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.
Highlights
The Network Hypothesis stated by Niels Jerne postulates that a network of interacting idiotypes is part of the immune regulatory system [1]
GAD65Ab levels at baseline were significantly higher in progressors compared to non-progressors, no difference in GAD65Ab levels between the groups was observed at the end of the follow up period (Figure 4)
In progressors in the Diabetes Prediction in Skane (DiPiS) cohort, we found that anti-Id levels tended to decline over time, in contrast to matched non-progressors whose anti-Id levels tended to increase with time, similar to our finding in the Natural History Study (NHS) cohort
Summary
The Network Hypothesis stated by Niels Jerne postulates that a network of interacting idiotypes is part of the immune regulatory system [1]. A specific subclass of these anti-Id recognize the binding site of the original antibody and can thereby prevent the binding of the original antibody to its antigen These ‘‘internal image antibodies’’ have been described in the control populations of several autoimmune diseases [2,3] and may have regulatory functions. The development of anti-Id towards human antibodies that are used for therapy is a well documented phenomenon and a major concern for the biological availability of the therapeutic antibody [10] While these studies show that anti-Id can be induced by administration of an exogenous antibody, or develop in response to an induced antibody increase, very little is known about the natural development of anti-Id. Type 1 diabetes (T1D) is an autoimmune disease characterized by lack of insulin due to the autoimmune-mediated destruction of the islet beta cells.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
