Project Summary:
Type 1 diabetes (T1D) arises from an autoimmune response towards the pancreatic β-cells, resulting in lifelong insulin replacement therapy as well as reductions in both life quality and expectancy. T1D pathogenesis involves adaptive immune responses, as evidenced by the presence of T- and B-cells within the insulitic lesion, the development of autoantibodies (aAb) towards islet antigens in most patients, and the partial successes of clinical trials targeting these cell types. Innate immunity, including altered monocyte activity, is also involved. Chemokines and cytokines also play a role by influencing immunocyte activity, impairing β-cell function, and inducing β-cell death.
Over the past several decades, worldwide T1D incidence has increased approximately 3-4% per year. T1D affects approximately 1.5 million Americans, including roughly 304,000 children. Coincident with the increasing incidence, there has been a decline in the age of onset, as well as a decrease in the prevalence of the high-risk HLA haplotypes historically associated with T1D risk 13. These shifts are consistent with new environmental pressures that promote β-cell autoimmunity and coincide with the increasing use of antibiotics and popularity of the low-fiber, high-gluten Western diet. These changes are thought to have altered the gut microbiome of modern humans, impairing the colonization of protective anti-inflammatory short-chain fatty acid producing taxa. Analyses performed by this project team suggest that these changes also coincide with increases in body mass index (BMI) among children.
Specifically, data of 1,618 Children’s Wisconsin T1D patients diagnosed between 1995 and 2004 revealed a two-fold increased incidence over the study period. The largest increase was observed in the youngest age groups, which also showed the greatest increase in BMI.
Many immunotherapies aimed at inducing clinical remission and re- establishing a balanced immune system have now been tested in recent onset T1D patients. Despite the knowledge gained, the positive therapeutic effects have been of limited duration and patient responses have been highly varied. This has been attributed to an incomplete understanding of the heterogeneity of T1D pathogenesis. T1D is a complex disease: there are more than 60 associated genetic risk loci and multiple environmental influencers that likely underlie the diverse immunobiology, metabolic characteristics and clinical course seen among patients. Age of onset is highly variable, with younger individuals exhibiting a more severe presentation with a more rapid decline in β-cell function after clinical onset. Ongoing efforts aim to characterize mechanisms underlying the phenotypic diversity in T1D, where the identification of subtypes (endotypes) possessing unique etiologies could foster the application of precision medicine in T1D. A precedent for this has been set in asthma, where heterogeneity in type-2 airway inflammation was used to define endotypes. This has fostered a new age of precision medicine that targets IL-5 for a subset of asthma patients. An understanding of the mechanistic heterogeneity underlying T1D pathogenesis will be impactful in Wisconsin and world-wide as it will foster the development of personalized prevention and treatment protocols.
This project aims to comprehensively immunophenotype groups 1 and 2 for T, B, and myeloid cell populations.