title: Decline in titers of anti-idiotypic antibodies specific to autoantibodies to GAD65 (GAD65Ab) precedes development of GAD65Ab and type 1 diabetes.
abstract: The humoral Idiotypic Network consisting of antibodies and their anti-idiotypic antibodies (anti-Id) can be temporarily upset by antigen exposure. In the healthy immune response the original equilibrium is eventually restored through counter-regulatory mechanisms. In certain autoimmune diseases however, autoantibody levels exceed those of their respective anti-Id, indicating a permanent disturbance in the respective humoral Idiotypic Network. We investigated anti-Id directed to a major Type 1 diabetes (T1D)-associated autoantibody (GAD65Ab) in two independent cohorts during progression to disease. Samples taken from participants of the Natural History Study showed significantly lower anti-Id levels in individuals that later progressed to T1D compared to non-progressors (anti-Id antibody index of 0.06 vs. 0.08, respectively, p = 0.02). We also observed a significant inverse correlation between anti-Id levels and age at sampling, but only in progressors (p = 0.014). Finally, anti-Id levels in progressors showed a significant decline during progression as compared to longitudinal anti-Id levels in non-progressors (median rate of change: -0.0004 vs. +0.0004, respectively, p = 0.003), suggesting a loss of anti-Id during progression. Our analysis of the Diabetes Prediction in Skåne cohort showed that early in life (age 2) individuals at risk have anti-Id levels indistinguishable from those in healthy controls, indicating that low anti-Id levels are not an innate characteristic of the immune response in individuals at risk. Notably, anti-Id levels declined significantly in individuals that later developed GAD65Ab suggesting that the decline in anti-Id levels precedes the emergence of GAD65Ab (median rate of change: -0.005) compared to matched controls (median rate of change: +0.001) (p = 0.0016). We conclude that while anti-Id are present early in life, their levels decrease prior to the appearance of GAD65Ab and to the development of T1D.
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Helena Elding
authors.initials: HE
authors.lastname: Larsson
authors.forename: Ida
authors.initials: I
authors.lastname: Jönsson
authors.forename: Ake
authors.initials: A
authors.lastname: Lernmark
authors.forename: Sten
authors.initials: S
authors.lastname: Ivarsson
authors.forename: Jared R
authors.initials: JR
authors.lastname: Radtke
authors.forename: Christiane S
authors.initials: CS
authors.lastname: Hampe
mesh_terms: D000293:Adolescent; D000328:Adult; D000888:Antibodies, Anti-Idiotypic / Q000097:blood / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology*; D018450:Disease Progression; D005500:Follow-Up Studies; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000888:Antibodies, Anti-Idiotypic; D001323:Autoantibodies; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2