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Histocompatibility Antigens in Patients with Leprosy

Author(s): Thomas H. Rea, Norman E. Levan, Paul I. Terasaki


Source: The Journal of Infectious Diseases, Vol. 134, No. 6 (Dec., 1976), pp. 615-618
Published by: Oxford University Press
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THE
JOURNAL
OF INFECTIOUS DISEASES * VOL. 134, NO. 6 * December 1976
c 1976 by
the
University
of
Chicago.
All rights reserved.
Histocompatibility Antigens
in Patients with
Leprosy
Thomas H.
Rea,
Norman E.
Levan,
and Paul I. Terasaki
From the Section
of Dermatology, Department of
Medicine, University of
Southern
California
School
of
Medicine; the
Department of Dermatology,
Los
Angeles
County-University of
Southern
California Medical
Center; and the
Department of Surgery, University of
California
School
of Medicine, Los
Angeles, California
The
frequencies
of distribution of 25
histocompatibility antigens
were determined
in 92 Mexican
patients
with
leprosy
and
compared
with those in 315 Mexicans who
did not have the disease. No
statistically significant
differences were found between
the
patients
and the controls in
regard
to
histocompatibility antigens,
and
subgroups
with a
significant
difference could not be identified
by
division of the
patients
accord-
ing
to the
density
of
Mycobacterium leprae
or the
presence
or absence of cell-medi-
ated
immunity
directed
against antigens
of M.
leprae.
Genetic factors are considered to be
important
in
leprosy
and influence both
susceptibility
to
the
disease
and its mode of
expression [1].
Im-
munologic
factors are also considered
impor-
tant in
leprosy;
observations of
impaired
cell-me-
diated
immunity
can be
interpreted
as
signifying
that immune
responses
determine
susceptibility
and mode of
expression [2].
These
immunologic
factors
may
be
genetic,
and there is
increasing
evidence that
specific
immune
response (Ir)
genes
control
responses
critical for
susceptibility
to disease and that these
Ir
genes
are associated
with the
major histocompatibility system,
HL-A
[3].
Several diverse diseases
already
have been
shown to be associated with HL-A
antigens [3].
Some of these diseases are
clearly genetic,
such
as
psoriasis [4],
and others are associated with
characteristic
immunologic responses,
such as
dermatitis
herpetiformis [5].
It is
logical
that HL-
A associations with
leprosy
have been
sought.
Such searches are based on the
hypothesis
that
susceptibility
to
leprosy (and/or
its mode of
expression)
is determined
by
an
immunologic
response (or
lack
thereof) directly regulated by
Received
for
publication
March
8, 1976, and in revised
fornm
June
8, 1976.
Access to the
patients
of the U.S. Public Health Service
Clinic in San Pedro, California was
graciously provided
by
Drs. Charles Buhrow,
Margaret
Storkan, and Carl Korn.
Please address
requests
for
reprints
to Dr. Thomas H.
Rea, Department
of
Dermatology,
Los
Angeles County-
University
of
Southern California Medical
Center, 1200
North State Street, Los
Angeles,
California 90033.
an Ir
gene.
The
finding
of a
statistically signifi-
cant difference in the distribution of HL-A anti-
gens
between
patients
and controls would be evi-
dence
supporting
the Ir
gene hypothesis
in sus-
ceptibility
to
leprosy.
This
paper
is a
report
of a
study
of HL-A anti-
gens
in
Mexican-born
patients
with
leprosy.
Materials and Methods
All 92
patients
with
leprosy
were born in Mexico
or were of bilateral Mexican descent. The
diag-
nosis of
leprosy
was confirmed
histologically
in
each case.
Forty-four patients
were from the Los
Angeles County-University
of Southern Califor-
nia Medical
Center; 41 from the U.S. Public
Health Service Clinic in San
Pedro, Calif.;
two
from the
private practice
of Dr. Ronald Smits in
Los
Angeles,
Calif.;
and five from the
private
practice
of one of us
(N.E.L.).
Blood relatives
were not included in the
study.
Controls were
315 individuals from Mexico or of Mexican ances-
try.
For classification the
seven-group system
of
Ridley
and Waters
[6]
was
used,
and individual
classifications were made on the basis of clinical
manifestations and
biopsy
index:
TT,
polar
tu-
berculoid; TI,
subpolar
tuberculoid; BT,
border-
line with tuberculoid features; BB, borderline;
BL, borderline with
lepromatous
features; LI,
subpolar lepromatous;
LL,
polar lepromatous.
Three
groupings
were made for
analysis
of the
data. In the first
grouping
controls were com-
pared
with all
patients
with
leprosy.
In the sec-
615
616
Rea, Levan,
and Terasaki
ond
grouping
controls were
compared
with
pa-
tients with
many
bacilli
(one
or more
per
10 oil-
emersion fields of a
histologic
slide from involved
skin,
BB-LL)
and with
patients
with few bacilli
(less
than one
per
10 oil-emersion
fields,
TT-BT).
