09637486.2011.634785.
K. Beyer. 2008. Identification of amino acids critical for IgE-binding
Clare, D. A., and H. E. Swaisgood. 2000. Bioactive milk peptides: A
to sequential epitopes of bovine j-casein and the similarity of these
prospectus. Journal of Dairy Science 83:1187–95. doi: 10.3168/jds.
epitopes to the corresponding human j-casein sequence. Allergy 63:
S0022-0302(00)74983-6.
198–204. doi: 10.1111/j.1398-9995.2007.01539.x.
Cong, Y. J., and L. F. Li. 2012. Identification of the critical amino acid
Haug, A., A. T. Høstmark, and O. M. Harstad. 2007. Bovine milk in
residues of immunoglobulin E and immunoglobulin G epitopes in
human nutrition—A review. Lipids in Health and Disease 6:25. doi:
b-lactoglobulin by alanine scanning analysis. Journal of Dairy
10.1186/1476-511X-6-25.
Science 95:6307–12. doi: 10.3168/jds.2012-5543.
He, M., J. Sun, Z. Q. Jiang, and Y. X. Yang. 2017. Effects of cow’s milk
Crittenden, R. G., and L. E. Bennett. 2005. Cow’s milk allergy: A com-
plex disorder. Journal of the American College of Nutrition 24: beta-casein variants on symptoms of milk intolerance in Chinese
582S–91S. doi: 10.1080/07315724.2005.10719507. adults: A multicentre, randomised controlled study. Nutrition 16:72.
de Kivit, S., E. Saeland, A. D. Kraneveld, H. J. van de Kant, B. Henry, G. E., R. A. Momin, M. G. Nair, and D. L. Dewitt. 2002.
Schouten, B. C. van Esch, J. Knol, A. B. Sprikkelman, L. B. van der Antioxidant and cyclooxygenase activities of fatty acids found in
Aa, L. M. J. Knippels, et al. 2012. Galectin-9 induced by dietary syn- food. Journal of Agricultural and Food Chemistry 50:2231–4. doi: 10.
biotics is involved in suppression of allergic symptoms in mice and 1021/jf0114381.
humans. Allergy 67:343–52. doi: 10.1111/j.1398-9995.2011.02771.x. Hill, D. J., S. H. Murch, K. Rafferty, P. Wallis, and C. J. Green. 2007.
Demeulemester, C., I. Giovannacci, and V. Leduc. 2006. Detecting The efficacy of amino acid-based formulas in relieving the symptoms
dairy and egg residues in food. In Detecting allergens in food, ed. S. of cow’s milk allergy: A systematic review. Clinical & Experimental
J. Koppelman and S. L. Hefle, 219–43. Woodhead Publishing. Allergy 37:808–22. doi: 10.1111/j.1365-2222.2007.02724.x.
Do, A. B., K. Williams, and O. T. Toomer. 2016. In vitro digestibility Hochwallner, H., U. Schulmeister, I. Swoboda, S. Spitzauer, and R.
and immunoreactivity of bovine milk proteins. Food Chemistry 190: Valenta. 2014. Cow’s milk allergy: From allergens to new forms of
581–7. doi: 10.1016/j.foodchem.2015.05.113. diagnosis, therapy and prevention. Methods 66:22–33. doi: 10.1016/j.

Dodig, S., and I. Cepelak. 2004. The facts and controverses about selen- ymeth.2013.08.005.
ium. Acta Pharmaceutica 54:261–76. https://www.uoguelph.ca/foodscience/book-page/dairy-science-and-tech-
Downs, M. L., J. L. Kabourek, J. L. Baumert, and S. L. Taylor. 2013. nology-ebook.
Milk protein allergy. In Milk and dairy products in human nutrition: https://www.westonaprice.org/the-biochemical-magic-of-raw-milk-and-
Production, composition and health, 111–128. John Wiley and Sons. other-raw-foods-glutathione/.
