Insulitis in the pathogenesis of type 1 diabetes

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease in which autoreactive T-cells and inflammation cause severe loss of pancreatic beta cells. Insulitis, the pathologic hallmark of T1D, is an inflammatory lesion consisting of immune cell infiltrates around and within the islets. New research initiatives and methodologies are advancing our understanding of pancreas pathology. Studies have revealed the predominant cellular types that infiltrate the islets, novel molecular aspects associated with insulitis, and the coexistence of additional pathological abnormalities. While insulitis is a critical element of T1D pathology and pathogenesis, it is typically present only in a modest proportion of islets at any given time, even at diagnosis, with overall limited relation to disease duration. Thus, the relative importance of insulitis as a determining factor of diabetes symptoms at disease onset appears to have been overestimated; growing evidence also shows that beta cell loss at diagnosis is more modest than previously thought. Thus, the sole targeting of the immune system may not afford full therapeutic efficacy if dysfunction affects beta cells that are not under immune attack and this is a key contributor to symptoms. Combination therapies that promote both immunoregulation and address beta cell dysfunction should be more effective in treating this chronic disease process. It remains a major goal to clarify the relation of insulitis with the dynamics of beta cell loss and coexisting mechanisms of dysfunction, according to clinical stage; such improved understanding is key to design therapeutic strategies that target multiple pathogenic mechanisms.

Autoreactive T cells in type 1 diabetes

“…The pathologic hallmark of T1D is insulitis, an inflammatory lesion of the islet associated with β cell loss (17)(18)(19). Inflammatory cells are observed in the islet periphery (peri-insulitis) or within the islet parenchyma.…”

Robo4‐mediated pancreatic endothelial integrity decreases inflammation and islet destruction in autoimmune diabetes

“…Infiltration of pancreatic islets by inflammatory cells, predominantly of lymphocytes, is a major feature of T1DM in mice and humans . Immunofluorescence staining for CD45 revealed increased leukocyte accumulation in the pancreatic islets of Robo4ko mice as compared to WT mice (Figure C,E).…”

“…Infiltration of pancreatic islets by inflammatory cells, predominantly of lymphocytes, is a major feature of T1DM in mice and humans. 2 Immunofluorescence staining for CD45 revealed increased leukocyte accumulation in the pancreatic islets of Robo4ko mice as compared to WT mice ( Figure 3C,E). This finding was accompanied by increased insulitis in Robo4ko mice as indicated by hematoxylin-eosin staining of the pancreatic islets and immunohistochemistry analysis for CD3, identifying lymphocytes, although quantification of lymphocytes per islet area did not reach statistical significance ( Figure 4A-C and Supporting Information Figure S3E).…”

From immunohistological to anatomical alterations of human pancreas in type 1 diabetes: New concepts on the stage

“…It represents the typical sign and the hallmark of autoimmune attack against β‐cells, and it is characterized by adaptive and innate immune cells surrounding and/or infiltrating pancreatic islets. Insulitis is a heterogeneous phenomenon; indeed, it is detected only in a subsets of T1D donors and, frequently, in a lobular manner (Table ).…”