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HLA-DR-DQ haplotypes and specificity of the initial autoantibody in islet specific autoimmunity.
Pediatr Diabetes. 2020 Jul 01 [Online ahead of print]PD

Abstract

OBJECTIVE

We aimed to clarify the association of various HLA risk alleles with different types of autoantibodies initiating islet specific autoimmunity.

METHODS

Follow-up cohorts from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and children diagnosed with type 1 diabetes (T1D) from the Finnish Pediatric Diabetes Register (FPDR) were analyzed for the presence of autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A); and genotyped for HLA DR/DQ alleles. In the DIPP study, autoantibodies were regularly analyzed from birth up to 15 years of age.

RESULTS

In the DIPP cohort, 621 children developed one single persistent autoantibody, GADA in 284, IAA in 268, and IA-2A in 40 cases. Highly significant differences in the specificity of the first autoantibody were observed between HLA genotypes. Homozygotes for the DR3-DQ2 haplotype had almost exclusively GADA as the first autoantibody, whereas a more even distribution between GADA and IAA was found in DR3-DQ2/DR4-DQ8 as well as DR3-DQ/x and DR4-DQ8/x genotypes (x referring to neutral haplotypes). In DR4-DQ8 positive genotypes with the DRB1*04:01 allele IAA was more often the first autoantibody than in DRB1*04:04 positive genotypes. Various neutral haplotypes also significantly affected the relative proportions of different initial autoantibodies. These findings were confirmed and expanded in a series of 1591 T1D children under the age of 10 years from FPDR.

CONCLUSIONS

These results emphasize the importance of HLA class II polymorphisms in the recognition of autoantigen epitopes in the initiation of various pathways of the autoimmune response.

Authors+Show Affiliations

Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland. Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland. Clinical Microbiology, Turku University Hospital, Turku, Finland.Pediatric Research Center, Children Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland. Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.Department of Pediatrics, PEDEGO Research Unit, Medical Research Center, University of Oulu, Oulu, Finland. Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.Pediatric Research Center, Children Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Folkhälsan Research Center, Helsinki, Finland. Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland.Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32613719

Citation

Mikk, Mari-Liis, et al. "HLA-DR-DQ Haplotypes and Specificity of the Initial Autoantibody in Islet Specific Autoimmunity." Pediatric Diabetes, 2020.
Mikk ML, Pfeiffer S, Kiviniemi M, et al. HLA-DR-DQ haplotypes and specificity of the initial autoantibody in islet specific autoimmunity. Pediatr Diabetes. 2020.
Mikk, M. L., Pfeiffer, S., Kiviniemi, M., Laine, A. P., Lempainen, J., Härkönen, T., Toppari, J., Veijola, R., Knip, M., & Ilonen, J. (2020). HLA-DR-DQ haplotypes and specificity of the initial autoantibody in islet specific autoimmunity. Pediatric Diabetes. https://doi.org/10.1111/pedi.13073
Mikk ML, et al. HLA-DR-DQ Haplotypes and Specificity of the Initial Autoantibody in Islet Specific Autoimmunity. Pediatr Diabetes. 2020 Jul 1; PubMed PMID: 32613719.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - HLA-DR-DQ haplotypes and specificity of the initial autoantibody in islet specific autoimmunity. AU - Mikk,Mari-Liis, AU - Pfeiffer,Sophie, AU - Kiviniemi,Minna, AU - Laine,Antti-Pekka, AU - Lempainen,Johanna, AU - Härkönen,Taina, AU - Toppari,Jorma, AU - Veijola,Riitta, AU - Knip,Mikael, AU - Ilonen,Jorma, AU - ,, Y1 - 2020/07/01/ PY - 2020/03/30/received PY - 2020/06/09/revised PY - 2020/06/22/accepted PY - 2020/7/3/pubmed PY - 2020/7/3/medline PY - 2020/7/3/entrez KW - HLA genotypes KW - islet specific autoantibodies KW - type 1 diabetes JF - Pediatric diabetes JO - Pediatr Diabetes N2 - OBJECTIVE: We aimed to clarify the association of various HLA risk alleles with different types of autoantibodies initiating islet specific autoimmunity. METHODS: Follow-up cohorts from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and children diagnosed with type 1 diabetes (T1D) from the Finnish Pediatric Diabetes Register (FPDR) were analyzed for the presence of autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A); and genotyped for HLA DR/DQ alleles. In the DIPP study, autoantibodies were regularly analyzed from birth up to 15 years of age. RESULTS: In the DIPP cohort, 621 children developed one single persistent autoantibody, GADA in 284, IAA in 268, and IA-2A in 40 cases. Highly significant differences in the specificity of the first autoantibody were observed between HLA genotypes. Homozygotes for the DR3-DQ2 haplotype had almost exclusively GADA as the first autoantibody, whereas a more even distribution between GADA and IAA was found in DR3-DQ2/DR4-DQ8 as well as DR3-DQ/x and DR4-DQ8/x genotypes (x referring to neutral haplotypes). In DR4-DQ8 positive genotypes with the DRB1*04:01 allele IAA was more often the first autoantibody than in DRB1*04:04 positive genotypes. Various neutral haplotypes also significantly affected the relative proportions of different initial autoantibodies. These findings were confirmed and expanded in a series of 1591 T1D children under the age of 10 years from FPDR. CONCLUSIONS: These results emphasize the importance of HLA class II polymorphisms in the recognition of autoantigen epitopes in the initiation of various pathways of the autoimmune response. SN - 1399-5448 UR - https://www.unboundmedicine.com/medline/citation/32613719/HLA_DR_DQ_haplotypes_and_specificity_of_the_initial_autoantibody_in_islet_specific_autoimmunity_ L2 - https://doi.org/10.1111/pedi.13073 DB - PRIME DP - Unbound Medicine ER -
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