Human Breast Milk Contains Bovine lgG. Relationship to Infant Colic?

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PEDIATRICS Vol. 87 No. 4 April 1991 439

Human

Breast

Milk Contains

Bovine

lgG.

Relationship

to Infant

Colic?

Patrick

S.

Clyne,

MD, and

Anthony

Kulczycki,

Jr, MD

From the Washington University School of Medicine, St Louis, Missouri

ABSTRACT. Previous studies have suggested that an unidentified cow’s milk protein, other than 9-lactoglob-ulin and casein, might play a pathogenetic role in infant colic. Therefore, a radioimmunoassay was used to analyze human breast milk and infant formula samples for the

presence of bovine IgG. Milk samples from 88 of the 97

mothers tested contained greater than 0.1 sg/mL of

bo-vine IgG. In a study group of 59 mothers with infants in the colic-prone 2- to 17-week age group, the 29 mothers of colicky infants had higher levels of bovine IgG in their breast milk (median 0.42 zg/mL) than the 30 mothers of noncolicky infants (median 0.32 g/mL) (P < .02). The highest concentrations of bovine IgG observed in human milk were 8.5 and 8.2 g/mL. Most cow’s milk-based infant formulas contained 0.6 to 6.4 ig/mL of bovine

IgG, a concentration comparable with levels found in many human milk samples. The results suggest that appreciable quantities of bovine IgG are commonly pres-ent in human milk, that significantly higher levels are

present in milk from mothers of colicky infants, and that bovine IgG may possibly be involved in the pathogenesis of infant colic. Pediatrics 199i;87:439-444; bovine

im-munoglobulin G, infant colic, human milk, infant formula, cow’s milk proteins.

Infant colic is a disorder that involves

intermit-tent unexplained excessive crying, usually

occur-ring in the first 4 months of life.’ The prevalence of colic is approximately 20% in both formula-fed

infants

and

exclusively breast-fed infants.3’4 Several

studies suggest that a cow’s milk protein in diets of

formula-fed infants may play a pathogenetic role in colic.1’2’4 To explain why colic affects infants who are exclusively breast-fed, it has been hypothesized

Received for publication Feb 5, 1990; accepted Apr 17, 1990.

Presented, in part, at the American Pediatric Society, Society

for Pediatric Research meeting, Washington, DC, May 1989.

Reprint requests to (A.K.) Division of Allergy and Immunology,

Washington University School of Medicine, 660 S Euclid, Box

8122, St Louis, MO 63110.

PEDIATRICS (ISSN 0031 4005). Copyright © 1991 by the

American Academy of Pediatrics.

that a cow’s milk protein responsible for colic might be absorbed from dietary sources by mothers and transferred in human breast milk.7’8 In previous

tests of this hypothesis,7’8 mothers of 85 nursing

infants with colic were given milk-free diets for

approximately a week. Colic disappeared in 48 of

the breast-fed infants and recurred in 35 of the 48

infants after reintroduction of cow’s milk into the

maternal diet.7’8 Ten mothers were further tested in double-blind crossover fashion; colic developed

in nine of their nursing infants after maternal

ingestion of capsules containing cow’s whey

pro-teins.8

Apparently the search for the responsible protein halted after findings of only minimal amounts of bovine 3-lactoglobu1in (5 to 33 ng/mL,#{176}i to 20 ng/ mL,’#{176}and 0.i to 6.4 ng/mL”2) and casein (i.5 to

i7 ng/mL’#{176}) in human milk. Such concentrations

appear comparable with levels of other dietary an-tigens in human milk” but insignificant relative to

the milligram

per

milliliter levels of casein and lactoglobulin in infant formula. However, human

milk has not previously been tested for the presence of bovine IgG, even though cow’s milk contains 0.7 mg/mL of bovine

IgG’3

and bovine IgG has been

shown to be antigenic in humans.’4”5

In this study we detected bovine IgG in uS of

i24 human breast milk samples by using a

solid-phase radioimmunoassay (RIA). Levels of bovine

IgG in some human milk samples were comparable with levels in several cow’s milk infant formulas. Levels of bovine IgG were significantly higher in breast milk fed to infants with colic than in breast milk of mothers without colicky infants. Implica-tions of these findings are considered.

METHODS

Study Population

and Human

Milk

Healthy breast-fed infants and their mothers

were recruited through outpatient private practices

at Viet Nam:AAP Sponsored on September 2, 2020

www.aappublications.org/news

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and the La Leche League. Colic was assessed ac-cording to these guidelines: prolonged paroxysms of vigorous crying in healthy infants with normal

physical examination results, with excessive crying

occurring at least 4 days/week for at least a week.

