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Institute of Diabetes Research (H.E.N.) and Institute of Diabetes Research and Academic Hospital Schwabing (A.-G.Z.), D-80804 Munich, Germany; and Istituto Scientifico San Raffaele (E.B.), I-20732 Milan, Italy
Address all correspondence and requests for reprints to: Prof. Dr. Anette-G. Ziegler, Institut für Diabetesforschung, Kölner Platz 1, D-80804 Munich, Germany. E-mail: anziegler{at}lrz.uni-muenchen.de
Abstract
Accurate assessment of type 1 diabetes risk in young children requires discrimination between antibodies that are produced by the child and antibodies acquired through the placenta from an islet antibody-positive mother. We studied 682 offspring from mothers with type 1 diabetes and 329 offspring from fathers with type 1 diabetes and nondiabetic mothers for insulin (auto)antibodies, glutamic acid decarboxylase antibodies, and tyrosine phosphatase IA-2 antibodies before age 1 yr and again at age 2 yr to ascertain transience or persistence. Antibodies were detected at age 9 months in 5 (1.5%) offspring from fathers with type 1 diabetes; all were insulin (auto)antibodies only, all persisted and developed multiple antibodies, and 1 developed type 1 diabetes. In contrast, 31 (4.5%) offspring from mothers with type 1 diabetes had antibodies at 9 months; 12 (1.8%) persisted at age 2 yr, and 19 (2.8%) did not persist, suggestive of transient residual maternal antibodies. Multiple antibodies at 9 months were usually persistent (3 of 4 offspring), as were single insulin (auto)antibodies in offspring from mothers with type 1 diabetes (8 of 13 offspring), whereas persistent glutamic acid decarboxylase antibodies (1 of 12) and tyrosine phosphatase IA-2 antibodies (0 of 2) were rare. Offspring with persistent antibodies at age 9 months had a high type 1 diabetes risk (100% by age 5 yr for those with multiple antibodies and 27% for single antibodies at 9 months), whereas offspring with transient antibodies had 0% type 1 diabetes risk (P < 0.01). Transience was associated with very high antibody levels at birth. For insulin (auto)antibodies, the measurement of subclass was also informative. Residual maternal antibody was indicated by similar insulin (auto)antibodies subclasses at 9 months and at birth, whereas different subclasses were indicative of nonmaternal antibody. Moreover, the presence of IgG1-insulin (auto)antibodies was associated with antibody persistence and type 1 diabetes risk. These strategies are helpful in discriminating high and low risk antibodies before age 1 yr and should be important for prognosis and reducing unnecessary parent anxiety.
ISLET AUTOANTIBODIES ARE important markers of preclinical type 1 diabetes (T1D) (1, 2, 3, 4). Recently they have been used in prospective studies from birth to determine when islet autoimmunity commences, whether prenatal islet autoimmunity exists, and whether one primary target autoantigen of T1D can be identified (5, 6, 7, 8, 9). These questions are relevant for our understanding of the pathogenesis of the disease and for the design of early intervention trials.
Most screening programs performed in very young cohorts include a substantial proportion of children from parents with T1D. In offspring from mothers with diabetes we and others have shown that antibodies from the mother are transmitted through the placenta to the child and persist in the circulation of the child for several months (8, 10, 11, 12). As a consequence it may be problematic to define whether an antibody detected in such a child early in life is indeed a de novo-produced antibody of the child or rather an antibody acquired from the mother (5). This distinction is clearly important when determining the appearance of antibodies and for the correct assignment of risk to children. In the present study we aimed to define how long maternally derived antibodies can persist in the circulation and whether there are antibody characteristics that can be used to distinguish between maternal antibodies and those from the child. To do this we took advantage of the BABYDIAB study, which follows offspring from mothers and fathers with T1D from birth with sequential blood samples at 9 months and 2, 5, 8, and 11 yr of age, and a related study in which relatives are included within the first year of life. We were able to compare autoantibody prevalence in the first year of life in offspring who had a mother with T1D and those who did not. Persistence of antibodies could then be determined through prospective follow-up of all offspring, and the antibody characteristics between maternal antibody and persistent offspring antibody compared. We found that maternally acquired antibodies can persist for at least 9 months after birth in offspring of mothers with T1D. Whereas insulin (auto)antibodies [IA(A)] at 9 months were usually nonmaternally acquired, glutamic acid decarboxylase (GAD) antibodies (GADA) were almost always transient and maternally acquired when detected at 9 months. The correct identification of de novo-produced islet autoantibodies before age 1 yr was diagnostically important because these offspring had a very high risk for T1D.
