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Novel insights of intracellular complement in pancreatic β-cell physiology

Rosberg, Rebecca (2017) MOBT01 20162
Degree Projects in Molecular Biology
Abstract
The complement system is a link between adaptive and innate immunity, which is a first line protection against pathogens. It can be activated through three different pathways which all lead to formation of C3 and C5 convertases and final complement-mediated lysis of cells. The system contains regulatory mechanisms at different steps of activation to avoid lysing of own cells. Recent years, have shown that different components of the complement system are involved in homeostatic mechanisms other than its role in immunity. Intracellular complement is now a widely expanding research area. The central protein C3, and the main complement inhibitor CD59, have shown to be highly expressed in pancreatic β-cells. An intracellular pool of CD59 seems... (More)
The complement system is a link between adaptive and innate immunity, which is a first line protection against pathogens. It can be activated through three different pathways which all lead to formation of C3 and C5 convertases and final complement-mediated lysis of cells. The system contains regulatory mechanisms at different steps of activation to avoid lysing of own cells. Recent years, have shown that different components of the complement system are involved in homeostatic mechanisms other than its role in immunity. Intracellular complement is now a widely expanding research area. The central protein C3, and the main complement inhibitor CD59, have shown to be highly expressed in pancreatic β-cells. An intracellular pool of CD59 seems to be involved in the exocytotic machinery for insulin secretion and C3 seems to play a role in autophagy regulation in β-cells. Here I will use the insulin secreting cell line INS-1 823/13 for investigating the role of complement proteins in insulin secretion mechanism. (Less)
Popular Abstract
Intracellular complement in Type-2 Diabetes

Traditionally, complement has represented the defence against invading pathogens by circulating serum protective proteins resulting in opsonisation and complement-mediated cell lysis of foreign cells. Recent years have revealed that complement has other functions than the classical defence immunity and is involved in a variety of basic cellular processes. Intracellular complement, also called the complosome, is a widely newly explored topic that has shown to be linked to a series of different diseases such as type 2 diabetes.

Activation of the complement system results in inflammation and targeting of bacteria. The final step of complement activation is the creation of a membrane attack... (More)
Intracellular complement in Type-2 Diabetes

Traditionally, complement has represented the defence against invading pathogens by circulating serum protective proteins resulting in opsonisation and complement-mediated cell lysis of foreign cells. Recent years have revealed that complement has other functions than the classical defence immunity and is involved in a variety of basic cellular processes. Intracellular complement, also called the complosome, is a widely newly explored topic that has shown to be linked to a series of different diseases such as type 2 diabetes.

Activation of the complement system results in inflammation and targeting of bacteria. The final step of complement activation is the creation of a membrane attack complex that lyse cells. The host own cells have developed regulatory mechanisms to prevent lysing of their own cells. CD59 is a protein that sits on the cell surface that inhibits the final step of the complement-mediated cell lysis. It does so by preventing the formation and assembly of the membrane attack complex. The complement inhibitory CD59 protein have been shown to be highly expressed in pancreatic β-cells, suggesting a role for this protein other than its classical complement inhibitory function.

Type-2 Diabetes is one of the most increasing metabolic disorders in the world. It has an adult-onset that has been linked to obesity and smoking. The β-cells in the pancreas normally secrete insulin in response to higher blood glucose after a meal. In type-2 diabetes there is lower secretion of the insulin hormone from pancreas and an insulin-resistance arise leading to higher blood sugars levels.

Intracellular complement in β-cells
It has been shown that mice expressing Type-2 diabetic symptoms have lower amount of CD59 expression compared to healthy mice. It has previously been shown that when CD59 is removed from β- cells they secrete less insulin. Here we wanted to investigate the role of CD59 in relation to insulin secretion. We have created a version of CD59 that can be expressed inside cells rather than at its classical position on cell surface. We then inserted this intracellular version of the protein into β-cells. From our experiments, we can rescue the β-cells insulin secretion capability using this intracellular version of the CD59 when the cells own CD59 is absent. This suggests that there is an intracellular version of the CD59 in β-cells that are responsible for functional insulin secretion. Suggesting it has another role in β-cells and not only its original complement inhibitor function on cell surface. These results give hope for a future diabetes treatment using this intracellular CD59 as a biomarker.

Master’s Degree Project in Molecular Biology 60 credits 2017
Department of Biology, Lund University
Advisors: Ben King, Anna Blom. Department of Translational Medicine, Malmö (Less)
Please use this url to cite or link to this publication:
author
Rosberg, Rebecca
supervisor
organization
course
MOBT01 20162
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
8905511
date added to LUP
2017-04-06 09:41:51
date last changed
2017-04-06 09:41:51
@misc{8905511,
  abstract     = {The complement system is a link between adaptive and innate immunity, which is a first line protection against pathogens. It can be activated through three different pathways which all lead to formation of C3 and C5 convertases and final complement-mediated lysis of cells. The system contains regulatory mechanisms at different steps of activation to avoid lysing of own cells. Recent years, have shown that different components of the complement system are involved in homeostatic mechanisms other than its role in immunity. Intracellular complement is now a widely expanding research area. The central protein C3, and the main complement inhibitor CD59, have shown to be highly expressed in pancreatic β-cells. An intracellular pool of CD59 seems to be involved in the exocytotic machinery for insulin secretion and C3 seems to play a role in autophagy regulation in β-cells. Here I will use the insulin secreting cell line INS-1 823/13 for investigating the role of complement proteins in insulin secretion mechanism.},
  author       = {Rosberg, Rebecca},
  language     = {eng},
  note         = {Student Paper},
  title        = {Novel insights of intracellular complement in pancreatic β-cell physiology},
  year         = {2017},
}