Molecular Footprints of the Immune Assault on Pancreatic Beta Cells in Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is a chronic disease caused by the selective destruction of the insulin-producing pancreatic beta cells by infiltrating immune cells. We presently evaluated the transcriptomic signature observed in beta cells in early T1D and compared it with the signatures observed following in vitro exposure of human islets to inflammatory or metabolic stresses, with the aim of identifying "footprints" of the immune assault in the target beta cells. We detected similarities between the beta cell signatures induced by cytokines present at different moments of the disease, i.e., interferon-α (early disease) and interleukin-1β plus interferon-γ (later stages) and the beta cells from T1D patients, identifying biological process and signaling pathways activated during early and late stages of the disease. Among the first responses triggered on beta cells was an enrichment in antiviral responses, pattern recognition receptors activation, protein modification and MHC class I antigen presentation. During putative later stages of insulitis the processes were dominated by T-cell recruitment and activation and attempts of beta cells to defend themselves through the activation of anti-inflammatory pathways (i.e., IL10, IL4/13) and immune checkpoint proteins (i.e., PDL1 and HLA-E). Finally, we mined the beta cell signature in islets from T1D patients using the Connectivity Map, a large database of chemical compounds/drugs, and identified interesting candidates to potentially revert the effects of insulitis on beta cells.

Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic β cells

“…1, E and F). These pathways, including "type 1 diabetes mellitus," were in general similar to previous observations made in  cells obtained from patients affected by T1D, from adult human islets, or from EndoC-H1 cells exposed to IFN (9,27,28). Among the downregulated pathways (Fig.…”

Environmental Triggering of Type 1 Diabetes Autoimmunity

“…Subsequent changes in b cells induces their senescence and further increases intra-islet immune cells infiltration. Studying the molecular footprint of stressed b cells allows to characterize the stressor (10). The link between stressed b cell and the induction of T1D is evident under the action of toxins such as alloxan or streptozotocin (138).…”

“…Transcriptomic studies after in vitro stimulation of b cells from recent-onset and long-standing T1D showed early activation of pattern recognition receptors (PRR), upregulation of major histocompatibility complex (MHC) class I expression. In a later phase, T-cell activation and recruitment profiles and upregulation of cytokines and immune check point molecules are observed (10). The recognition of host nucleic acids by TLR 3, 8 or 9, retinoic acid inducible gene (RIG-1) or melanoma differentiation-associated protein 5 (MDA-5) leads to transcriptional expression of inflammatory mediators to eliminate pathogens, but also activate an autoimmune response, as a side effect.…”

“…However, many environmental factors have been identified regardless of whether they trigger the initial seroconversion to anti-islet cell antibodies or accelerate the disease process in autoantibody-positive individuals (5)(6)(7)(8)(9). The first events associated with the disease process is an increased expression of class I major histocompatibility genes and the expression of interferon a and homing genes (10). In an era where the pathogenesis of the disease is not fully elucidated and a cure is still lacking, the identification of triggering factors is crucial for prevention.…”

Means, Motive, and Opportunity: Do Non-Islet-Reactive Infiltrating T Cells Contribute to Autoimmunity in Type 1 Diabetes?

“…CXCR3 expression in T cells has been identified in inflamed pancreata and pancreatic draining lymph nodes from donors with T1D ( 9 , 10 ) along with islet β-cell expression of monocyte chemoattractant protein-1 [MCP-1 ( 11 )]. Further potential contributors to a chemoattractive/pro-inflammatory environment are the expression of IFN-α ( 12 ), and later in disease progression, IL-1β ( 13 ), the latter potentially secreted by virally infected β cells or by α cells ( 14 ). In addition, the scene in the islets appears altered with increased HLA Class I (HLA-I) expression in both α and β cells ( 15 ) and changes in the extracellular matrix ( 16 ) (among others) that can be interpreted as signs of a confrontation.…”