We mainly recruited and studied infants with colic and infants in the colic-prone age range of 2 to i7 weeks3 and excluded borderline cases. All infants were assessed for the presence of colic during their

first 10 weeks and had been exclusively breast-fed during that period. Mothers collected samples of

breast milk into sterile tubes by using either breast

pumping or manual expression. Samples were

im-mediately refrigerated and assayed promptly (47% within 24 hours, 75% within 72 hours) or frozen.

Purification

of Bovine

IgG, Rabbit Antiserum

to

Bovine

IgG Fc Fragments

Bovine IgG was purified from raw cow’s milk as

described previously.’6 Bovine milk IgG was di-gested with i% mercuripapain for 3 hours at 37#{176}C in 0.Oi mol/L sodium phosphate-0.i5 mol/L NaCl pH 7.4 buffer, (phosphate-buffered saline),

contain-ing 2 mmol/L EDTA and iO mmol/L L-cysteine.’7

Bovine Fc fragments were isolated by DE-52 chro-matography,’7 eluting in 7 mmol/L phosphate-0.i mol/L NaCl pH 7.7 buffer, and were free of intact

IgG and Fab fragments on immunoelectrophoretic analysis.

A 3-month-old New Zealand White rabbit was immunized intraperitoneally with 0.5 mg of bovine milk IgG Fc fragments in complete Freund’s adju-vant (Difco, Detroit, MI). Simultaneously, toler-ance to human IgG was induced by intravenous injection of 2.5 mg of half human IgG (chromato-graphically purified, Cappel Laboratories, West Chester, PA), and 2.5 mg of human IgG purified from a normal donor’s serum. The rabbit was boosted every 2 weeks with 0.5 mg of bovine Fc

fragments in incomplete Freund’s adjuvant

(GIBCO, Grand Island, NY), equally divided

be-tween intraperitoneal and subcutaneous injections.

Antiserum was obtained 2 weeks after the fifth

boosting immunization. This antiserum was shown

by immunoelectrophoresis to bind bovine IgG and

its

Fc fragments but not bovine serum IgA nor human IgG. The IgG fraction of the antiserum, obtained by precipitation with 40% saturated (NH4)2S04, was used for the RIA.

Solid-Phase

Radioimmunoassay

for Bovine

IgG

Polystyrene tubes (i3 x iOO mm, Becton

Dick-inson, Oxnard, CA) were coated with i mL of the

IgG fraction (i:3000 dilution) of the rabbit

anti-serum to bovine milk IgG Fc fragments in 0.Oi mol/

L Tris buffer (pH 9.0) by incubation overnight at

37#{176}Cand then 4 hours at 4#{176}C.To minimize

non-specific binding, 0.i mL of the IgG fraction (i:34 dilution in the same buffer) of normal rabbit serum

was added and the incubation sequence was

re-peated. Tube contents were aspirated and tubes were stored in i.0 mL of 0.02% sodium azide at 4#{176}C

until assay. Purified bovine milk IgG was labeled

with 1251 by the chloramine T method’8 with 3.7 x

io

Bq (i mCi) carrier-free 1251 and iOO zg of

chlor-amine T per

400

ig of protein in 0.5 mL yielding

specific activities of approximately i.5 x i06 cpm/

sg.

The RIA was performed in triplicate in phos-phate-buffered saline buffer containing 0.02% so-dium azide and 0.i% human serum albumin (essen-tially globulin-free, Sigma Chemical Co, St Louis, MO). Assay mixtures were added to the antiserum-coated polystyrene tubes in a 0#{176}Cbath. In order of addition, assay mixtures consisted of buffer (0.7 mL), appropriately diluted samples (0.i mL) or

purified bovine IgG standards (2 to i000 ng in 0.i

mL), and 50 000 cpm of ‘25I-labeled bovine milk

IgG

(0.1

mL). After vortex mixing, tubes were

counted and incubated overnight at 37#{176}C.Tube

contents were aspirated and tubes were washed once and recounted.

The limit of sensitivity, 0.05 to 0.i ig/mL of

sample, was determined by the linear range (probits

graph) of the standard curves. Further validation

of the assay was performed by measurement of

multiple sample dilutions, eg, legend to Figure. Ad-ditions of samples or standards to known samples demonstrated that constituents of human milk and diluted formula did not significantly affect the

as-say results. As an internal control, pasteurized cow’s milk samples (measured in i:iOO and i:200

dilutions) contained ‘-500 &g/mL of bovine IgG, comparable with levels in raw cow’s milk.” Also, this assay did not cross-react with bovine casein, 3-lactoglobulin, or a-lactalbumin (all from Sigma Chemical) at iO g/mL, nor with 3 mg/mL of human secretory IgA (Accurate Chem Corp, West-bury, NY), iO mg/mL of human IgG (Cappel), or

iO mg/mL of human serum albumin. (In testing for

human serum albumin cross-reactivity 0.i% oval-bumin was substituted as carrier protein in the

buffer.) Intraassay coefficients of variation ranged

from 3% to 6%; interassay coefficients of variation ranged from 6% to 20%.