Subjects and Methods
Offspring of mothers and fathers with T1D
Within the first year of life, 682 offspring from mothers with T1D and 329 from fathers with T1D and nondiabetic mothers were tested for IA(A), GADA antibodies to and the protein tyrosine phosphatase IA-2 (IA2A). This included samples at birth or within the first 6 months of age plus a second sample between 6 months and 1 yr of age. All 1011 offspring were tested for the same antibodies at two years of age to determine antibody persistence or transient elevations. Islet antibodies in offspring with elevated islet antibodies at 9 months of age or thereafter were characterized for their IgG subclass, and epitope reactivity, and this was compared with that found in the mother at delivery.
Antibody testing
Antibodies against insulin, GAD, and IA-2 and their subclasses were measured using radiobinding assays as previously described (13, 14). The upper limit of normal values, which was defined by the 99th percentile of antibody levels in nondiabetic control children, was 1.5 U for IA(A), 8.5 U for GADA, and 2.5 U for IA2A. For total antibody levels, samples with values above the linear portion of the standard dilution curve were retested after dilution in sample buffer, and the value was derived after multiplying by the dilution factor. Antibodies to the two major GAD epitopes, middle [amino acids (aa) 96–444] and C-terminal (aa 445–585) were determined by radiobinding assay to GAD65/67 chimeras as previously described (15). To compare the relative amount of antibody to each epitope, samples were titrated to end point using doubling dilutions in sample buffer. The end point was defined as the highest dilution with levels above the threshold for positivity previously determined on control samples (15).
Statistical analysis
Kaplan-Meier life-table analysis was used to determine the cumulative risk to develop T1D. Follow-up started at birth and ended with diabetes onset or with the day of last contact with the family. Differences in diabetes-free survival were compared by the log-rank test. Differences in antibody levels at birth between offspring with persistent, transient, or negative antibody results were determined by the Mann-Whitney U test. For all statistical methods the Statistical Package for Social Sciences (SPSS, Inc., Chicago, IL) was used.
Results
Antibody frequency in the first year of life in offspring of mothers with and without type 1 diabetes
The frequency of antibodies to insulin, GAD, and IA-2 at birth and
within the first year of life are shown in Fig. 1
. For all three antibody specificities
the highest antibody prevalence in offspring from mothers with T1D was
found in cord blood and continuously decreased in the samples of older
children. Decline of the antibody prevalence was comparable for IA(A)
and IA2A and was less pronounced for GADA, suggesting a longer
persistence of maternally acquired GADA in the circulation of the
offspring from type 1 diabetic mothers compared to maternally acquired
IA(A) and IA2A. One offspring of a father with T1D and a nondiabetic
mother had IA(A) at birth, but, as in all IA(A)-positive newborns of
mothers with T1D, analysis of the sample of his mother at delivery also
revealed IA(A) in a comparable amount (child, 8.0 U; mother, 10.3 U),
suggesting transplacental transmission of maternal antibodies also in
this case. Another offspring from a father with T1D had GADA at birth,
but the serum was highly hemolysed, and antibody positivity could not
be confirmed on a follow-up sample. After birth, first antibody
positivity in offspring of fathers with T1D and nondiabetic mothers was
detected at the age of 9 months for IA(A) (n = 5) and in the 2 yr
sample for GADA and IA2A. Here, mothers were antibody negative at
delivery, suggesting de novo production of islet antibodies
in these children.
