0022-1554/90/$3.30

Thejournal ©

Copyright

Vol.

of Histochemistry and Cytochemistry 1990 by The Histochemical Society,

Received

ofLegal for

Medicine,

publication

NISHI,

MITSURU

Nara Medical

December

18,

1989

University,

Kashihara

and in revised

form

the distribution ofblood group-related antian indirect immunoperoxidase method with monoclonal antibodies (MAb) directed to A, B, H, Lewis a (Lea), Lewis b (kb), x (Le’), and Lewis y (LeY) antigem and Type 1 precursor chain in human pancreas. Effects ofprior digestion with exoglycosidases on MAb stainings were simultaneously investigated. A, B, H, b, and LeY antigens were detected in acinar cells and interlobular duct cells but not in centroacinar cells, intercalated duct cells, and islet of Langerhans cells. The expression ofthese antigens in acinar cells was not dependent on Lewis type and secretor status of the tissue donors, whereas that in interlobular duct cells was strictly dependent on secretor status. The distribution pattern of these antigens in acinar cells was not homogeneous, i.e., cells producing H antigens expressed both Leb and LeY antigens but not A or B antigens, whereas those producing A or B antigens did not seaete Leb and LeY as well as H antigens. Digestion with a-N-acetylgalactosaminidare or a-galactosidase resulted in the appearance of Lb and Le antigens as well as H antigen in acinar cells producing A and/or B antigens. Type 1 precursor chain was not de-

Introduction group-related

using creas

monoclonal antigens

analysis several

have

with

recently

of carbohydrate histochemical

to localize blood (10,13,20,21,31,32,36-39),

concerned

antibodies

malignant

(MAb)

been

directed

developed

and

to blood used

April

4, 1990;

group-related antigens in human panmost ofthese studies were mainly and

effects

ofthe

Lewis

type

and

accepted

it is necessary

gens

in normal In a series

ing method procedures of blood

and

submandibular

studies

the

3-based control

against To whom

correspondence

should

be addressed.

to know

distribution

and

fucosylation of the

tam

oligosaccharide MAb

combined

developed and

analyze

(14-19).

Type

antigens

of the anti-

of the Type secretor

(Se)

2, and

exact

gene.

in human

results

of these

(8,11),

glycosidase

strucpancreas previous

O-glycosidically in pancreatic chain

Because have

staindiges-

chemical

chains

3 precursor

antigens

structures with

The

1, Type

the lectin

endoglycosidase

the

are secreted

group-related

with

exo-

carbohydrate

glands

that

we have

with

to localize

ABH

blood

the precise

studies,

group-related

suggested

understand

I

(9A1862).

tissues. ofprevious

tures

that

in malignant

1990

in combination

tion

and

glycosylation

6,

in pancreatic tissues from reactors but appeared in cells producing H antigen after a-L-fucosidase digestion, which also disclosed Lea but not Lea antigen in acinar cells expressing both jb and LeY. In some non-reactors, MAb against Type 1 precursor chain reacted with acinar cells without enzyme digestion. Although Lea antigen was not detected in acinar cells, it was found in centroacinar cells, intercalated duct cells, and interlobular duct cells from all individuals examined except two Lc(a- b-) reactors. After sialidase digestion, Le antigen appeared in centroacinar and intercalated duct cells from some individuals. Sialidase digestion also elicited reactivity with MAb against Type 1 precursor chain in islet ofLangerhans cells from some individuals. These results demonstrate the complexity in the pattern of expression and regulation of blood group-related antigens in different cell types ofhuman pancreas. Such complexity may largely be ascribed to differences in individual genotypes and in gene expression patterns ofdifferent cell types. (J Histochem Cytochem 38:1331-1340, 1990) KEY WORDS: Blood group antigen; Immunohistochemistry; Monoclonal antibody; Exoglycosidase; Pancreas.

Type

ofaberrant

April

tected

secretor status of individuals on the expression of these antigens have not yet been fully explored in normal pancreatic tissues. To the mechanism

OKAMURA,

acinar

for

chains in different tissues (11). studies have been carried out by

tissues,

YOSHIRO

Nara 634, Japan.

tissues,

well-defined

structural Although

Artide

NAKAJIMA,

We examined gem using

Many

1990

USA.

Localization and Analysis of Blood Antigens in Human Pancreas Using with Monoclonal Antibodies and Digestion

NOBUAKI ITO,1 KATSUJI and TADAOMI HIROTA Department

1331-1340,

Printedin

Original

Histochemical Group-related Immunostaining Exoglycosidase

No. 9, pp.

38,

Inc.

rigid

linked acinar

is in part

well-defined specificity

cells under MAb

for cer-

an immunostaining

method

digestion

may also

procedure

1331

Downloaded from jhc.sagepub.com at VIRGINIA COMMONWEALTH UNIV on March 13, 2015

1332

ITO,

provide

a useful

bohydrate

means

chains

in

In the present using

several

nation

with

definite

tion

and

and

10%

study,

MAb

blood

formalin

filter

paper,

tissue

in human

MAb-H MAbLea

autopsy

formalin,

cases.