Statistical Analysis

In the statistical analysis, mothers are the unit

of comparison of the groups, eg, when multiple milk

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I 0 z 0 I-. z uJ I-) z

9

‘-I Ui z > 0 I II. I SI II. 0 --6 0 0 0,

TABLE 1. Comparison of Bovine IgG Concentrations in Fresh Human Breast Milk Samples and Their Skim Fractions*

ARTICLES 441

an individual mother, the mean value is used as a

single data point. The concentrations of both

groups in the Figure (and log transformation of one

group) do not fit a gaussian distribution. Therefore, a nonparametric statistical method, the analysis of

variance, was performed by using the general linear models procedure from the SAS computer package

(SAS Institute, Cary, NC).

RESULTS

One hundred twenty-four human milk samples

from 97 mothers were analyzed for bovine

IgG

by solid-phase RIA. One hundred fifteen samples from 88 mothers contained greater than 0.i tg/mL of

bovine IgG or its antigenically detectable

frag-ments. In the study group of 59 mothers (80 breast milk samples) with infants in the colic-prone 2- to i7-week age range, samples from 56 mothers (77 milk samples) contained measurable levels of

bo-vine IgG (greater than 0.i g/mL). All 29 mothers

of infants with colic provided samples containing greater than 0.22 g/mL of bovine IgG (Figure). In contrast, breast milk from 8 of 30 mothers of non-colicky infants contained less than 0.22 jzg/mL of bovine IgG, ie, no exclusively breast-fed infant

de-veloped colic if maternal milk contained less than

0.22 g/mL during the colic-prone period. The con-centrations of bovine IgG in milk samples

associ-ated with infant colic (median 0.42 sg/mL) are significantly higher than concentrations in samples associated with absence of colic (median 0.32 g/

mL) (P ‘= .0i54). There were no significant differ-ences in age or source of referral between the

groups.

Bovine IgG levels were also measured in milk

samples from additional mothers whose children

were either younger than 2 weeks of age (i5

sam-ples) or older than i7 weeks of age (24 samples).

The highest bovine IgG concentrations, 8.5 and 8.2 g/mL, were measured in breast milk from mothers

of infants younger than 2 weeks old, one who later

developed severe colic and one without colic,

re-spectively. Overall, 7 milk samples from four

moth-ers contained greater than i tg/mL of bovine IgG.

Fresh milk samples from seven mothers were

centrifuged at 30 000 X g at 4#{176}Cand cream, skim,

and cellular fractions were separated. Bovine IgG

concentrations of skim fractions paralleled levels of whole breast milk measured in the same assay

(Table i). In several experiments cream and cellular

fractions were analyzed and only a small fraction (usually <iO%) of the bovine IgG content of fresh human milk was detected in the cream supernatant or the cellular pellet. The bovine IgG measured in

skim fractions of two samples was not precipitated

COLIC NO COLIC

Figure. Concentrations of bovine IgG in human milk and presence of colic in infants between the ages of 2 and

17 weeks. Milk samples were obtained from 29 mothers

(38 samples) with colicky infants (#{149})and from 30

moth-ers (42 samples) with noncolicky infants (0). These data

represent single samples from 43 mothers and the average

of samples obtained on different days from 16 mothers. Of the 80 samples, 21 were measured in at least two independent assays and average values are presented. The three lowest values were undetectable at, and are

plotted at, 0.05 and 0.1 ig/mL. Dashed lines

(- - -)

indicate median values. A twofold dilution of the sample

with the highest bovine IgG level (4.6 .tg/mL) resulted in the expected concentration (2.2 tg/mL).

Individual Milk, tg/mL Skim, ig/mL % of Bovine

IgG in Skim

1 0.i69 0.ii4 67

2 0.230 0.132 57

3 <0.05 <0.05 ...

4 2.24 1.5 67

5 0.272 0.125 46

6 0.232 <0.10 <43

7a 0.240 0.112 47

Th 0.236 0.131 56

7c 0.174 0.i28 74

* Each value represents the average of triplicate

deter-minations in a single assay in which both whole milk and skim fractions are compared. Aliquots of freshly obtained

samples were centrifuged at 30 000 X g for 30 minutes at

4#{176}C.After removal of solid cream layers with cold spa-tulas, skim fractions were aspirated from the cellular

pellets. Three samples of breast milk were obtained over

a period of 40 h from donor 7.

