Decline in Titers of Anti-Idiotypic Antibodies Specific to Autoantibodies to GAD65 (GAD65Ab) Precedes Development of GAD65Ab and Type 1 Diabetes.

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

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Sample information of the NHS cohort.

<p>Sample information of the NHS cohort.</p

GAD65Ab level in progressors and non-progressors.

<p>GAD65Ab levels at baseline and at diagnosis (or final sampling in non-progressors) are shown for progressors and non-progressors of the NHS cohort. GAD65Ab levels and median for each group are presented. Significant differences are indicated by the horizontal bar and asterix.</p

Longitudinal changes in anti-Id levels during the first measured interval (2–3 years of age) in GAD65Ab converters and matched controls.

<p>Changes in anti-Id over time are presented as rate of change (as described above) and are shown as black circles. For comparison to individual samples, anti-Id levels at ages 2 and 3 are shown as white circles. Significant differences in the medians are indicated by the horizontal bar and asterix.</p

Longitudinal changes in anti-Id levels during follow up in progressors and non-progressors of the NHS cohort.

<p>Longitudinal changes are expressed as rate of change (anti-Id level at diagnosis or final sampling – anti-Id level at baseline)/duration of follow up in months). Changes in anti-Id levels and median for each group are presented. Significant differences are indicated by the horizontal bar and asterix. Actual anti-Id levels at baseline and over time are shown in the respective insets.</p

Sample information of the DiPiS cohort.

<p>Sample information of the DiPiS cohort.</p

Anti-Id levels in progressors and non-progressors of the NHS cohort at baseline and at time of clinical diagnosis.

<p>Anti-Id levels and median for progressors at baseline (white circles) and at onset (black circles) and non-progressors at baseline (white squares) and at the last sample of the follow up (black squares) are presented. Significant differences between medians are indicated by horizontal bars and asterisks.</p

Anti-Id levels in progressors of the NHS cohort at baseline in relation to age at sampling.

<p>Anti-Id levels were plotted against age at sampling. Linear regression line is shown.</p