They

embedded

were fixed

in paraffin,

in

sections

were

incubated

with

MAb

MAbLex

at 0C

for

MAb-LeY

Donor

group,

sex, Blood

no.

and

age

Group

of the

tissue

donors” Age (years) 27

0

Le(a-b+)

S

M

0

Le(a-b-)

S

F

0

46E

0

Le(a

) NS

M

15

Le(a+b-)

73

+b

-

73E

0

NS

M

821

A Le(a-b+)

S

M

875

A Le(a-b+)

S

M

876

A

S

F

881

A Le(a+b-)

NS

M

7E

A

S

M

46

A

S

M

50

S

M

1

S

M

0

Le(a-b+)

A2 Le(a-b+)

37 9 months

4 0

747F

B

772

B

S

F

843

B

Le(a+b-)

NS

M

944

B

Le(a+b+)

S

M

S

M

89

S

M

20

S S

F M

35

AB

703 848

AB

850

AB

853

AB 4

I

Gal-U3 1-4)-GlcNAcl3Gal-(1-3)-GlcNAc-

a Gal, D-galactose; N-acetyl-D-glucosamine.

Le(a-b+) Le(a-b-)

S. secretor;NS. non-secretor; M. male; F. female.

GalNAc,

N-acetyl-D-galactosamine;

Fuc,

GIcNAc.

L-fucose;

nex; Dublin, CA). Finally, the sections were counterstained with hematoxylin, dehydrated, and mounted in balsam. A mouse MAb (1gM class) against the Trypanosoma surface antigen (a gift from Dr. Y. Takahashi, Department ofParasitology, Nara Medical University)was used as a negative control. As thehistochemical positive and negative controls for MAbLea, .jb Le5 -Le, and -Type 1, reactivity of these antibodies with the following tissue sites were examined: stomach surface mucosac from secretors (positive with MAbLeb and negative with MAb-Le5) and non-secretors (positive with MAb-Le5 and negative with MAbLeb); Brunncr’s gland (positive with MAbLeX and Le and negative with MAb-Le5 and Leb) (27); and proximal tubule and Henle’s loop of kidney (positive with MAb-Le5 and -Type 1) (8). These tissues were obtained from autopsy cases. Staining of sections from B and 0 donors with MAb-A or from A and 0 donors with MAb-B was also carried out as negative built-in control for MAb-A and -B. a-Galactosidase(green coffee beans)was purchased from Sigma(St Louis, MO); a-N-acetylgalactosaminidase (Acremonium sp.) was from Seitetsu (Tokyo,

Japan);

a-L-fucosidase

(Indianapolis,

(bovine IN),

and

kidney)

was

neuraminidase

from

Boeh-

(Arthmbacter

was obtained from Marukinshoyu (Tokyo, Japan). Digestion with a-galactosidase was carried out by incubating tissue sections in a solution containing the enzyme at a concentration of 2-2.5 U/mI in 3.2 M (NFLg)2SO4 solution, pH 6.0, at 37’C for 20-24 hr (19). Digestion with a-N-acetylgalactosaminidase and a-L-fucosidase was similarly performed by incubating sections in a solution containing the enzyme at a concentration of 1 U/mI in 0.1 M citrate buffer, pH 4.5 (17), and in 0.1 M citrate phosphate buffer, pH 5.2 (18), respectively, for 20 hr at 37’C. Digestion with neuraminidase was carried out by immersing sections with enzyme buffer solution (0.25 U/mI ofthe enzyme in 0.1 M acetate buffer, pH 5.2) for 6-24 hr at 37C (14). Sequential digestions ofsections were carried out by using the same incubation conditions described above for each enzyme. After the first enzyme digestion, sections were washed with distilled water and then incubated for a second enzyme digestion. ureafaciens)

Sex

845

M3

I Gafl3-

Fuc-(al-3) / Gal-(31-3)-GlcNAc3-

1

ringer-Mannheim

832

80E

in

Gal-(131-4)-GlcNAcl3Fuc-(al-3) / Gal-(31-4)-GlcNAcl3-

Fuc-(al-2)-

MAb-Type

Kogyo 1 . Blood

used

MAb

Fuc-(al-4) / Gal-(31-3)-GlcNAc3-

Fuc-(al-2)-

and

4 hr. MAb were used at dilution of i:so-i:io with PBS-BSA. Tissue sites reactive with MAb were visualized with the streptavidin-biotin-peroxidase complex method (4), using a StreptAvidin Immunostaining Kit (BioGe-

Table

by

GalNAc-(a1-3)-Gal3Fuc-(al-2) Gal-(al-3)Fuc-(al-2) Fuc-(al-2)-

distribu-

pancreas.

defined

HIROTA

Fuc-(al-4) from

neutralized

tissue

structures

OKAMURA,

study’