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As most offspring had samples around 9 months of age, we examined
whether positivity at this age was persistent or transient in their 2
yr sample. Offspring were grouped into persistent antibody-positive
offspring if they had antibodies at both 9 months and 2 yr of age and
transient antibody-positive offspring if they had antibodies only at 9
months of age. Of offspring from fathers with T1D and nondiabetic
mothers, 5 (1.5%) had antibodies at age 9 months (Fig. 2). All 5 had single IA(A) at 9 months,
which were persistent in follow-up samples, all developed multiple
antibodies, and 1 developed T1D at age 30 months. In contrast, of the
offspring from mothers with T1D, 12 (1.8%) had persistent
(P = 1.0 vs. offspring from fathers with
T1D) and 19 (2.8%) had transient antibodies (P <
0.001 vs. offspring from fathers with T1D; Fig. 2). Eleven
of the persistents had IA(A), including 1 also with GADA and IA2A, 1
also with GADA, and 1 also with IA2A, and 1 had GADA only. All 12
developed multiple islet antibodies, and 7 developed T1D, including all
3 with multiple islet antibodies at 9 months. Five of the 19 transient
antibody-positive subjects had IA(A) only, 1 had IA(A) and GADA, 11 had
GADA only, and 2 had IA2A only. Only 2 of the transient
antibody-positive offspring developed islet autoantibodies in samples
obtained after age 2 yr. In 1 of these (case 7, Table 1) low titer IA(A) were present at 9
months of age and not at birth or in samples obtained after 9 months,
and GADA were detected at age 5 yr and in all samples thereafter. The
second (case 13, Table 1) had very high levels of GADA at birth and low
levels at 9 months, suggestive of residual maternally acquired
antibodies, but developed GADA at 5 yr of age. None of the transient
antibody-positive offspring have developed T1D. T1D risk is shown in
Fig. 3. Within offspring who had
persistent antibodies at age 9 months the risk of developing T1D by age
5 yr was 100% in offspring with multiple antibodies already at age 9
months, and 27% in offspring with single antibodies at age 9 months
(P < 0.01 vs. 9 month persistent multiple
antibody-positive offspring). Within offspring who had persistent islet
antibodies from age 2 yr, the T1D risk by age 5 yr was 27% in
offspring with multiple antibodies at age 2 yr, and 17% in relatives
with single antibodies at age 2 yr. T1D risk in offspring with 9 month
transient antibody positivity was 0%. Of all persistent or transient
antibody-positive offspring from mothers with T1D, 23 were selected for
further testing based upon availability of samples and are shown in
Table 1.
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Offspring with residual maternally acquired antibodies at 9 months
would be expected to have high antibody titers at birth. We therefore
examined the antibody titers of IA(A) and GADA at birth in offspring
from mothers with T1D who had antibodies at 9 months and offspring from
mothers with T1D who were antibody negative at 9 months of age (Fig. 4). Offspring with no antibody at 9
months showed a wide range of antibody levels in their birth sample
[IA(A) as well as GADA]. All but 1 offspring with transient
antibodies had very high titers of IA(A) or GADA at birth. The
exception (case 7, Table 1
) developed GADA at 5 yr, as discussed above.
Remarkably, in many of the transient GADA-positive offspring, GADA at
birth were still positive when diluted at 1:1000 (data not shown).
Antibody titers at birth in offspring with persistent antibodies ranged
between negative and very high. Of the 5 cases shown with persistent
IA(A) at 9 months, 2 had low titer IA(A) at birth (cases 4 and 5),
strongly suggestive that IA(A) at 9 months were not maternally
acquired; 1 had moderate titer IA(A) at birth (case 3); and 2 had high
titers at birth (cases 1 and 2). Of the 3 cases shown with persistent
GADA at 9 months, 2 were negative at birth (cases 4 and 5), again
strongly suggestive that GADA at 9 months were not maternally acquired,
and the third had a GADA titer at birth that was similar to those of
offspring with transient GADA (case 6). The presence of low titer or
negative antibodies at birth was, therefore, a useful guide to
identifying de novo antibody production in the child.
However, some offspring who had persistent islet autoantibodies from 9
months of age had very high maternally acquired antibody titers at
birth, and the origin of these required further investigation.
