Diabetes and other autoimmune endocrine diseases
Cellular phenotypes associated with T1D include multiple cell types which together, may offer clues to pathogenesis and guide therapeutic choices. Defining and ranking these phenotypes has been challenging due to patient heterogeneity, cellular variability, and limited global cellular analyses. Thus, we designed a large (n=100/group), age and gender matched, cross-sectional study of control and T1D subjects including approximately 300 reproducible (intra-assay CV; median 0.13) parameters of B and T cells using 3 steady-state and 4 cytokine stimulation flow cytometry panels. T cell activation (HLA-DR, CD25, CXCR3) and early B cell markers including IgD were most prominent in single parameter analyses between controls and T1D after applying multiple testing correction. To understand differing relationships between parameters, we correlated all pairs of parameters within cohorts and then compared these correlations between T1D and controls, revealing networks of significantly altered relationships. Prevalent altered relationships occurred between cell types, not within cell types, and were enriched for CCR4, cytokine responses, and early B-cell maturation markers. Using these same correlations to build networks between multiple parameters, control and T1D networks exhibited altered central parameters. IL-2 and IL-7 response and early B cell markers differed the most, with T1D networks being less connected indicating broad defects in these pathways. Together, our findings move beyond single parameter analyses of disease, offering a more comprehensive understanding of the phenotypes associated with T1D. Understanding these altered relationships between immune parameters has implications for selection and stratification of subjects for treatment of T1D with immune-mediated therapies.
Director, Diabetes Program
Benaroya Research Institute