MAb-B

more

Methods

the

Determinant

MAb-A

sectioned serially at 4 tm. Typing ofdonor blood groups for ABO and Lewis was performed by routine hemagglutination testing of the donor’s blood samples. Secretor status of the donors was determined by the Lewis blood type or was histochemically deduced from the presence (secretor) or absence (non-secretor) ofH antigen in serous cells ofcorresponding submandibular glands (16). The blood samples and submandibular glands were also obtained from autopsy cases. The blood group ABO, Lewis, secretor status, sex, and age of the tissue donor are summarized in Table 1. MAb directed to A, B, and H antigens (MAb-A, MAb-B, and MAb-H) were purchased from Dako (Santa Barbara, CA). MAb against Le and Leb antigens (MAbLea and MAbLeb) were from BioCarb Chemicals (Lund, Sweden) or Signet Laboratories (Cambridge, MA), and MAb against Lex, Le, and precursor Type 1 chain (MAbLex, MAb-Le, and MAb-Type 1) were also from Signet Laboratories. The antigenic structures defined by these MAb are illustrated in Table 2. Tissue sections were dc-waxed, hydrated, and incubated in 0.1 M phosphate buffer, pH 7.2, containing 0.2 M NaCI (PBS), three times (each for 3 mm) at room temperature, and then incubated in PBS containing 1 mg/mI of bovine serum albumin (PBS-BSA) for 20 ruin. After being blotted dry with

2.

MAbLeb

were obtained

or 10%

Table

NAKAJIMA,

in combi-

to provide

as to the

antigens

method

antigens

procedures

information

of these

and

of car-

an immunostaining

group-related

digestion

comprehensive

tissues

structure

thepresent

we developed

against

regulation

the chemical

sections.

exoglycosidase

Materials Pancreatic

for analyzing tissue

NISHI,

6 months 51 1

month

50

Results Distribution

ofABH,

Immunoperoxidase antigens

showed

in acinar

cells

staining that

Le”, with

and MAb

A, B, H, Leb,

but not in centroacinar

Downloaded from jhc.sagepub.com at VIRGINIA COMMONWEALTH UNIV on March 13, 2015

Ley Antigens against

and

blood

LeY antigens

cells,

intercalated

group-related are secreted duct

cells,

I

.

,

. .f. .

s

.

‘-.-..,

,.

-p

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.

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.

4’ .

I

‘-

,

.

w

‘-,

.,

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.;4aT

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.;,

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.,.

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.

.

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-

-

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--. -

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:.4.

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:

4.

:

-

I

.

;

-

-

4

I

.c..

.-,.

%

,4’.

I

,:::;

t_

#{149}-;.‘‘

,

.,-

. - ..

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..,

-.

S

..

.

.‘4’

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.

.

-,

1

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f#{149}

C

-



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3A

r

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4

L3B

11

.b4.

4,,

Figure 1. Sections of pancreas from a blood group AG secretor individual (donor and MAb-A- or -B-unreactive cells are stained with both MAbLeb and MAb-LeY.

no. 848) stained with (A) MAb-H, Bars = 100 tm.

Y

(B) MAbLeb,

and (C) MAb-LeY.

MAb-H-reactive

Figure 2. Sections of pancreas from a blood group AG secretor (donor no. 703) stained with MAb.Lea. (A) Nearly all the centroacinar cells and intercalated duct cells are stained with MAb-Le8. (B) Strong surface and cytoplasmic staining is seen at higher magnification. Interlobular duct cells are also stained with MAb-Le5. Bars: A = 200 tm; B = 50 tm.

a

Figure not react Figure

Bar

4. =

Sections of pancreas from a blood group at all with the pancreatic tissue, whereas Section

100 tm.

of pancreas

from

a blood

group

0, Le(a-b-) secretor individual MAb.Leb reacts with the acinar A non-secretor

(donor

no. 881)

(donor no. 845) stained cells. Bars - 200 tm.

stained

with

MAb-Type

with

1. Some

Downloaded from jhc.sagepub.com at VIRGINIA COMMONWEALTH UNIV on March 13, 2015

(A) MAb.Lea

acinar

cells

and (B) MAbLeb.

are

slightly

MAb-Le8

or moderately

does

stained.

1334

ITO,

, .

.

-nt

OKAMURA,

HIROTA

1%’

=,.

.“-‘

,..

:-..j.

.4 .

..c

.

.,,

-‘

.

-

.

NAKAJIMA,

l.,,t_..

#{149}) ::

#{149}

NISHI,

.

;

‘-

,

: -

.

4H. ,-.

5A

-

.

2.-

f’

‘f ‘

-

_t

I

.

,J

,.

?

:

.

:-

.

a

,-



-,

.

.

,‘4*

..

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#{149}

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...

.

0

d’

.

..-;,a-

‘6B

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.,,-,

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‘#{149}c4

L .1

#{149}‘

Figure 5. Sections of pancreas from a blood group B secretor individual (donor no. 772) stained with (A) MAbLeb and (B) MAbLeb after u-galactosidase digestion. MAbLeb reacts with acinar cells expressing H antigen but not with those expressing B antigen. as shown in Figure 1. After enzyme digestion, MAbLeb reacts with nearly all the acinar cells, including those expressing B antigen. Islet of Langerhans cells (arrowheads) are not stained by MAbLeb before or after enzyme digestion. Bars = 200 rim. 6.

