Cell type–specific immune phenotypes predict loss of insulin secretion in new-onset type 1 diabetes
Matthew J. Dufort, … , Cate Speake, Peter S. Linsley
Matthew J. Dufort, … , Cate Speake, Peter S. Linsley
Published February 21, 2019
Citation Information: JCI Insight. 2019;4(4):e125556. https://doi.org/10.1172/jci.insight.125556.
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Research Article

Cell type–specific immune phenotypes predict loss of insulin secretion in new-onset type 1 diabetes

Abstract

The rate of decline in insulin secretion after diagnosis with type 1 diabetes (T1D) varies substantially among individuals and with age at diagnosis, but the mechanism(s) behind this heterogeneity are not well understood. We investigated the loss of pancreatic β cell function in new-onset T1D subjects using unbiased whole blood RNA-seq and verified key findings by targeted cell count measurements. We found that patients who lost insulin secretion more rapidly had immune phenotypes (“immunotypes”) characterized by higher levels of B cells and lower levels of neutrophils, especially neutrophils expressing primary granule genes. The B cell and neutrophil immunotypes showed strong age dependence, with B cell levels in particular predicting rate of progression in young subjects only. This age relationship suggested that therapy targeting B cells in T1D would be most effective in young subjects with high pretreatment B cell levels, a prediction which was supported by data from a clinical trial of rituximab in new-onset subjects. These findings demonstrate a link between age-related immunotypes and disease outcome in new-onset T1D. Furthermore, our data suggest that greater success could be achieved by targeted use of immunomodulatory therapy in specific T1D populations defined by age and immune characteristics.

Authors

Matthew J. Dufort, Carla J. Greenbaum, Cate Speake, Peter S. Linsley

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Figure 1

C-peptide loss follows exponential decay.

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C-peptide loss follows exponential decay. (A) C-peptide AUC from 2-hour ...
(A) C-peptide AUC from 2-hour mixed-meal tolerance test. Each line shows an individual subject’s values across multiple visits. The dashed line represents the lower limit of detection of the assay. n = 846 measurements from 152 subjects. (B) Prediction of C-peptide AUC at 2 years based on baseline C-peptide AUC, age at study entry, and AUC at 6- or 12-month visits. Predicted values are model predictions from leave-one-out cross-validation. Predictive R2 summarizes correspondence between observed and predicted values; the dashed line represents equivalence of predicted and observed values. n = 109 subjects for each model. (C) Rate of C-peptide AUC change varies with age. Model fit line is based on a logarithmic function; shading shows standard error of the model. Variance in C-peptide change is greater in younger subjects (Breusch-Pagan test, P = 0.002). n = 152 subjects. (D) Rate of C-peptide change does not vary consistently with HLA genotypes that confer T1D risk. The dashed line shows linear model fit (P = 0.4). Genotype categories are from Winkler et al. (28); DRx represents alleles that are not DR3 or DR4-DQ8. n = 124 subjects with HLA genotyping.