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As the origin of islet autoantibodies at 9 months was unclear in
offspring with high antibody titers at birth, we investigated whether a
comparison of the subclass distribution and/or epitope reactivity at 9
months and birth could help discriminate maternally acquired from
de novo produced antibodies. For IA(A), antibody isotype and
IgG subclass analysis was performed in three persistent (Table 1, cases
1, 2, and 3) and, for comparison, five transient antibody-positive
offspring (cases 8, 9, 10, 11, and 12), all of whom had high titer
IA(A) at birth (Table 2). In all
cases the IA(A) subclass distribution in the birth sample was similar
to that in the mother’s serum (data not shown). In all three
persistent antibody-positive offspring, IgG4-IA(A) were heavily
dominant over other subclasses at birth. However, at 9 months and 2 yr
of age IgG1 was the dominant IA(A) subclass in case 1 and 3, suggesting
that IA(A) at 9 months were not residual maternally acquired
antibodies. In case 2, IgG4 was still the dominant subclass at 9 months
of age as it was at birth, but at 2 yr IgG1 was dominant, suggesting
that IA(A) may have been maternally acquired at 9 months. In children
with transient antibodies, in contrast, the IgG subclass of IA(A) was
similar at 9 months as it was at birth. IgG4-IA(A) were strongly
dominant at birth in four offspring (cases 9–12); in two of these
(cases 10 and 11) IgG4-IA(A) was the strongest subclass at 9 months,
and in the other 2 cases no subclass IA(A) were detectable, presumably
because IA(A) levels were too low. The remaining transient
IA(A)-positive offspring analyzed (case 8) had dominant IgG1-IA(A) at
birth and at 9 months.
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and 4). Subclasses of
GADA were IgG1 dominant both at birth and
at 9 months and 2 yr of age in all offspring and therefore were not
useful in discriminating maternally acquired antibody from de
novo-produced antibodies (Table 3). We therefore examined antibody
titers to different epitopes of GAD with the assumption that maternally
acquired antibodies would show similar relative titers to each epitope
at 9 months and at birth, and that relative titers may differ from the
birth sample if antibodies at 9 months were not maternally acquired.
The relative antibody titer to the two major epitopes of GAD65, the
middle (aa 96–444) and C-terminal (aa 445–585) epitopes, were
examined (Table 4). In transient GADA-positive offspring, the
middle/C-terminal epitope antibody titer ratio at birth and at 9 months
was the same in three offspring, differed by only 1
log2 dilution in three offspring, and differed by
2 log2 dilutions in three offspring. As examples
of nonmaternally acquired GADA, we compared epitope titers at birth and
at first GADA positivity in three offspring who were GADA negative at 9
months. Only 1 log2 dilution difference was
observed in these cases, suggesting that GADA epitope titer was also
unlikely to be useful in discriminating maternally acquired and
de novo-produced GADA. The one persistent 9 month GADA
offspring had similar middle/C-terminal epitope antibody titer ratios
at birth and at 9 months (case 6). Antibodies to other minor epitopes
were not detected in this child (data not shown), and we were therefore
not able to determine whether antibodies at 9 months were de
novo produced in this child. An interesting observation was the
fall in GADA epitope titer in the first 9 months and the differences
between offspring. This ranged from a fall of less than 5
log2 titers (case 18) to almost 10
log2 titers (case 15), with a median fall of 7.5
log2 titers. A difference of 5
log2 titers between cases 18 and 15 is well
beyond normal assay variation and suggests additional biological
factors influencing removal of antibody from the circulation.
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This study addresses whether maternally transmitted islet antibodies can be distinguished from those produced by the child. This has become a critical issue for prospective studies of early autoimmunity and early intervention that focus on using genetically at risk relatives of patients with T1D. We show that maternally transmitted islet antibodies can persist in the circulation of the offspring for longer than 9 months. Indeed, the majority of offspring examined who had antibodies at 9 months of age, no longer had antibodies at 2 yr of age and were from mothers with T1D and very high islet antibody titers. This was particularly so for GADA, which can be present in the mother and in the cord blood sample at very high titers. In only two offspring could GADA at 9 months of age be shown to be from the child and not from the mother, and these children also had IA(A) and IA2A and developed T1D at 15 and 26 months of age. As previously reported, de novo-produced IA(A) were more common at 9 months (5, 16). We could not find evidence for autoantibodies from the child at birth as previously suggested (10), as in all cases antibodies were also found in the mother, or in one case with GADA, the sample was obviously unsatisfactory, and all repeat samples were not islet antibody positive.