El-Agamy, E. I. 2007. The challenge of cow milk protein allergy. Small Insel, P., R. E. Turner, and D. Ross. 2004. Nutrition. Sudbury, MA:
Ruminant Research 68:64–72. doi: 10.1016/j.smallrumres.2006.09.016. Jones and Bartlett Publishers.
El-Agamy, E. I. 2016. Milk protein allergy. In Reference module in food Jaiswal, L., H. Ismail, and M. Worku. 2020. A review of the effect of
sciences, 1–5. Elsevier doi: 10.1016/B978-0-08-100596-5.00971–9. plant-derived bioactive substances on the inflammatory response of
El-Agamy, E. I., Z. I. Abou-Shloue, and Y. I. Abdel-Kader. 1997. A ruminants (sheep, cattle, and goats). International Journal of
comparative study of milk proteins from different species. II. Veterinary and Animal Medicine 3:130.
Electrophoretic patterns, molecular characterization, amino acid J€arvinen, K. M., L. Geller, R. Bencharitiwong, and H. A. Sampson.
composition and immunological relationships. In Proceedings 3rd 2011. Presence of functional, autoreactive human milk-specific IgE
Alexandria Conference of Food Science and Technology, Alexandria, in infants with cow’s milk allergy. Clinical and Experimental Allergy
Egypt, 67–87. 42:238–47.
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 15

Jensen, V. B., I. M. Jørgensen, K. B. Rasmussen, C. Mølgaard, and P. immunoblotting and mass spectrometry. Molecular Nutrition &
Prahl. 2004. Bone mineral status in children with cow milk allergy. Food Research 48:363–9. doi: 10.1002/mnfr.200400011.
Pediatric Allergy and Immunology 15:562–5. doi: 10.1111/j.1399- Niki, T., S. Tsutsui, S. Hirose, S. Aradono, Y. Sugimoto, K. Takeshita,
3038.2004.00191.x. N. Nishi, and M. Hirashima. 2009. Galectin-9 is a high affinity IgE-
Kami
nski, S., A. Cie
sli

nska, and E. Kostyra. 2007. Polymorphism of binding lectin with anti-allergic effect by blocking IgE-antigen com-
bovine beta-casein and its potential effect on human health. Journal plex formation. Journal of Biological Chemistry 284:32344–52. doi:
of Applied Genetics 48:189–98. doi: 10.1007/BF03195213. 10.1074/jbc.M109.035196.
Kappeler, S. 1998. Compositional and structural analysis of camel milk Park, Y. W. 2009. Overview of bioactive components in milk and dairy
proteins with emphasis on protective proteins. Doctoral diss., ETH products. In Bioactive Components in Milk and Dairy Products, ed.
Zurich. Y. W. Park, 3–14. Ames, IA: Wiley-Blackwell Publishers.
Keenan, T. W., and S. Patton. 1995. The structure of milk: Park, Y. W., G. F. W. Haenlein, and W. L. Wendorff. 2017. Overview
Implications for sampling and storage: A. The milk lipid globule of milk of non-bovine mammals. In Handbook of milk of non-bovine
membrane. In Handbook of milk composition, 5–50. Academic Press. mammals, 1–9. Oxford, UK: Wiley-Blackwell Publ.
Korsrud, G. O., M. O. Keith, and J. M. Bell. 1978. A comparison of the Savilahti, E., and M. Kuitunen. 1992. Allergenicity of cow milk pro-
nutritional value of crambe and camelina seed meals with egg and teins. Journal of Pediatrics 121:S12–S20. doi: 10.1016/S0022-
casein. Canadian Journal of Animal Science 58:493–9. doi: 10.4141/ 3476(05)81401-5.
cjas78-063. Sidnell, A., S. Pigat, S. Gibson, R. O’Connor, A. Connolly, S. Sterecka,
Kris-Etherton, P. M., T. A. Pearson, Y. Wan, R. L. Hargrove, K. and A. M. Stephen. 2016. Nutrient intakes and iron and vitamin D
Moriarty, V. Fishell, and T. D. Etherton. 1999. status differ depending on main milk consumed by UK children
High–monounsaturated fatty acid diets lower both plasma choles- aged 12–18 months–secondary analysis from the Diet and Nutrition
terol and triacylglycerol concentrations. American Journal of Clinical Survey of Infants and Young Children. Journal of Nutritional
Nutrition 70:1009–15. doi: 10.1093/ajcn/70.6.1009. Science 5:e32. doi: 10.1017/jns.2016.24.