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after acidification to pH 4.5 (unlike casein) but was

85% to 96% precipitable in 50% saturated

ammo-nium sulfate (as expected for an immunoglobulin). Multiple samples from individual mothers had little variability in bovine IgG levels, eg, three milk

and skim samples collected within a 40-hour period (donor 7 in Table i) had coefficients of variability

of i7% and 8%, respectively. Also, bovine IgG levels from nine refrigerated samples assayed before and

after freezing matched closely (median difference,

2%).

Commercially available infant formulas were

as-sessed for bovine IgG concentration by solid-phase

RIA (Table 2). As expected, soy-based and hydro-lyzed casein-based formulas had no detectable bo-vine IgG (Table 2 legend). All cow’s milk-based formulas contained detectable levels of bovine IgG. Milk-based formulas contain i5 mg/mL of protein, i4%’#{176}to 60% of which is whey protein. Inasmuch as IgG accounts for ....J/7 ofwhey protein,’9 one might

anticipate a bovine IgG level of 0.3-i.3 mg/mL. However, heat lability of bovine IgG2#{176}may account

for the lower and variable levels observed. In

gen-era!, milk-based formulas prepared from liquid con-centrates contained the lowest levels of bovine IgG (0.6-2.5 sg/mL). The highest levels of bovine IgG

were found in three different lots ofa whey-predom-inant powdered formula from one company. Com-parison of human milk with cow’s milk-based

for-mula preparations surprisingly shows that 20

hu-man milk samples had higher bovine

IgG

levels

than one milk-based formula.

DISCUSSION

In this study bovine IgG was detected in

concen-trations from 0.i to 8.5 sg/mL in most human milk samples. Both the nature of this protein and its

levels are remarkable. Bovine

IgG

is a unique

an-tigen because it can bind to Fc receptors of human antigen-presenting cells,’6’2’ it can (in these

concen-trations) modulate antibody secretion by human B cells in vitro,2’ and it has a prolonged half-life. The

concentrations of bovine IgG in human milk are

much greater than other dietary antigens previously

reported (only nanogram per milliliter

concentra-tions),9’2 are appreciable relative to reported con-centrations of human

IgG

in milk (averaging 29 ig/

mL),22 and are comparable with the serum levels of immune complexes present in various disease

states.23 The microgram per milliliter levels of

bo-vine IgG in some human milk samples suggest that maternally ingested bovine IgG may be relatively

resistant to proteolysis or selectively absorbed or

transported. A precedent for transport is that

bo-vine and human IgG bind equally well to bovine mammary gland tissue.24

Although individual mothers tend to have repro-ducible levels of bovine IgG in repeated samples of their breast milk, a marked variability of bovine IgG concentrations was observed among different

mothers. The sources of population variability are not known but might be related to dietary intake

of dairy products, presence of antibodies to bovine IgG, completeness of digestion of bovine IgG, and! or variability of absorption of bovine IgG.

This is the first demonstration of a foreign

pro-tein in human milk in concentrations comparable

with the concentrations found in infant formulas (Figure and Table 2). In the context of previous

studies,7’8 these findings raise the question of

whether bovine

IgG

might play a role in the etiology of infant colic. Results of some previous studies of breast-fed infants with colic and their mothers have

been interpreted to mean that a cow’s milk protein

TABLE 2. Bovine IgG Content of Standard Cow’s Milk Infant Formula Preparations*

Product Type of Formula Bovine IgG, tg/mL

Enfamil (Mead Johnson and Ready-to-use 4.4, 4.6, 4.9, 6.4

Co, Evansville, IN) Concentrate Powder

0.9, 2.5 72, 110, 128

Similac (Ross Laboratories, Co- Ready-to-feed i.3, 2.6, 3.9, 4.5

lumbus, OH) Concentrate

Powder

0.8, 1.4

2.6, 3.i, 3.3, 5.2

SMA (iron fortified) (Wyeth Ready-to-feed 2.4, 3.5, 4.2 Laboratories, Philadelphia, Concentrate 0.6, 1.0

PA) Powder 1.5

* Each value represents a determination for one lot number of purchased formula. All lots

of the formulas available in the St Louis area were purchased and analyzed. Values are

given for concentrates and powders diluted according to manufacturers’ recommendations.

