Thinking Outside the Cell: A Key Role for Hyaluronan in the Pathogenesis of Human Type 1 Diabetes

Bogdani, Marika

doi:10.2337/db15-1750

Cited by 16 publications

(10 citation statements)

References 99 publications

(110 reference statements)

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“…In particular, when chemokine signals are sufficiently high, if the membrane is incapable of being repaired, all of the beta cells may ultimately be killed, whereas in other situations, we find residual beta cells even after long simulation times (not shown). The importance of the basement membrane during insulitis in our model is in line with a recent study of this membrane in samples from human patients with T1D (Bogdani, 2016). …”

Section: Discussionsupporting

confidence: 87%

Spatiotemporal Dynamics of Insulitis in Human Type 1 Diabetes

et al. 2016

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Type 1 diabetes (T1D) is an auto-immune disease characterized by the selective destruction of the insulin secreting beta cells in the pancreas during an inflammatory phase known as insulitis. Patients with T1D are typically dependent on the administration of externally provided insulin in order to manage blood glucose levels. Whilst technological developments have significantly improved both the life expectancy and quality of life of these patients, an understanding of the mechanisms of the disease remains elusive. Animal models, such as the NOD mouse model, have been widely used to probe the process of insulitis, but there exist very few data from humans studied at disease onset. In this manuscript, we employ data from human pancreases collected close to the onset of T1D and propose a spatio-temporal computational model for the progression of insulitis in human T1D, with particular focus on the mechanisms underlying the development of insulitis in pancreatic islets. This framework allows us to investigate how the time-course of insulitis progression is affected by altering key parameters, such as the number of the CD20+ B cells present in the inflammatory infiltrate, which has recently been proposed to influence the aggressiveness of the disease. Through the analysis of repeated simulations of our stochastic model, which track the number of beta cells within an islet, we find that increased numbers of B cells in the peri-islet space lead to faster destruction of the beta cells. We also find that the balance between the degradation and repair of the basement membrane surrounding the islet is a critical component in governing the overall destruction rate of the beta cells and their remaining number. Our model provides a framework for continued and improved spatio-temporal modeling of human T1D.

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Section: Discussionsupporting

confidence: 87%

Spatiotemporal Dynamics of Insulitis in Human Type 1 Diabetes

et al. 2016

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“…Later studies by Wan and colleagues using an insulin-specific B cell model in NOD mice, demonstrated that insulin-binding B cells can form Spt-GCs in multiple lymphoid organs including the draining lymph node, spleen, and non-draining lymph nodes in NOD mice (73). Finally, Spt-GC structures with self-antigen reactive B cells were also observed in the spleens and lymph nodes of human T1D patients (31). …”

Section: Role Of Spt-gcs In Several Autoimmune Diseasesmentioning

confidence: 95%

“…In support of the role of Spt-GCs in promoting autoimmunity, the increased GC sizes correlated with an increased number of autoantibody-producing B cells (25). Also, in type 1 diabetes patients, Spt-GC structures form and specifically recognize self-antigen (31). …”

Section: Spontaneous Germinal Centers (Spt-gcs)mentioning

confidence: 99%

Spontaneous germinal centers and autoimmunity

2017

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Germinal centers (GCs) are dynamic microenvironments that form in the secondary lymphoid organs and generate somatically mutated high-affinity antibodies necessary to establish an effective humoral immune response. Tight regulation of GC responses is critical for maintaining self-tolerance. GCs can arise in the absence of purposeful immunization or overt infection (called spontaneous GCs, Spt-GCs). In autoimmune-prone mice and patients with autoimmune disease, aberrant regulation of Spt-GCs is thought to promote the development of somatically mutated pathogenic autoantibodies and the subsequent development of autoimmunity. The mechanisms that control the formation of Spt-GCs and promote systemic autoimmune diseases remain an open question and the focus of ongoing studies. Here, we discuss the most current studies on the role of Spt-GCs in autoimmunity.

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“…As such, inspection of images of inflamed human islets immediately suggest the existence of a physical barrier which impedes the further progress of immune cells towards the islet core. It is widely understood that islets are encased within a basement membrane composed of various proteoglycans, collagen and other fibrous proteins . As such, it seems likely that this structure will be porous to secreted hormones, chemokines and metabolites but impervious to immune cells.…”

Section: Insulitis: a Critical Mechanism In Type 1 Diabetes?mentioning

confidence: 99%

Bringing the human pancreas into focus: new paradigms for the understanding of Type 1 diabetes

Morgan

2017

Diabet. Med.

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Type 1 diabetes affects increasingly large numbers of people globally (including at least half a million children under the age of 14 years) and it remains an illness with life-long and often devastating consequences. It is surprising, therefore, that the underlying aetiology of Type 1 diabetes remains poorly understood. This is largely because the cellular and molecular processes leading to the loss of β cells in the pancreas have rarely been studied at, or soon after, the onset of disease. Where such studies have been undertaken, a number of surprises have emerged which serve to challenge conventional wisdom. In particular, it is increasingly understood that the process of islet inflammation (insulitis) is much less florid in humans than in certain animal models. Moreover, the profile of immune cells involved in the inflammatory attack on β cells is variable and this variation occurs at the level of individual patients. As a result, two distinct profiles of insulitis have now been defined that are differentially aggressive and that might, therefore, require specifically tailored therapeutic approaches to slow the progression of disease. In addition, the outcomes are also different in that the more aggressive form (termed 'CD20Hi') is associated with extensive β-cell loss and an early age of disease onset (<7 years), while the less aggressive profile (known as 'CD20Lo') is associated with later onset (>13 years) and the retention of a higher proportion of residual β cells. In the present review, these new findings are explained and their implications evaluated in terms of future therapies.

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Thinking Outside the Cell: A Key Role for Hyaluronan in the Pathogenesis of Human Type 1 Diabetes

Cited by 16 publications

References 99 publications

Spatiotemporal Dynamics of Insulitis in Human Type 1 Diabetes

Spatiotemporal Dynamics of Insulitis in Human Type 1 Diabetes

Spontaneous germinal centers and autoimmunity

Bringing the human pancreas into focus: new paradigms for the understanding of Type 1 diabetes

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