The finding that maternally acquired antibodies could still be detected in the circulation at 9 months of age is in contrast to a Finnish study of 20 infants of mothers with T1D (8). However, the same group recently reported that 1 of 47 offspring of mothers with T1D had residual GADA at 12 months of age, a finding that is more consistent with our study of 682 offspring from mothers with T1D, where at least 12 (1.8%) were likely to have residual GADA at 9 months of age (12). Although transient antibody positivity was readily detected in this cohort of offspring with mothers with T1D, most cases were probably due to the persistence of maternally acquired antibodies and not from true autoimmunity in the child. This is in contrast to a recent report of the Australian BABYDIAB study, which reported transient islet autoantibodies in 18% of first degree relatives of patients with T1D prospectively followed from birth, suggesting that true transient islet autoimmunity was relatively frequent (17). In the German BABYDIAB cohort we observed only 1 case of transient autoimmunity that could not be attributed to the persistence of maternally acquired antibodies, suggesting that true transient autoimmunity is rare in such relatives, a finding that is supported by data from a prospective study in the U.S. (18).
The correct identification of de novo-produced islet autoantibodies before age 1 yr is diagnostically important, because these offspring have an increased risk to develop T1D before age 5 yr (16). In the DAISY study a high diabetes risk was found in offspring with IAA before age 1 yr regardless of the presence of other islet autoantibodies (100% by age 5 yr). In our study the risk was particularly high in offspring who had multiple islet antibodies at the age of 9 months (100% by age 3 yr), but was significantly lower in those with IAA in the absence of other antibodies (32% by age 5 yr). Combining the data of persistent antibody-positive offspring from both cohorts, we found that all 4 offspring with IA(A) plus GADA before age 1 yr developed T1D between age 1 and 2.8 yr (100% risk by age 5 yr), and 7 of 16 offspring with IA(A) before age 1 yr in the absence of other antibodies developed T1D between the age of 1.8 and 7.3 yr (45% risk by age 5 yr); in comparison, 0 of 22 offspring with transient maternally acquired antibodies developed T1D.
As expected, antibody titer at birth was a major factor in determining how long maternally acquired antibodies persisted in the circulation. This was, however, unable to exclude maternally acquired antibodies in a number of offspring of mothers with T1D in whom antibodies persisted after 9 months of age. In these cases we resorted to examining other characteristics of antibodies to determine the likelihood that antibodies were not from the mother. For IA(A), the subclass of the antibodies proved useful. As we previously reported, the major subclass of IA(A) after insulin injection is often IgG4, whereas that of IA(A) in early prediabetes is usually IgG1 (13, 14). This was the case in the mother-child pairs of persistent IA(A)-positive offspring examined in this study and in each of the offspring enabled the likelihood of the IA(A) at 9 months to be clarified. In all three offspring the major subclass of IA(A) at birth was IgG4 and that of IA(A) at 2 yr was IgG1. In two offspring the subclass of IA(A) at 9 months differed from that at birth and was similar to that of the 2 yr sample, strongly suggesting that IA(A) in the 9 month sample was not maternally acquired, whereas in one of the offspring the subclass of IA(A) in the 9 month sample was similar to that in the birth sample and differed from that in the 2 yr sample, suggesting that the 9 month IA(A) was maternally acquired. Even in the absence of a birth sample, the subclass of IA(A) may help define risk, because the detection of IgG1-IA(A) at 9 months was associated with antibody persistence and the development of multiple islet autoantibodies in all but one of the offspring analyzed. Subclass measurement alone could not always exclude diabetes risk, as in two offspring with transient 9 month IA(A) positivity no IA(A) subclasses were detectable, presumably because IA(A) levels were too low.
Subclass was not useful for discrimination in the offspring with persistent GADA or IA-2A, as IgG1 was the major subclass both before and after diabetes onset. Analysis of the epitope reactivity of antibodies was also unable to establish whether the antibodies were from the mother. We examined the major GADA epitopes, because minor epitopes are of lower titer and therefore less likely to persist. As expected, the relative titers to the two major GAD epitopes were similar at birth and at 9 months of age in offspring with transient maternally acquired GADA. Unfortunately, this was also the case in offspring with clear de novo-produced GADA who developed GADA at 2 yr of age or later after having been negative at 9 months. One of the 9 month persistent antibody-positive offspring had very high GADA titers at birth, GADA at 9 months and thereafter, and subsequently developed both IA(A) and IA2A. GADA at 9 months in this child were consistent with those at birth, and therefore we cannot exclude that they are residual maternal antibodies. This was the only child in our BABYDIAB cohort who did not have IA(A) in the first autoantibody-positive sample obtained by age 2 yr.
