Cell type–specific immune phenotypes predict loss of insulin secretion in new-onset type 1 diabetes
Matthew J. Dufort, Carla J. Greenbaum, Cate Speake, Peter S. Linsley
Matthew J. Dufort, Carla J. Greenbaum, Cate Speake, Peter S. Linsley
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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 4

B cell gene expression varies with C-peptide loss in T1D subjects in an age-dependent manner.

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B cell gene expression varies with C-peptide loss in T1D subjects in an ...
(A) Median B cell gene expression levels (CD19.mod) over time. Points show individual patient values over the study time frame; lines show model estimates for fast and slow progressors. Expression values were batch-corrected to remove differences by trial and RNA-seq batch. Fit lines have identical slopes, as there was no evidence of an interaction between study day and progressor group; significance is for difference in intercept between groups from linear mixed-effects model. n = 470 measurements from 138 subjects. (B) Expression of B cell genes (CD19.mod) at study baseline in relation to subject age. Model fit line is based on a logarithmic function; shading shows standard error of the model. Significance values are from linear model contrasts. Gene expression values shown are for baseline visits only. n = 124 subjects. (C and D) Rate of change in C-peptide versus baseline B cell gene expression (CD19.mod), with subjects stratified by age at study entry. (C) Subjects were divided into 3 equal-sized groups by age. The slope of the relationship is more negative in the younger than the older patient group (P = 0.038 by linear model contrast). n = 39, 41, and 44 subjects in the youngest, middle, and oldest groups, respectively. (D) Subjects were divided into 2 groups using sliding-window analysis, which predicted a break at 20 years of age. The relationship is more negative in the younger than the older patient group (P = 0.032 by linear model contrast). n = 89 and 35 subjects in the younger and older groups, respectively.