Larson, B. L. 1979. Biosynthesis and secretion of milk proteins: A Soza
nska, B. 2019. Raw cow’s milk and its protective effect on allergies
review. Journal of Dairy Research 46:161–74. and asthma. Nutrients 11:469. doi: 10.3390/nu11020469.
Linn, J. G. 1988. Factors affecting the composition of milk from dairy Spuergin, P., H. Mueller, M. Walter, E. Schiltz, and J. Forster. 1996.
cows. In Designing foods: Animal product options in the marketplace, Allergenic epitopes of bovine as1-casein recognized by human IgE
224–241. Washington, DC: National Academies Press US.. and IiG. Allergy 51:306–12. doi: 10.1111/j.1398-9995.1996.tb04614.x.
Lourenco, R., and M. E. Camilo. 2002. Taurine: A conditionally essen- Spuergin, P., M. Walter, E. Schiltz, K. Deichmann, J. Forster, and H.
tial amino acid in humans? An overview in health and disease. Mueller. 1997. Allergenicity of alpha-caseins from cow, sheep, and
Nutrici
on Hospitalaria 17:262–70. goat. Allergy 52:293–8. doi: 10.1111/j.1398-9995.1997.tb00993.x.

Vannay, and A. Haczku. 2012. Galectin-9: A suppressor of
Sziksz, E., A.
Majamaa, H., P. Moisio, H. Kautiainen, H. Majamaa, K. Turjanmaa,
food allergy? Allergy 67:293. doi: 10.1111/j.1398-9995.2011.02774.x.
and K. Holm. 1999. Cow’s milk allergy: Diagnostic accuracy of skin
Thomas, P. C. 1983. Milk protein. Proceedings of the Nutrition Society
prick and patch tests and specific IgE. Allergy 54:346–51. doi: 10.
42:407–18. doi: 10.1079/pns19830048.
1034/j.1398-9995.1999.00834.x.
Thormar, H., C. E. Isaacs, K. S. Kim, and H. R. Brown. 1994.
Masterjohn, C. 2010. The biochemical magic of raw milk and other
Inactivation of visna virus and other enveloped viruses by free fatty
raw foods: Glutathione. Mother Nature Obeyed Blog, 241–6.
acids and monoglycerides. Annals of the New York Academy of
Matsuo, H., T. Yokooji, and T. Taogoshi. 2015. Common food aller-
Sciences 724:465–71. doi: 10.1111/j.1749-6632.1994.tb38948.x.
gens and their IgE-binding epitopes. Allergology International 64:
Toma, S., C. Dragomir, M. Habeanu, M. Ropota, A. Cismileanu, and
332–43. doi: 10.1016/j.alit.2015.06.009.
H. Grosu. 2015. Effects of replacing sunflower meal with camelina
Mercer, N., L. Guzman, E. C. Rua, R. Drut, H. Ahmed, G. R. Vasta,
meal on dairy cows performances. Archiva Zootechnica 18:85.
M. A. Toscano, G. A. Rabinovich, and G. H. Docena. 2009.
Toscano, M. A., G. A. Bianco, J. M. Ilarregui, D. O. Croci, J. Correale,
Duodenal intraepithelial lymphocytes of children with cow milk
J. D. Hernandez, N. W. Zwirner, F. Poirier, E. M. Riley, L. G.
allergy preferentially bind the glycan-binding protein galectin-3. Baum, et al. 2007. Differential glycosylation of TH 1, TH 2 and TH-
International Journal of Immunopathology and Pharmacology 22: 17 effector cells selectively regulates susceptibility to cell death.