Iron-fortified and low-iron varieties of Enfamil and Similac were tested and had similar

bovine IgG levels. Bovine IgG was not detectable in any soy-based (Isomil and RCF, both

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ARTICLES 443 (presumably absorbed by mothers from dietary

sources and transferred in breast milk to infants)

was implicated in the etiology of the infant colic.7’8 After ingestion ofwhey protein capsules by mothers of previously colicky infants, 9 of 10 breast-fed

infants demonstrated recurrences of colic in a

dou-ble-blind placebo-controlled study.8 However, the causative protein was not identified. The implica-tion that bovine 9-lactoglobulin might cause infant colic9 is difficult to reconcile with the following observations: (i) human milk contains nanogram

per milliliter concentrations of bovine

fi-lactoglobulin9’2; (2) cow’s milk formulas contain concentrations of 3-1actog1obulin in the milligram per milliliter range; and (3) the prevalence of infant colic is approximately 20% in both formula-fed and breast-fed infants.3’4 On the other hand, the hy-pothesis that bovine IgG may be an etiologic factor

in colic would be a tenable hypothesis consistent with previous and present observations.

We have found significantly higher

concentra-tions of bovine

IgG

in milk from mothers of colicky

infants compared with breast milk from mothers of noncolicky infants. This association supports, but does not prove, our hypothesis that bovine IgG may be one possible etiologic factor in colic. It should be noted that we are examining only one potential

factor, the bovine IgG concentration in human

milk. We are not testing other potentially impor-tant variables, eg, the infant’s ability to absorb (or to react to) bovine IgG, nor have we attempted yet

an interventional study. In considering the

poten-tial clinical significance of our testable hypothesis, one might explain why maternal avoidance of dairy products for i week results in improvement of colic in most breast-fed infants.7’8 The persistence of colic in some instances7’8’25 might have several pos-sible explanations: (i) dairy products were not strictly avoided25; (2) maternal levels of bovine IgG

were so high or half-life of bovine IgG was so long

that 2- to 7-day trials were sometimes insufficient; or (3) other etiologic factors may be involved. In considering treatment of colic in infants fed cow’s milk-based formula by switching to a casein hy-drolysate formula,2 the prolonged half-life of bovine

IgG might explain why short dietary trials may not give conclusive results.

ACKNOWLEDGMENTS

This study was supported by National Institutes of

Health grants P50 AI15322 and ROi A124005.

We thank Dr Kathleen Winters for enthusiastic help in obtaining breast milk samples and evaluation of in-fants in her practice. We are indebted to the St Louis Chapter of the La Leche League and to Dr Pat Wolff and

the physicians and assistants of the Health Key Medical

Group for assisting us in collecting milk samples. We are

grateful to Dr Charles Janeway (Yale University, New

Haven, CT) for advice in tolerizing rabbits during

im-munization and Dr Arthur Hirata (Abbott Labs, North

Chicago, IL) and Dr Renata Cathou (Technical

Evalua-tions, Lexington, MA) for advice on solid-phase RIA protocols. We acknowledge Michael A. Province

(Wash-ington University, Division ofBiostatistics) for statistical

analysis of the data and Carolyn Davinroy for secretarial assistance. We thank Dr John E. Butler (University of Iowa, Iowa City, IA) for helpful discussions and Drs

Harvey R. Colten and Charles W. Parker for reviewing

the manuscript.

REFERENCES

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NEW

ELEMENT

DISCOVERED

The heaviest element known to science was recently discovered by physicians at Whatsamata U. The element, tentatively named Administratium, has no protons or electrons and thus has an atomic number of 0. However, it does have

i neutron, i25 assistant neutrons, 75 vice-neutrons and iii assistant vice-neutrons. This gives it an atomic mass number of 3i2. These 3i2 particles are held together in the nucleus by meson-like particles called memos. Since it has

no electrons, Administratium is inert. However, it can be detected chemically

as it impedes every reaction it comes in contact with.

According to the discoverers, a minute amount of Administratium caused one reaction to take 4 days to complete when it would normally take i second.

Administratium has a normal half-life of approximately 3 years, at which time it does not actively decay, but instead undergoes a reorganization in which assistant neutrons, vice-neutrons and assistant vice-neutrons exchange places. Some studies have shown that atomic mass number actually increases after reorganization.

Research at other laboratories indicates that Administratium occurs naturally

in the atmosphere. It tends to condense and concentrate at certain points such

as government agencies and universities, and can usually be found in the newest, best-appointed and best-maintained buildings.

Scientists point out that Administratium is known to be toxic at any level of

concentration, and can easily destroy any productive reaction where it is allowed

to accumulate. Attempts

are

being made to determine how Administratium can be controlled to prevent irreversible damage, but results to date are not

prom-ising.

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