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.

T cells presenting viral antigens or autoantigens induce cytotoxic T cell anergy

“…For example, anti-idiotype antibodies play a role in limiting humoral immune responses (11)(12)(13)(14)(15) and regulatory T cells can be induced in the periphery (16).…”

B-CD8+T Cell Interactions in the Anti-Idiotypic Response against a Self-Antibody

“…Several studies have shown the existence of physiological anti-idiotypic responses, which are absent or diminished during the development of several autoimmune diseases, suggesting they play important roles in the control of autoreactivity [ 10 – 12 ]. Studies about systemic lupus erythematosus, type I diabetes, Sjögren's syndrome, and neonatal lupus syndrome showed that high anti-idiotype levels were found during remission in patients with autoimmune diseases but were diminished during the acute, active phases of the disease [ 11 , 58 – 62 ].…”

Immunomodulatory Potential of anti-idiotypic Antibodies for the Treatment of Autoimmune Diseases

“…In healthy individuals, the circulating GAD65Abs in sera are not detectable using GAD65-specific methods, which may be due to the binding of anti-ID antibodies to the antigen-binding region of GAD65Abs. In contrast, the decline of anti-ID antibodies in T1D patients, causing the exposure of GAD65Abs, then can be served as critical serum markers in the diagnostics of diabetes [ 83 ].…”