In the third
grouping
controls were
compared
with
patients having
some cell-mediated
immunity
to
Mycobacterium leprae (TT-LI)
and with
pa-
tients
having
no cell-mediated
immunity
to M.
leprae (LL),
as inferred from classification accord-
ing
to the
system
of
Ridley
and Waters
[6].
HL-A
antigens
were identified
by
the
microlym-
phocytotoxic technique
as
previously
described
[7].
Our results are recorded to conform to re-
cently adopted
nomenclature
[8].
The results
from other studies cited are recorded as
pub-
lished.
Results
The distribution of HL-A
antigens
is summar-
ized
in table 1.
Using
a
x2
test with Yates' correc-
tion, we obtained an uncorrected P value of
<0.05 under the
following
circumstances: HLA-
B13
is more
frequent
in LL and LL-BB
pa-
tients than in
controls;
W16 is more
frequent
in
LI-TT
patients
than in
controls; HLA-BW21
is
less
frequent
in all
leprosy patients
than in con-
trols. These differences are not
statistically sig-
nificant when the P value is
multiplied by
25,
the number of
specificities
tested.
Discussion
In
previous
studies of HL-A
antigens,
summarized
in table
2,
Escobar-Gutierrez et al.
[9]
found a
Table 1.
Frequencies
of the distribution of 25
histocompatibility antigens (HL-A)
in 92 Mexican
patients
with
leprosy
and in 315 Mexicans who did not have
leprosy (controls).
All
leprosy
LL-BB BT-TT LL LI-TT
HL-A
(old nomenclature) patients (92) patients (82) patients (10) patients (72) patients (20)
Controls
HLA-A1 (HL-A1)
13 15 0 17 0 16
HLA-A2
(HL-A2)
54 56 40 54 55 48
HLA-A3
(HL-A3)
14 13 20 15 10 13
HLA-AW23
(W23)
3 4 0 3 5
6
HLA-AW24
(W24)
23 23 20 22 25 22
HLA-A10 (HL-A10)
9 6 30 4 25 12
HLA-All
(HL-A11)
15 15 20 15 15 12
HLA-A28
(W28)
15 13 30 15 15 16
HLA-A29
(W29)
7 7 0 8 0
9
HLA-AW30
(W30)
24 26 10 25 20 19
HLA-AW32
(W32)
3 2 10 1 10 4
HLA-B5
(HL-A5)
15 16 10 17 10 15
HLA-B7
(HL-A7)
9 9 10 10 5 15
HLA-B8
(HL-A8)
5 6 0 7 0
8
HLA-B12
(HL-A12)
23 26 0 25 15 24
HLA-B13
(HL-A13)
5 6* 0 6* 5
1
HLA-BW35
(W5, Te50)
34 35 20 32 40 30
HLA-BW22
(W22)
5 5
10 4 10 5
HLA-B27
(W27)
1 1 0 1 0 5
HLA-B14 (W14)
14 12 30 11 25 13
HLA-BW15 (W15)
5 5 10 6 5 7
HLA-B18 (W18)
3 4 0 3 5 9
HLA-BW40
(W10, Te60)
15 15 20 15 15 14
W16 24 21 40 19 35* 15
HLA-BW21
(W21)
3* 4 0 4 0 11
NOTE. LL-BB
=
polar lepromatous, borderline;
BT-TT
=
borderline with tuberculoid
features, polar tuberculoid;
LL
=
polar
lepromatous;
and LI-TT
=
subpolar lepromatous, polar
tuberculoid. LL-BB patients were considered to have many bacilli and
BT-TT to have few. LL
patients"
were considered to have no cell-mediated
immunity
to
Mycobacterium leprae
and LI-TT were
considered to have some cell-mediated
immunity (see
Materials and
Methods).
Numbers in
parentheses
are numbers of
patients.
*P
<0.05
(uncorrected).
Histocompatibility Antigens
in
Leprosy
617
Table 2.
Summary
of studies of
typing
of
histocompatibility antigens (HL-A)
in
patients
with
leprosy.
No. of
No. of
specifi-
No. of con- cities Ethnic
Study patients
trols tested
group
studied
Findings
Escobar-Gutidrrez
et al.
[9]
50 200 7 Mexican
(mestizo)
Low HL-A2 and low HL-A3
Thorsby
et al.
[2]
39 36 27
Ethiopian (Amharas) Significantly
increased W21 in all but LL*
patients
Smith et al.
[10]
82 50 28
Filipino
No differences
Reis et al.
[
1I]
26 32 23 Brazilian No differences
Kreisler et al.
[12]
30 149 21
Spanish (Caucasian) Significantly
increased HL-A14
especially
in
lepromatous patients
Dasgupta
et al.
[13]
70 40 11 Indian HL-A9
insignificantly
decreased in
nonlepromatous,
and HL-A8
insignificantly
increased in
lepro-
matous
subjects
Present
study
92 315 25 Mexican No differences
*LL =
polar lepromatous.
decrease in
frequency
of HL-A2 and HL-A3 when
50 Mexican
patients
and 200 controls were com-
pared
in a
study
of seven HL-A
antigens;
these
investigators
stated that technical difficulties with
behavior of
lymphocytes
from some
patients
with
leprosy
diminished the forcefulness of their find-
ings.
