title: Role of humoral beta-cell autoimmunity in type 1 diabetes.
abstract: Islet cell antibodies (ICA) were found for the first time more than 40 yr ago in patients with autoimmune endocrine deficiencies, including type 1 diabetes (T1D). ICA detected by indirect immunofluorescence represent a heterogeneous group of autoantibodies targeting a series of biochemical autoantigens, such as the protein tyrosine phosphatase related islet antigen 2 (IA-2), the 65 kD isoform of glutamic acid decarboxylase (GA65), and zinc transporter 8 (ZnT8) as well as currently unidentified autoantigens. The general view is that the diabetes-associated autoantibodies are not directly involved in beta-cell destruction but function as biomarkers of an ongoing destructive process. The diabetes-associated autoantibodies remain the strongest predictive marker for future development of T1D. Positivity for multiple (≥2) autoantibodies is highly predictive of clinical disease both among first-degree relatives and in the general population. Autoantibody titers are highly variable during the preclinical phase, but in many cases the titers tend to decrease before diagnosis. The first signs of beta-cell autoimmunity may appear early during the first months of life. The majority of those individuals diagnosed with T1D before puberty seroconvert to autoantibody positivity before the age of 3 yr. The natural course and duration of preclinical diabetes vary substantially from one individual to another. The characteristics of the isotype-specific response during preclinical diabetes appear to be antigen-specific. Diabetes-associated autoantibodies may be useful surrogate markers of the subsequent development of T1D in primary prevention trials. T1D may occur, albeit rarely, in the absence of any signs of humoral autoimmunity at diagnosis.
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.|Folkhälsan Research Center, Helsinki, Finland.|Center for Child Health Research, Tampere University Hospital, Tampere, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Heli
authors.identifier: 0000-0002-6899-2822
authors.initials: H
authors.lastname: Siljander
authors.affiliation: Immunogenetics Laboratory, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.affiliation: Center for Child Health Research, Tampere University Hospital, Tampere, Finland.|Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.affiliation: Department of Pediatrics, PEDEGO Research Group, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
mesh_terms: D001323:Autoantibodies; D001324:Autoantigens; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral; D050417:Insulin-Secreting Cells / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens
keywords: autoantigens; diabetes-associated autoantibodies; disease process; epitope-specific autoantibodies; isotype-specific autoantibodies