Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of β-cell loss, responsiveness to immunotherapies and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multi-parameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly-diagnosed disease. Multi-dimensional cluster analysis showed two equal-sized patient agglomerations, characterized by pro-inflammatory (IFN-γ+, multi-autoantibody-positive) and partially-regulated (IL-10+, pauci-autoantibody-positive) responses. Multi-autoantibody-positive non-diabetic siblings at high-risk of disease progression showed similar clustering. Second, pancreas samples obtained post mortem from a separate cohort of 21 children/adolescents with recently-diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesion, distinguishable by degree of cellular infiltrate and presence of B-lymphocytes, that we term “hyper-immune CD20Hi” and “pauci-immune CD20Lo”. Notably, subjects had only one infiltration phenotype and were partitioned by this into two equal-size groups that differed significantly by age of diabetes diagnosis, hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with, and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment/prevention strategies.
* These authors contributed equally
- Received March 3, 2014.
- Accepted June 12, 2014.
- © 2014 by the American Diabetes Association.
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