Figure

Sections

tion. Without after enzyme

and

of pancreas

islet of Langerhans stained

by

cells

weakly

with

reacted

not

distribution

Figure

of

homogeneous.

observed

7. Sections

the

acinar

of pancreas

digestion. After Bars = 100 m.

a small

-B, -H,

cells

producing

pattern

of

from

a blood

digestion,

and

(donor

of cells

interlobular

expressing

enzyme

A secretor

number

only

MAb-A,

cells

group

Although

MAb.Leh,

A reverse

between

fucosidase digestion.

=

a blood

only a limited 200 rim.

cells.

ubiquitously

The

from

enzyme treatment, digestion. Bars

duct

antigens

distribution

AB

MAb-Type

and

secretor

with

H antigen

but

not

verse

was

a mosaic

(donor

Leb,

Nearly

and

antigens.

both

Leb

and

cell

u-N-acetylgalactosaminidase

and

their

clusters

cells

diges-

are reactive

Thus,

the

Le’

antigens

cell

distribution

producing

with

MAb-LeY

clusters

express-

(Figures

1A-1C)

was

exactly

the

A or B antigen.

re-

Such

pattern of antigen distribution was observed in all the AB individuals examined, although the number of cells

stained

expressing

of the

after

all the acinar

Le’

produce

of that

no. 848)

(B) MAb-Le

A or B antigen,

A, B, and

with a cell cluster

and

MAb-LeY.

H,

ing

was

those

individual

1 reacts

(A) MAb-LeY

expressing

these

-Le’.

A or B antigen

group

of

with

are reactive

cells were

number

these

antigen

no. 7E) stained

or cell clusters

with

(A) MAb-H,

H antigen.

(B) MAb-Type

No reactivity

with

1, and

MAb-Type

(C) MAb-Type

1 is seen

without

1 after

cz-L-

enzyme

Figure 8. Sections of pancreas from a blood group B secretor (donor no. 944) stained with (A) MAb-Le’ and (B) MAb-Le5 after a-L-fucosidase digestion. No reactivity is seen withoutthe enzyme digestion. After the enzyme digestion, reactivity with MAb-Le’ appears in the supranuclear region of some acinar cells. Bars = 50 tm. Figure

9.

intercalated

Section

duct

of pancreas

cells,

from

a blood

and interlobular

duct

group

cells

B secretor

are reactive

individual

with

Figure 10. Section of pancreas from a blood group A secretor (donor are stained with MAb-Type 1 after enzyme digestion. Bar = 100 tm.

(donor

MAbLex

no. 944) stained

after

enzyme

no. 821) stained

with

with

MAbLex

digestion.

Bar

MAb-Type

1 after

after =

100

neuraminidase

neuraminidase

Downloaded from jhc.sagepub.com at VIRGINIA COMMONWEALTH UNIV on March 13, 2015

digestion.

Centroacinar

cells,

m.

digestion.

Islet cells of Langerhans

BLOOD

GROUP

ANTIGENS

IN

HUMAN

1335

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4 .

.:,

..

ITO,

1336

expressing

H, Leb, and

als. In half

of the

of cells gens,

produced

in others

cells

Leb,

and

and

nearly

LeY antigens

small

among

examined,

in all the

was relatively

0 individuals,

was variable

B individuals

H, Leb,

whereas

ofthese

LeY antigens

A and

not

than

MAb

the number

10%).

cells were

30-50%

In blood

stained

Leb and Ley antigens region of acinar cells,

cated

in the cytoplasm

gens

were

also

with

The expression of the secretor detected

at the

of these antigens status of the tissue

in interlobular

MAb-A,

-B, and

cells from

fine

duct

-H reacted

corresponding

granular

lateral

gen

cells

from

red blood

blood

ABH

anti-

of acinar

cells.

in acinar cells was independent donors; these antigens were not

with group

cells and endothelial Le antigen

from

any

blood

Distribution

Type

Le-’,

Precursor

reacted

dividuals,

with

whereas

a small

number

of acinar

in others

observed. Such individual group ABO and secretor was not detected

with MAbLea tercalated duct

no reactivity

with

variability was not status of the donors.

in acinar

cells,

cells

antibody

or strong

of centroacinar of interlobular

WAS

ever, staining tion with

these

ofSialidase

Sialidase

digestion

in-

nar cells and

was

uals

examined

secretors some

acinar

(Figure

cells from

some

4). In one blood

centroacinar

and

stained by MAb-Type with red blood cells

(Figures

shown).

3A and

MAb-Type

reactivity

tion. ABO

cells, induct cells

elicited reactivity 10). Such effects

non-secretors group

intercalated

but not those

AB, Lu (aduct

3B) and

1 occasionally

cells

react

resulted

cells, intercalated affected by enzyme

reactivity

in slight

fucosidase

acinar

Pre-existing

diges-

and in the perinuclear

after

with

with

sequential

fucosidase MAbLeb appeared

Le antigen not

the reHow-

reactivity

diges-

cells

reactivity

duct cells, digestion.

after with

and

enMAb-

interlobular

Digestion reactivity duct

(Figure

with

cells from

9). In some

cells reacted

cases,

with

MAb-Le’ some only

MAb-Le’

in centroaci-

but not all individa limited after

Such individual variability was not related and secretor status of the donors. Sialidase

number

enzyme

diges-

to the blood group digestion likewise

with MAb-Type 1 in islet ofLangerhans cells (Figure ofsialidase were also observed in a limited numIn one blood

with

MAb-Type

group

0, Le (a-

1 appeared

b

-)

at the surface

secretor,

weak

of most

of the

centroacinar cells and intercalated duct cells after enzyme digestion_ In other individuals, only a small number of these cells were with the MAb results obtained findings

after enzyme in this study

digestion. are summarized

as to the distribution

b-)

individual,

sor chains

(14,15)

moderately

included

in l#{224}ble3.

and

Type

3-based

ofType ABH

in Table

2 and Type

antigens

3.