Thorsby
et al.
[2]
examined 39
patients
and 36
ethnically
similar,
normal individuals from Ethi-
opia
for the
presence
of 27
antigens. (These
au-
thors
used
histologic
criteria in
defining
their LL
category
which made it a more uniform
group
than
ours,
as ours
undoubtedly
contained
pa-
tients who would be
histologically
classed as
LI;
however,
their tuberculoid
group
was
probably
similar to our BT-TT
group.)
In
patients
classed
as tuberculoid and "LL
+
LI," Thorsby
et al.
[2]
found a
statistically significant
increase in the
frequency
of
antigen cW21,
which was absent in
LL
patients
and controls.
Smith et al.
[10]
examined 82
Filipino patients
and
50
Filipino
controls for the
presence
of 28
antigens
and found no
statistically significant
dif-
ferences in the distributions of
antigens.
These
authors made a distinction between tuberculoid
(TT-BT)
and
lepromatous (BL-LL)
conditions
that was similar to our distinction between few
and
many
bacilli.
Antigen
W21 was
normally
dis-
tributed.
Reis et al.
[11]
examined 26
patients
and
32
ethnically
matched individuals
(presumably
Bra-
zilian)
for the
presence
of 23
antigens
and found
no
statistically significant
differences in
antigen
distribution. Their distinction between
leproma-
tous and tuberculoid
patients
was made without
explicit
criteria; these criteria were
presumably
similar to those used to make our distinction be-
tween few and
many
bacilli.
They
did not state
whether the W21
antigen
was
sought.
Kreisler et al.
[12],
who studied
Spaniards,
found that 30
patients
with
leprosy
had a
signifi-
cantly higher
incidence of
HL-A14
than did 149
controls. In this series the
high
incidence of this
antigen
was
particularly
evident in the 17 Mit-
suda-negative patients.
Dasgupta
et al.
[13] sought
11
antigens
in 70
patients
and 40 controls in India.
Using
criteria
similar to
ours,
they
found a
statistically insig-
nificant, increased
frequency
of HL-A8 in 40
lepromatous subjects
and a
statistically insignifi-
cant,
decreased
frequency
of HL-A9 in 30 non-
lepromatous subjects.
The
"significant" findings
in the studies de-
scribed
are not uniform. The tentative
findings
of
Escobar-Gutierrez
et al.
[9] concerning
HL-A2
and HL-A3 have not been confirmed in
any
other
study, including
ours. The
statistically significant
distribution of W21 found
by Thorsby
et al.
[2]
was not confirmed
by
Smith et al.
[10],
Kreisler et
al.
[12],
or us. The
high
incidence of
HL-A14
noted
by
Kreisler et al.
[12]
has not been found
by
any
other
investigators.
Similarly,
our own
suggestive findings
have not
been confirmed
by
others. HLA-B13,
perhaps
in-
618
Rea, Levan,
and Terasaki
creased in our LL and LL-BB
groups,
was absent
in the
lepromatous patients
examined
by
Thors-
by
et al.
[2]
and Smith et al.
[10]
and
present
in
normal
frequency
in the studies of Kreisler et al.
[12]
and
Dasgupta
et al.
[13].
The distribution of
W16,
perhaps
increased in our LI-TT
group,
was
similar in
patients
and controls in the studies of
Thorsby
et al.
[2]
and Smith et al.
[10].
HLA-
BW21,
perhaps
increased in all
patients
with
leprosy
but absent in the LI-TT and BT-TT
groups,
was
present
in increased
frequency
in the
tuberculoid
patients reported by Thorsby
et al.
[2]
and in normal
frequency
in the
patients
re-
ported by
Smith et al.
[10]
and Kreisler et al.
[12].
Including
the
present paper,
seven studies of
HL-A
frequencies
in
leprosy
have been
reported.
In three of these studies
[10, 11],
no differences
were found;
in two
[9, 13] equivocal
differences
were found,
and in two other studies
[2, 12]
sta-
tistically significant
differences were found. Can
these diverse results be reconciled? The
"signifi-
cant"
findings
of
Thorsby
et al.
[2]
and Kreisler et
al.
[12]
cannot be dismissed
easily
as a chance mat-
ter,
but the seven studies
collectively provide
no evidence that a
single
HL-A
antigen
is asso-
ciated with
susceptibility
to
leprosy
or with a
par-
ticular clinical
expression
of
leprosy.
It is
possi-
ble that,
within
particular
ethnic
groups,
a
par-
ticular HL-A
antigen
is associated with a
particu-
lar clinical
expression
of
leprosy; alternatively,
the differences
among
these seven studies
may
be
attributable to chance variations in
sampling.
References
I.
Spickett,
S. G. Genetic mechanisms in
leprosy.
In R. G.
Cochrane and T. F.
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theory
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practice.
2nd ed. Williams and Wilkins, Balti-
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p.
98-124.
2.
Thorsby,
E., Godal, T.,
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and
susceptibility
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