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Neonatal lupus erythematosusHaplotypic analysis of HLA class II alleles in childmother pairs.

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Neonatal lupus erythematosus: haplotypic analysis of
HLA class I1 alleles in child/mother pairs
The syndrome of neonatal lupus erythematosus (NLE)
is an uncommon disease of neonates and is characterized by
isolated congenital heart block (CHB), cutaneous lupus
lesions, or both (1). Babies with NLE have maternal autoantibodies against Ro/SS-A and/or La/SS-B (1,2). Although
previous immunogenetic studies have suggested that the frequencies of HLA-DR3 and DQ2 were increased among
mothers of NLE infants in white and North American black
populations (1,3), and a few investigators have questioned
whether fetal HLA antigens are contributory, no prior study
has addressed whether the maternal-fetal HLA relationship
affects the immunopathogenesis of NLE. We report herein the
results of a haplotypic analysis of HLA-DR, DQ, and DP
alleles in Japanese NLE child/mother pairs.
The subjects in this study consisted of 16 Japanese
children with NLE, 5 asymptomatic siblings, and their 13
mothers. The mothers were unrelated, and had been documented to be positive for anti-F.o/SS-A and/or anti-La/SS-B
during the perinatal period or before delivery of the affected
infants. The 16 children with NLE included 7 with isolated
CHB, 7 with only cutaneous lesions during the neonatal
period, and 2 with both symptoms.
Methods for antibody studies as well as HLA class I1
genotyping using polymerase chain reaction-restriction fragment length polymorphism have been described previously (4).
Normal controls for HLA typing consisted of 916 unrelated
race-matched subjects (5). DRBl/DQAl/DQBl haplotypes
were assigned on the basis of known linkage disequilibria in
Japanese subjects ( 5 ) along with data obtained in this study of
childimother pairs. Fisher’s exact test was used for statistical
Results of the haplotypic analysis in the 9 children with
CHB, their mothers, and their unaffected siblings are summarized in Table 1. Four of the 9 children with CHB (patients 4-1,
6, 7, and 8) had 2 heterozygous HLA-DRBl/DQAl/DQBl
haplotypes, both of which were identical to those of the
mothers, while none of the 12 children without CHB showed
such findings. The difference was significant by Fisher’s exact
test (P < 0.02). In this study, however, the results may be
subject to Type I error since the sample size was small; studies
with larger samples may not substantiate the difference between affected and unaffected children. Furthermore, a true
comparison with mothedchild pairs in the general Japanese
population is not possible at this time since the data are not
DQB1*0602 and DRB1*1101/DQA1*0501/DQB1*0301were
shown in 4 and 3 of the 13 mothers, respectively (both were
found in 4 of the 26 chromosomes tested). These haplotype
frequencies were significantly higher than those in the Japanese control population (5). The frequency of DRB1*0405linked haplotypes was higher in the mothers than in controls.
However, the difference failed to reach statistical significance.
The mothers had neither HLA-DR3 nor DQ2 alleles, which
are reportedly associated with NLE among whites and North
American blacks (1,3) but are extremely rare in Japanese
populations. We were unable to show an association of DPBl
alleles with NLE. The maternal-fetal haplotypic sharing did
not extend to HLA-DPBl alleles.
The transplacental immunologic characteristics of the
NLE syndrome have been well established (6). The transient
skin lesions and cytopenia reflect the effect of passively
acquired antibodies on those organ systems. CHB is irreversible due to fibrosis of the fetal cardiac conduction system (7).
Maternal anti-Ro/SS-A and anti-La/SS-B antibodies cross the
placenta and react with the fetal cardiac tissue. Immunofluorescence staining of hearts from fetuses that died of CHB has
suggested that CHB is mediated through a fetal immune
inflammatory response, provoked by binding of the maternal
antibodies to the fetal cardiac conduction system (8,9).
However, anti-Ro/SS-A or anti-La/SS-B positive
mothers of affected infants can also give birth to disease-free
infants, as exemplified in some of our patients. Maternal
antibody profiles were similar between affected and unaffected
infants, suggesting that antibody passage to the fetus by itself is
not sufficient to cause CHB (10). Clearly, if anti-Ro/SS-A
andlor anti-La/SS-B antibodies are involved, the mechanism is
complex and more than the existence of the antibodies is
required to cause disease.
Possible molecular mechanisms by which the
maternal-fetal HLA relationship might be involved in the
pathogenesis of NLE remain unclear at present. However,
identity or similarity of HLA class I1 molecules between
Table 1. HLA-DRBlIDQAlIDQBl haplotypes in children with congenital heart block (CHB), their unaffected siblings, and their mothers
4- 1
14 years
13 years
11 years
9 years
8 years
7 years
Skin lesions
CHB, skin lesions
CHB, skin lesions
3 years
1 year
13 years
11 years
11 years
4 years
4 months
13 years
10 years
14031050310301, 150110102/0602
14031050310301, 15011010210602
04051030110302, 040510302/0401
04051030210401, 16021010210602
0405/0302/0401, 13011010310603
040510302/0401, 1301/010310603
Not examined
0405/0302/0401, 15011010210602
15011010210602, 1501/010210602
0803210103/0601, 04051030210401
04051030210401, 090110302/0303
0405/0302/0401, 15011010210602
09011030210303, 15011010210602
08021030110302, 1202/060110301
Not examined
080321010310601, 15011010210602
0803210103/0601, 09011030210303
15011010210602, 15021010310601
040510301/0302, 16021010210602
0405/0302/0401, 080321010310601
0405/0302/0401, 15011010210602
0803210103/0601, 14061050310301
04051030210401, 09011030210303
0405/0302/0401, 15011010210602
09011030210303, 15011010210602
04051030210401, 08021030110302
080321010310601, 080321010310601
* Third child born to mother 3; died of heart failure at age 3 years, despite implantation of pacemaker.
t First child born to mother
10; died of heart failure at age 2 months, despite implantation of pacemaker.
mother and fetus might play a role in the inflammatory process
in the fetus, which is currently presumed to be secondary to
placentally transferred maternal antibodies. Regarding the
involvement of the HLA relationship between mother and
fetus in other diseases, Nelson et a1 (11) suggested the
importance of maternal-fetal disparity of HLA-DR and DQ
antigens in the pregnancy-induced remission of rheumatoid
In summary, 2 heterozygous HLA-DRBlIDQAlI
DQBl haplotypes, both of which were identical to those of
mothers, in addition to placentally transmitted maternal antibodies, could account for 44% of the CHB cases in this study
(4 of 9 patients). These findings suggest that the relationship
between fetal and maternal DRBl/DQAl/DQBl genotypes
might be important in the immunopathogenesis of CHB in
NLE. It is hoped that this report will prompt further investigations into the mechanisms that induce CHB as well as other
manifestations of NLE.
Sachiko Miyagawa, MD
Takaya Fukumoto, MD
Kazuko Hashimoto, MD
Akira Yoshioka, MD
Toshihiko Shirai, MD
Nara Medical University
Nara, Japan
Koji Shinohara, MD
Kin-Ichi Kidoguchi, MD
Tomio Fujita, MD
Osaka Medical Center and Research Institute for Maternal
and Child Health
Osaka, Japan
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and the pregnancy-induced amelioration of rheumatoid arthritis.
N Engl J Med 329:466-471, 1993
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class, lupus, allele, hla, pairs, analysis, neonatal, childmother, erythematosushaplotypic
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