3 precur-

(17-19)

are also

LeY antigens

in aci-

1. MAbLex, Lea, and -Type 1 did not react and endothelial cells from any blood group

Discussion Although

of a-galactosidase

and

a-N-acetylgalactosaminidase Although producing

Digestion

H, Leb, and Le antigens A or B antigen, prior

a-galactosidase

digestion

both

and

ing

with

not shown).

were

examined.

Effects

anti-

MAb-Type

a-N-acetylgalactos-

cells after

did

revealed

duct

Previous

with

cells

not

with

individuals,

Digestion

intercalated

of intercalated

from

reacted

in acinar (data

other

MAb-H

with

In some

intensity with with MAbLex

(data

Effects

stained The

cells

with

reactivity

in any acinar

cells expressing

digestion

in-

observed

enzymes.

8), MAbLea

MAb-Le

duct

reactivity

the

digestion

weak.

not appear

of acinar (Figure

ber ofindividuals.

o5

Sequential

was usually 1 did

MAb-Type

throughout the glands from all individuals examined (Figures 2A and 2B), except for one blood group 0 and one blood group AB, Lu (a - b - ) secretor individual. In these two cases, Lea antigen could not be detected in any cells, whereas reactivity with MAbLeb and terlobular

the

unmasked

7A-7C).

Lea in centroacinar duct cells was not

related to the blood Although Lea anti-

moderate

observed at the surface cells, and in the cytoplasm

in some

the

reduced

simultaneously

1 (Figures

zyme

1 Chain

MAb-Le’

gen

and

with

aminidase or a-galactosidase and a-L-fucosidase imparted activity with MAb-Type 1 in cells expressing A or B antigen.

tion

group.

ofLe”,

and

region

was usu-

ally detected on red blood cells only from blood group 0 donors, while Leb antigen was not found on red blood cells or endothelial cells

and pattern

Digestion

digestion

reduction of staining Although reactivity

non-secretors.

donors.

ofa-L-fucosidase

a-L-fucosidase

in the were lo-

form.

membrane

intensity

HIROTA

used.

Effects

MAb-H,

were mainly distributed whereas ABH antigens

in a diffuse,

detected

the staining

OKAMURA,

group

and

Usually, perinuclear

did not affect

NAKAJIMA,

A or B anti-

AB individuals

(less

all the acinar

but

enzymes

individu-

about

NISHI,

MAbLeb

A or B antigens

B, or AB individuals

revealed

MAbLey,

or eliminated

or intensified as MAb-H,

(Figures

5 and

6). Red

likewise

reacted with stained

with these only

a-N-acetylgalactosaminidase the reactivity

with

in cells blood

MAb-H enzymes. by MAb-H

cells and

with

producfrom LeY,

A, but

or -B, respectively.

reduced These

of A, B, H, Leb,

appears not to be under the of the Type 1 precursor chain

secretors

suggests

part that

under the fucosylation

chain cells

On the other after enzyme

or a-galactosidase MAb-A

in cells or

the reactivity

as well

not with Leb, after digestion hand, endothelial cells were digestion.

could not be detected a-N-acetylgalactosaminidase

the expression

nar cells presence

that

fucosylation

of the Type

control of the Se gene. of the O-glycosidically

is also under

the

control

and

control of the in non-secretors

of the

Previous linked

Se gene, the but not in

1 chain

may

be in

studies suggested Type 3 precursor

Se gene

in pancreatic

as a regulator

gene

acinar

(17,19). The

Se gene

the expression

has been ofthe

synthesis (41). Recently, model which postulates ent a-2-L-fucosyltransferase. gene expressed mainly

regarded

H gene,

which

codes

controlling

for a-2-L-fucosyltransferase

Oriol et al. (29) proposed a new genetic that the H and Se gene codes for a differAccording to their in tissues of mesodermic

Downloaded from jhc.sagepub.com at VIRGINIA COMMONWEALTH UNIV on March 13, 2015

hypothesis, the H origin encodes an

BLOOD

GROUP

Table

3.