207–17. doi: 10.1177/039463200902200123. Nature Immunology 8:825–34. doi: 10.1038/ni1482.
Mici
nski, J., I. M. Kowalski, G. Zwierzchowski, J. Szarek, B. Truswell, A. S. 2005. The A2 milk case: A critical review. European
Piero_zy

nski, and E. Zabłocka. 2013. Characteristics of cow’s milk Journal of Clinical Nutrition 59:623–31. doi: 10.1038/sj.ejcn.1602104.
proteins including allergenic properties and methods for its reduc- Vandenplas, Y., M. Brueton, C. Dupont, D. Hill, E. Isolauri, S. Koletzko,
tion. Polish Annals of Medicine 20:69–76. doi: 10.1016/j.poamed. A. P. Oranje, and A. Staiano. 2007. Guidelines for the diagnosis and
2013.07.006. management of cow’s milk protein allergy in infants. Archives of
Monaco, S., G. Russo, A. Romano, L. Liotti, M. C. Verga, and S. M. Disease in Childhood 92:902–8. doi: 10.1136/adc.2006.110999.
Sopo. 2019. Yogurt is tolerated by the majority of children with IgE- Verhoeckx, K. C., Y. M. Vissers, J. L. Baumert, R. Faludi, M. Feys, S.
mediated cow’s milk allergy. Allergologia et Immunopathologia 47: Flanagan, C. Herouet-Guicheney, T. Holzhauser, R. Shimojo, N. van
322–7. doi: 10.1016/j.aller.2018.10.005. der Bolt, et al. 2015. Food processing and allergenicity. Food and
Mulakala, B., E. Eluka-Okoludoh, S. Adjei-Fremah, E. Asiamah, K. Chemical Toxicology 80:223–40. doi: 10.1016/j.fct.2015.03.005.
Ekwemalor, H. Ismail, S. Ibrahim, and M. Worku. 2018. PSVIII-29 Villa, C., J. Costa, M. B. Oliveira, and I. Mafra. 2018. Bovine milk aller-
Galectin 9 secretion in cow milk a marker for homostasis and gens: A comprehensive review. Comprehensive Reviews in Food
health. Journal of Animal Science 96:30–1. doi: 10.1093/jas/sky404. Science and Food Safety 17:137–64. doi: 10.1111/1541-4337.12318.
069. Worku, M., K. Ekwemalor, E. Asiamah, S. Adjei-Fremah, B. Osei, B.
Nakajima-Adachi, H., S. Hachimura, W. Isea, K. Honma, S. Nishiwakia, Mulakala, E. Eluka-Okoludoh, and H. Ismail. 2018. Expression and
M. Hirotaa, N. Shimojo, T. Katsuki, A. Ametani, Y. Kohno, et al. secretion of circulating galectins in domestic ruminants. Journal of
1998. Determinant analysis of IgE and IgG4 antibodies and T cells Animal Science 96:29–30. doi: 10.1093/jas/sky404.067.
specific for bovine as1-casein from the same patients allergic to cow’s Wray, J.D. (1978) Maternal Nutrition, Breast-Feeding and Infant
milk: Existence of as1-casein–specific B cells and T cells characteristic Survival. In: Nutrition and Human Reproduction, ed. W. H. Mosley,
in cow’s-milk allergy. Journal of Allergy and Clinical Immunology 101: 197–229. Springer, Boston, MA.
660–71. doi: 10.1016/S0091-6749(98)70175-7. W€uthrich, B., and S. G. Johansson. 1995. Allergy to cheese produced
Natale, M., C. Bisson, G. Monti, A. Peltran, L. Perono Garoffo, S. from sheep’s and goat’s milk but not to cheese produced from cow’s
Valentini, C. Fabris, E. Bertino, A. Coscia, and A. Conti. 2004. milk. Journal of Allergy and Clinical Immunology 96:270–3. doi: 10.
Cow’s milk allergens identification by two-dimensional 1016/S0091-6749(95)70021-8.