Although antibody titer in the transient maternally acquired antibody-positive offspring declined over time, this decline was not always consistent with that expected from the 20- to 21-d half-life of circulating IgG (19). Antibody titers at age 9 months would be expected to be more than 212-fold less than those at birth. However, for GADA to both the middle and C-terminal epitopes, we observed reductions of only 25 to 210, and this differed considerably between offspring. This observation is consistent with a reported longer than expected half-life of maternally acquired tetanus antibodies (20) and suggests that other biological factors influence the persistence of maternally acquired antibodies in infancy. Such factors could include the uptake of maternal antibodies in breast milk by intestinal IgG receptors (21, 22). No relationship between a decline in titer and breast-feeding time was observed, however. Breast-feeding times in offspring with transient antibodies at age 9 months ranged from 0–24 months and did not differ from those in offspring who were antibody negative at age 9 months (data not shown). Alternatively, tissue-sequestered antibodies may be released to establish equilibrium as levels in the circulation decline. This would be consistent with our observation of rapid equilibrium and only partial removal of GADA in a patient who underwent several rounds of Ig immunoadsorption therapy (23). A further possibility is a prolonged presence of maternal autoantibody producing B lymphocytes in the child (24).
In summary, the relatively long persistence of maternally acquired autoantibodies must be considered when screening for T1D-associated autoantibodies within the first year of life, particularly, but not only, in offspring of mothers with T1D. GADA alone are almost always maternally acquired when detected before age 1 yr, whereas several children with nonmaternally acquired IA(A) before age 1 yr could be identified in our cohort. In all cases of islet antibody positivity in the first year of life, comparison of titers to those found at birth or in the mother’s serum at delivery and in a follow-up sample is essential to establish whether autoantibodies are likely to be de novo produced by the child and therefore associated with a high risk for T1D. High antibody titers at birth and declining antibody titer in follow-up samples are typical characteristics of transient maternally acquired antibodies, which are associated with a relatively low risk for developing T1D. Defining this is of diagnostic importance when multiple islet autoantibodies are detected before age 1 yr, because if produced in the child, these children are likely to develop T1D rapidly. In dubious cases of IA(A) positivity, a comparison of the subclass distribution of the IA(A)-positive sample with that obtained at birth can be helpful in identifying de novo-produced antibodies. Care in assigning antibody status in the first year of life will reduce false positives in early screening programs and reduce unnecessary parent anxiety.
Acknowledgments
We thank Annette Schimmel for her help with antibody testing, and Mike Schenker and Michael Hummel for sample collection. We also thank all obstetric departments, pediatricians, and family doctors in Germany that participated in the recruitment and follow-up of families in the BABYDIAB study.
Footnotes
This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG 310/12-3), Juvenile Diabetes Foundation (1-2000-619), Deutsche Diabetesgesellschaft (Dr. Buding-Stiftung), Stiftung Das zuckerkranke Kind, and the von Humbold Stiftung.
Abbreviations: aa, Amino acids; GAD, glutamic acid decarboxylase; GADA, glutamic acid decarboxylase antibodies; IA(A), insulin (auto)antibodies; T1D, type 1 diabetes.
Received January 30, 2001.
Accepted June 25, 2001.
References
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; n = 682) and fathers with T1D and
nondiabetic mothers (
;
n = 329) in the first 2 yr of life. Three samples from each of the
1011 offspring were tested. The first was obtained at birth (n =
351 from children of mothers with T1D; n = 251 from children of
fathers with T1D) or before age 6 months (n = 331 from children of
mothers with T1D; n = 78 from children of fathers with T1D), the
second sample was obtained between age 6 and 12 months, and
the third sample was obtained at around 2 yr of age. Prevalences are
shown at birth and at 0.1–2, 2.1–4, 4.1–6, 6.1–9, 9.1–12, and 24
months of age.