ANTIGENS

Blood

grou

IN

HUMAN

p-related

1337

PANCREAS

antigens

dete

cted

in

human

Acinar cells

Antigen ABH

(Type

pancreas

Centroacinar

t heir

and

distribution”

and

intercalated

duct

Interlobular

cells

duct

cells

+

-

-

I ;- (S),

-

ABH (Type

2)

+

-

-

I

+

(5),

- (NS)

ABH

3)

+

-

-

I

+

(5),

-

-

+

+

-

-1+

-

Lea Leb Le’

Endothelial

cells

-

-

-

+

-

-

-

-

(NS)

1)

(Type

Islet

cells

(NS)

+

+(S),-(NS) -

+(S),-(NS)

-

-

-

-

LeY

+

-

ALeb,BLeb

+

-

-

-

-

ALeY,BLeY

+

-

-

-

-

SialylLea

-

+

-

-

Sialyl-Le’

-

+

-

-

Type

+

I

-

+

-(S),+(NS)

1 PR

Type2PR Type

-

+

-(S),+(NS)

3 PR

-

-

-

+

-

-1+

-

-

-

+

-

Sialyl-Type

1 PR

-

Sialyl-Type

2 PR

-

-

-

+

+

Sialyl-Type

3 PR

+

+

+

+

+

a

S,

b

Positive

secretor;

NS. in

non-secretor;

one

Le(a

a-2-L-fucosyltransferase whereas the Se gene This

cent

different

that

reacts

gene

studies

present

suming

and

that

ferases

are

- I

no.

+

antigens

.

which

previous

both

the H and in acinar

with

(17,19) and

occurs

in the

absence

reacts preferentially with these The expression of Leb antigens

positive

non-secretors

could

the H gene-specified In fact,

also

enzyme

the H gene-specified

the Type

1 and

Type

by as-

H gene-specified

although of these

Se gene-specified

precursors. in acinar

cells

from

by the

presence

1 precursor

a-2-L-fucosyltransferase

Lewisof

can use both

substances

duct

(28).

to be likewise the

Se gene

In these

under (28).

tissues

the control In contrast

cells, the expression dependent on the

the expression

(2,33).

of H antigen

of the products to acinar

cells,

of both

Ex-

the

Se gene-specified

fucosyltransferase

the

al-2

of precursors.

fucosylation

is believed The

the H and

to function

enzymes

In agreement munohistochemical

encoded with

by the previous

studies

(39),

A, B, and lectin

but

not others.

pattern

of distribution

im-

producing

H, Leb,

Ley antigens

suggested

Erythrina

finity

for

Consistent

and

with

LeY antigens

the

in pancreatic

existence

those

acinar

cells

of SBA-reactive

ofSBA

The

2 precursor

which

not

to Type results

with

Gal-

pancreas

3 precursor of the

BLeb,

a high

with

acinar

producing

afcells

A and/or

quite

B

well with

for the a-GalNAc

irrespective

with

we found

has

residues

by SBA (14) but not by ECA.

1 and Type

obtained

which

correspond

except

be attnibuta-

study,

reacted

those

sites ofECA

digestion

ALeY,

(9,40),

can be recognized

appeared

a-galactosidase

(ALeb,

but

SBA may

(ECA),

chain

the binding in human

antigen,

with

In a preliminary

agglutinin

H antigen

In contrast

chain.

cristagalli

Thus,

son chain

the reactivity

2 precursor

Type

producing

ofA

digestion,

Type

prior

chains, secretor

the Type 2 precurstatus

of the

donor.

a-N-acetylgalactosaminidase

suggest

that

BLeY) are produced

difucosyl

A and

in acinan

cells

or B antigens

along

with

the monofucosyl Type 1, Type 2, and Type 3-based A and B antigens. The presence of difucosyl A and B antigens carried by glycosphingolipids definite

(5).

has been However,

information

disclosed Because

(15) and

study.

Let’, and LeY antigens may be regarded but not Lea and Lex antigens, is the

of Leb and

fucosidase to the

intestine

activity of than that

in the present

in cells

studies

that

Se genes.

histochemical

a mosaic

in

appearance

of Lea and Leb antigens in these cells suggests that the the Le gene-specified enzyme is much more prominent of the

duct

to be strictly hence, only

preferential

after

seems

in interlobular

of blood group antigens appears secretor status of the donors and,

precursor

antigens.

chains.

pression of Leb antigen in non-secretors has been reported in unnary epithelium (30), deep glands ofdigestive mucosa (24,35), and sweat

individuals

(1-3,4)-GlcNAc in acinarcells expressing H antigen (14). Because MAb-Type 1 reacted with acinar cells expressing H antigen only ble

enzyme

was observed

Le’ antigen

Previous

a-2-L-fucosyltransthe

as acceptor

some

and the coexpression ofH, as evidence that H antigen, (26,41).

can use Type

2 precursors

of cells from

antigens

Lea and

direct

be explained

be explained

that

1

can

that

of the

number

these results, the pattern of distribution of Leb and LeY antigen is likewise the reverse of that of A or B antigen. The absence of

in different tissues gene model, the results

Se gene-specified cells

in a small

of ABH

by releast two

enzyme can use the Type 1 and Type 3 precursor chains, its affinity for these precursors is low and the accumulation that

detected

were

the Type

has been supported the presence ofat

showed

studies

expressed

precursors

+

853).

preferentially

model

types of a-2-L-fucosyltransferase On the basis ofthis two-structure

(2,23,25).

ofthe

chain;

(donor

I

reacting preferentially with Type 2 chains, expressed in epithelial tissues encodes a different

two-structure

biochemical

precursor

b - ) individual

-

a-2-L-fucosyltransferase chain.

PR.

