Anneli K. Carlsson

Prevalence of IgA-Antiendomysium and IgA-Antigliadin Autoantibodies at Diagnosis of Insulin-Dependent Diabetes Mellitus in Swedish Children and Adolescents

Objective. This study was conducted to investigate the prevalence of celiac disease (CD) in children and adolescents at diagnosis of insulin-dependent diabetes mellitus (IDDM) before insulin treatment was started. Material and Methods. At diagnosis of IDDM, and before treatment was started, 115 children and adolescents were screened for IgA- antiendomysium (EMA) and IgA-antigliadin antibodies (AGA). Those found to be EMA-positive and/or AGA-positive were investigated further with intestinal biopsy. Results. Of the 115 patients, 2 had known CD at diagnosis of IDDM; of the remainder of patients, 6% (7/113) were found to be EMA-positive and 9% (10/113) were found to have AGA levels above normal. Of the 6 patients who underwent biopsy, 5 manifested villous atrophy. In addition, 2 patients with high EMA and AGA antibody titers refused biopsy, and 4 patients with low EMA and/or AGA titers were found to have normal titers at control before biopsy decision. Conclusion. Because the prevalence of CD at diagnosis of IDDM would seem to be 6% to 8%, screening for CD seems to be justified among patients with newly diagnosed IDDM.

The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes.

Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative. Methods: A total of 686 patients diagnosed in 1996–2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes. Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%—a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1*X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA. Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1*X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.

Prediction of silent celiac disease at diagnosis of childhood type 1 diabetes by tissue transglutaminase autoantibodies and HLA

Abstract: Aims: The aims were to estimate the diagnostic sensitivity and specificity of autoantibodies to tissue transglutaminase (IgA‐ and IgG‐tTG), gliadin (AGA) and endomysium (EMA) in relation to human leukocyte antigen (HLA)‐DQB1 alleles to identify silent celiac disease at diagnosis of type 1 diabetes.

Glutamate decarboxylase antibodies in non-diabetic pregnancy precedes insulin-dependent diabetes in the mother but not necessarily in the offspring.

We studied the risk for diabetes of glutamate decarboxylase (GAD65Ab) and islet cell (ICA) autoantibodies in non-diabetic pregnant mothers and their children. Pregnancy and cord blood sera were collected in 1970-87 from about 35,000 mothers who delivered a child in the city of Malmö, Sweden. A total of 42 mothers were identified in 1988 who, 1-18 years after their pregnancies, had developed either insulin-dependent (n = 22) or non-insulin dependent (n = 20) diabetes mellitus. First, in 123 pregnant mothers selected as controls, 0.8% had GAD65Ab and 0.8% ICA. Second, among the mothers with non-insulin dependent diabetes, 7/20 (35%) had GAD65Ab eight months to 13 years, 10 months before clinical diagnosis. Third, in mothers who later developed insulin-dependent diabetes, 12/22 (55%) had GAD65Ab and 10/22 (45%) had ICA in pregnancies preceding the clinical diagnosis by 13 months to 9 years, 4 months. In 1996, none of the children born to the 42 mothers have developed diabetes. GAD65Ab and ICA in non-diabetic pregnancies may predict insulin-dependent diabetes in the mother but not necessarily in the offspring.

Relationship Between Ljungan Virus Antibodies, HLA-DQ8, and Insulin Autoantibodies in Newly Diagnosed Type 1 Diabetes Children

Environmental factors, including viral infections, may explain an increasing and fluctuating incidence of childhood type 1 diabetes (T1D). Ljungan virus (LV) isolated from bank voles have been implicated, but it is unclear whether LV contributes to islet autoimmunity, progression to clinical onset, or both, of T1D. The aim was to test whether LV antibodies (LVAb) were related to HLA-DQ and islet autoantibodies in newly diagnosed T1D patients (n=676) and controls (n=309). Patients, 0-18 years of age, diagnosed with T1D in 1996-2005 were analyzed for LVAb, HLA-DQ genotypes, and all seven known islet autoantibodies (GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, and ZnT8QA). LVAb at 75(th) percentile, defined as cut off, was 90 (range 6-3936) U/mL and 4(th) quartile LVAb were found in 25% (170/676) of which 64% were <10 (n=108, p<0.0001), and 27% were<5 (n=45; p<0.0001) years old. The 4(th) quartile LVAb in children <10 years of age correlated to HLA DQ2/8, 8/8, and 8/X (p<0.0001). Furthermore, in the group with 4(th) quartile LVAb, 55% were IAA positive (p=0.01) and correlation was found between 4(th) quartile LVAb and IAA in children <10 years of age (p=0.035). It is concluded that 1) LVAb were common among the young T1D patients and LVAb levels were higher in the younger age groups; 2) 4(th) quartile LVAb correlated with IAA; and 3) there was a correlation between 4(th) quartile LVAb and HLA-DQ8, particularly in the young patients. The presence of LVAb supports the notion that prior exposure to LV may be associated with T1D.

Prevalence of β-cell and thyroid autoantibody positivity in schoolchildren during three-year follow-up

The prevalence of autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GAD65Ab), insulin (IAA), islet cells (ICA), thyroid peroxidase (TPOAb) and thyroglob-ulin (TgAb), in relation to HLA-DR types, was assessed in 310 (HLA in 280) twelve-year-old children during three-year follow-up. Altogether, 26.8% (83β10) of the children were found to carry at least one autoantibody. The HLA-DR3/DR4 genotype was significantly more prevalent in the subgroup of children GAD65Ab-positive on at least one occasion than among GAD65Ab-negative children |33% (2/6) vs. 5% (12/274);β = 0.03|, as was the HLA-DR4/x genotype among children seropositive for at least one thyroid autoantibody, compared to the corresponding seronegative subgroup [52% (34/65) vs. 34% (74/215); p = 0.01]. The proportion of children seropositive in at least one of the three tests was 1.9% (6β10) for GAD65Ab, 2.6% (8β10) for IAA, 5.2% (16β10) for ICA, 11.3% (35β10) for TPOAb and 19.4% (60β10) for TgAb. All autoantibodies except GAD65Ab...

Reduced display of conformational epitopes in the N-terminal truncated GAD65 isoform: relevance for people with stiff person syndrome or DQ8/8-positive Type 1 diabetes mellitus

To investigate whether the N‐terminal truncated glutamic acid decarboxylase 65 (GAD65) isoform is as well recognized by people with stiff person syndrome as it is by people with Type 1 diabetes, and whether conformational GAD65 antibody epitopes are displayed properly by the isoform.