Insulitis is an inflammatory infiltration of the islets of Langerhans found especially in young patients with recent onset type 1 diabetes (<1 year). The infiltrate classically consists of cytotoxic T cells, but macrophages, T helper cells and B cells may form part of the infiltrating cell mixture. Insulitis is limited to islets that still contain beta cells: it is only rarely found in islets in which the disease has run its course and where the beta cells have disappeared. It is not known why the islets become inflamed, why the inflammation only targets beta cells or how it results in the destruction of >70% of the beta cell mass at diagnosis.
What is insulitis?
Insulitis is a subtle and easy to miss lesion that is found in 5–10% of the islets of Langerhans in about 70% of children with recent onset disease. It consists of a peri- or intra-islet accumulation of immune cells, mainly of the CD3+CD8+ lymphocyte subtype, together with CD68+ macrophages, CD3+CD4+ T-helper cells and CD20+ B-lymphocytes. The infiltrate may be present as a single cluster of immune cells at one pole of the islet (peri-insulitis) or have a more diffuse pattern of infiltration within the islet (intra-insulitis). At clinical onset only a small fraction of islets show insulitis, most other islets (on average 50–60%) appear to be 'pseudo-atrophic', meaning that they have already lost virtually all their insulin-containing beta cells. This specific loss of beta cells is a hallmark of the disease, in which a T cell-mediated auto-immune process appears to be directed against an unknown beta cell antigen. Not all islets are affected by the disease, a variable proportion (on average some 30%) do not show any histopathological changes. The residual beta cell mass slowly decreases with time after onset and some beta cells remain in most patients even after a disease duration of more than 50 years.
Insulitis in human type 1 diabetes: islet cells are stained for insulin (blue), infiltrating cells are stained for the T-cell marker CD3 (green) and CD8 (red).
How is insulitis defined?
There is no common definition of insulitis: different pathologists in different studies have used their own interpretation of their microscopic observations. One reason for this lack of a common standard is the small number of human cases that have been studied, only about 150 cases with insulitis have been described over the past century and half of these cases were collected in the context of two large studies, one from 1965 and one from 1986. The low number of cases reflects the difficulty in obtaining study material: the pancreas is difficult to biopsy, only a small fraction of islets is involved, and the lesion is mainly found in young children in the first year after diagnosis who died of keto-acidosis. A renewed interest in human insulitis derives from the realisation that animal studies will not resolve many of the questions that have to be answered. Major efforts are therefore underway to collect human pancreas from organ donors with either established disease or humoral evidence of an ongoing immune process.
How was it discovered?
The presence of an inflammatory infiltrate in the islets of Langerhans was first noticed in 1902 by the German pathologist Martin Schmidt in the pancreas of a 10-year-old child with diabetes. It was initially considered to be a rare event and not characteristic for the disease. It was only after Philip LeCompte in 1958 found the lesion in four children with acute onset disease that it was speculated that insulitis might be much more frequent than initially thought. The Brussels-based pathologist Willy Gepts was the first to collect a sufficient number of cases to state unequivocally that insulitis is characteristic for early onset of diabetes in children and suggested that the inflammation might indicate an ongoing process of auto-immunity, thus setting the stage for an important new domain of research.
Willy Gepts (1922-1991)
Is it present in all patients?
Insulitis is most frequently found in young (<14 years) patients shortly after the diagnosis is clinically made (73% of patients), it is much less frequent in patients with chronic disease (4%). In patients that develop the disease at an older age (>14 years) insulitis is more difficult to detect. Such patients also show a higher proportion of islets that still contain beta cells, indicating that the disease runs a less fulminant course in older individuals. Even after 50 years of disease patients may still have residual beta cells in their islets, especially when they developed the disease at a later age.
Do we know which antigens are targeted?
Studies in experimental animals have indicated a range of autoantigens against which an autoimmune response might be generated. In how far these studies are relevant to the human situation is open to discussion. Recently, the specificity of infiltrating CD3+CD8+ cytotoxic T lymphocytes was analysed using so-called tetramer staining on sections of human pancreas from recent onset and chronic type 1 diabetes patients. The results suggest that these cytotoxic T cells are directed against several different autoantigens, including insulin, tyrosine phosphatase-like protein (IA-2), islet specific glucose-6-phosphatase catalytic subunit related protein (IGRP), preproinsulin, glutamic acid decarboxylase (GAD65) and islet amyloid polypeptide precursor protein (ppIAPP). Interestingly, these specificities are similar to those of the circulating autoantibodies that are found in type 1 diabetes patients and in individuals that are at a higher risk for developing the disease. A key question remains whether these reactive T cells and autoantibodies are a cause or of a consequence of beta cell destruction.
Is a virus involved?
An important hypothesis that is still being investigated is that beta cell death and autoimmunity are triggered by a viral infection. In 1969 a significant correlation was found between seasonality of type 1 diabetes and the prevalence of coxsackie B4 virus infection. Many other different types of viruses have also been implicated, including rubella virus, cytomegalovirus, mumpsvirus and enterovirus. Some cases of recent onset type 1 diabetes are known in which a virus was isolated from the pancreas from patients with signs of insulitis and beta cell destruction, but the stringent criteria of Koch to prove a viral involvement in this disease have only been met in a single case. Most indications of a viral involvement are indirect, including the presence of immunoreactivity for the viral capsid protein (VP1) and overexpression of HLA class I antigens on islet cells. Whether virus infections are a causal factor or have a modulatory role in the development of the disease together with other environmental factors and a genetic predisposition remains to be resolved.
^ In’t Veld P. Insulitis in human type the quest for an elusive lesion. Islets 2012;3(4):131–8
^ Keenan HA, Sun JK, Levine J, et al. Residual insulin production and pancreatic beta cell turnover after 50 years of Joslin Medalist study. Diabetes 2010;59(11):2846–53
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^ Coppieters KT et al. Demonstration of islet-autoreactive CD8 T-cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med 2012;209:51–60
^ In’t Veld P. Insulitis in the human Does a viral infection lead to inflammation and beta cell replication? Diabetologia 2011 Sep;54(9):2220-2.