-

about

by the the

that

present

the ALeb

and

the

tissue

histochemical once

transferase

BLeb structures

Downloaded from jhc.sagepub.com at VIRGINIA COMMONWEALTH UNIV on March 13, 2015

in human

biochemical

Leb structure,

the A or B gene-specified that

reported

pancreas

study origin

could of these

and small not

provide

antigens,

as

an acceptor

for

study. formed, (22,34),

is not

it has been

are constructed

presumed

by the fucosyla-

1338

ITO,

lion

ofthe

C-4 position

gen (41). The

ofGlcNAc

process

ofthe

is catalized

1-based

A or B anti-

by a-4-L-fucosyltransferase

Type

coded

antigen

appear

not

ing is in contrast

NISHI,

NAKAJIMA,

to be hydrolyzed

to the fact

OKAMURA,

HIROTA

by the fucosidase.

that

Fuc residues

This

of Type

find-

1, 2 H anti-

by the Le gene. A similar mechanism may be operating in the synthesis of ALey and BLeY structures (26). In this case, it is presumed

gens and Le antigen are hydrolyzed by the enzyme in histochemical systems as disclosed in the present study as well as a previous

that

one

Type

2-based

fucosylated

A or B antigens

the ALeX and A or B antigen

and

were

not

sized

in the manner

detected,

the Type

1 and

precursor

because these

ture

and

difucosyl

and

then

by the X gene

cells

may

(41) and Lloyd

A or B antigen

may

are

to give

serve

be synthe-

digestion

the biochemical

is compatible

expressing

with

their

LeY antigen

substrates

systems,

and

Le or X gene

struc-

acceptor

can

a-4-Luse

substrates

Type

in these

1 and

cells.

the presence of sialylated Lea antigen tnoacinar and ductular cells.

Table

4.

Chemical

Precursor

structures

terminal

of

blood

of Lea and Le’ an(1). In the present

Fuc residues

group-related

of the

antigens

the

Leb

found

wA

observed

whether present

Because

in

human

Uchida

the Le (a

-

b

et al. (39)

-

coded

2 precursor

strong

and

reactivity

Itai

by the

chains with

as

MAb-

et al. (13) reported

on the

) individual

membrane

is presumed

of cen-

to lack

the

Le

(Type

2)

(Type

2)

pancreas Gal31-3GlcNAc-

(Type

1). Gal31-4GlcNAc3-

Ga131-3GalNAcal-Ser/Thr H antigen

beprevi-

sialidase digestion, it is difficult to ascerLea antigen is produced in these cells in

without

sialylated study.

Type

Because

antigenic structures, tigen are only slowly

however,

different

as reported

or a-3-L-fucosyltransferase

the

tam

systems,

the Fuc residues

is somewhat

histochemical

Lea

whereas those by the enzyme

used

their

and

in this

respectively, hydrolyzed

of the fucosidase

to hydrolyze

to the stenic effect of al-4 Fuc It is notable that the ability

ously (14,16,18). The preferential expression of Lea, x and their sialylated forms in centroacinar cells and intercalated duct cells means that only

Thus,

as the direct

chemical

enzyme

study. In biochemical systems, the Fuc residues of both Lob and Ley antigens are hydrolyzed by the fucosidase, yielding Lea and Le’

histochemical

specificity

to attack

sialyltransferase

in cells

ofthe

be attributable of Leb antigen.

biochemical

tween

A or B antigen. of Lex antigen

inability

of the enzymes

Le antigens (26).

(18). The

ofLeb antigen may residues on GIcNAc

of difucosyl monofucosyl

Leb and

determinants

by Watkins

Type 2-based

appearance

fucosidase

in these

proposed

of difucosyl

after

produced

coded

BLeY structures. Because the expression is strictly confined to cells producing

A or B antigen,

The

are first

by cz-3-L-fucosyltransferase

(Type

Gal3l.-3GlcNAc3-

(Type

Gall31-4GlcNAc3-

1),

1-2

1-2

Fuca Gal3

3)

Fuccz I

-3GalNAca

1 -Ser/Thr

(Type

3)

1-2

Fuca A(B) antigen

GaINAc(Gal)ct

1 -3Gal

1-3GIcN

Ac

(Type

I)

(Type

2)

1-2

Fucts GaINAc(Gal)a

I -3Gal3

1 -4GIcNA4I 1-2

Fuca GalNAc(Gal)a

1-3Gal

1-3GalNAca I -2

Fuca

Le4 antigen

Gal

I -3GlcNAcl1-4 Fuca

Leb antigen

Ga113 1 -3GlcNAcl1-2

Fuca A(B)Leb

antigen

GaINAc(Gal)a

1 -3Gal

l-3GlcNAc1-2

Fucct Le” antigen

1-4

Fuca

Gal5

1-4

Fucci I -4GlcNAc1-3

Fucu

Le antigen

Gal3

l-4GlcNAc31-2

Fuc

A(B)LeY antigen

GalNAc(Gal)a

1-3Gal3

1-4GlcNAc31-2

Fuca

Downloaded from jhc.sagepub.com at VIRGINIA COMMONWEALTH UNIV on March 13, 2015

1-3

Fuc 1-3

Fucci

1 -Ser/The

(Type

3)

BLOOD

GROUP

:

ANTIGENS

Centroacinar

and duct

HUMAN

IN

-

intercalated

cell

- --

.

i-

-

A(type

1-

Le,

.X.?ee

Precu,so,

-

precursor

(type

Langerhans

1,

,/Le

-

Lea

-

1.

type

1,

Literature

group-related in Table

antigens

found

in human

4.

1.

type

2)-it.Leb.

jB

2(

B(type

1.

Le’

K, McKibbinJM,

2. Betteridge A, Watkins a-2-L-fucosyltransferase 13:1126, 1985

gene

type

Cited

Hakomori 5: The monoclonal antibody to difucosylated type 2 chain (Fuca1-2Gal1-3[Fuca1-3]GlcNAc; determinant). J Biol Chem 258:11793, 1983

1. Abe

gene

gene

type

of blood

are presented

ALeS’

;

7(

jSe

H(type

l)-,I.ALCb.

IA gene Se

..__...H(type

gene

type

J

H,

structures

Le,xgene

Le

.

Sialylated

ical

pancreas

.

H LCa.

1339

PANCREAS

2)BLeb.

directed Y

WM: Acceptor substrate specificities from different tissues. Biochem

of human

Soc Trans

BLe

3. Bj#{246}rk S, Breimer jLe.

Leb.

11. Proposed

in different

cell

-

4.

duct

scheme

types

gene

Le’

(nter(obu(ar

Figure

X

ME, Hansson GC, Karlsson K-A, Leffler H: Structunes of blood group glycosphingolipids of human small intestine. A relationship between the expression offucolipids ofepithelial cells and ABO, Le and Se phenotype ofthe donor.) Biol Chem 262:6758, 1987

cell

for the biosynthesis

of human

pancreas.

of blood-group

In centroacinar

and

ABH antigens intercalated

duct

cells and interlobular duct cells, Type 2-based Le#{176} and Le antigens are minor components or not expressed, whereas Type 1-based Lea and Leb antigens are consistently expressed. Le#{176} antigen is usually detected in its sialylated form in centroacinar

gene

and

and

fails

Lea antigen

cult

form

with

blood

the

presence

of Leb in urinary

of an

Orntoft

with

a-4-L-fucsyltransferase

individual,

that

the

and

antigens,

such

reported

the

urothelium

Lewis

type

8. Cordon-Cardo

C, Lloyde

9.

Dc Boeck

H, Loontiens

10.

of an of erythro-

12. Franqois B, Oriol

Sialylated

rule

out

not correspond

Type

1 precursor

of Langerhans

cells

from

the possibility to that chains

some

that

the Lewis

ofpancreatic

are likewise

individuals.

type

acinar detected

Sialidase

cells.

digestion soybean obsenva-

tions).

recognize

3 precur-

Because

these

lectins

the Type

2 or Type

tic forms by sialylation. The results obtained in the present distribution pattern of blood group human differences

pancreas.

Such

complexity

in the individual

expression ofdifferent cell types. The ways of blood group-related antigens pression

in different

cell types

may

largely and

that complex

14.

the in

be explained

in the pattern

by

of gene

proposed biosynthetic pathand the patterns of gene cx-

are illustrated

in Figure

11. The

them-

in

individu-

Finstad

CL,

McGroarty

ME,

Reuter

VE,

FG, Lis H, Sharon

N: Binding

ofsimple

carbo-

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mdi-

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Itai 5, Arii

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Y, Yamabe

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hara Y, Shigeta K, Kannagi R: Significance of 2-3 and of Lewis a antigen in pancreas cancer. Cancer 61:775,

chains, i.e., to their cryp-

study demonstrate antigens is very

genotypes

Vox Sang 13.

cells with peanut agglutinin, and Ito et aL, unpublished

son chain (9,16,17), three different types of precursor Type 1, 2, and 3 chains, are produced and converted

reaction

in islet

elicited the reactivity ofislet agglutinin, and ECA (14,40;

B human

Ernst C, Thurin J, Atkinson B, Wurzel H, Herlyn M, Stromberg N, Civin C, Koprowski H: Monoclonal antibody localization of A and B isoantigens in normal and malignant fixed human tissues. Am) Pathol 117:451, 1984

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group 1984

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its

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has been (3), and red

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in the

suggesting

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Recently,

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it is diffi-

in acinar

occurrence

of

and

cells

However,

antigen

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(6,12,24).

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chain

duct

) individuals.

-

an unexpected

to crossreactions

Le (a-b-)

b

-

1 precursor

individual.

of Leb

Le (a

the

intercalated

antigen in Le (a-b-) epithelium (30), small

Such

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presence

of Type and

of this

cells from

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be due as Le

presence

the genotype

duct

occurrence reported

the

a-4-L-fucosyltransfenase,

in centroacinar

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terlobular

cells.

to produce and

sialylated

patible

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ofsome

human

blood

groups.

Histochemical localization and analysis of blood group-related antigens in human pancreas using immunostaining with monoclonal antibodies and exoglycosidase digestion.

We examined the distribution of blood group-related antigens using an indirect immunoperoxidase method with monoclonal antibodies (MAb) directed to A,...
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