Skip to the content
 

Organ Specific Autoimmunity

Autoimmune diseases

These studies are performed in collaboration with Professor Ban-Hock Toh

General Background

Autoimmune diseases are the consequence of an inappropriate immune response directed to self-antigens. Autoimmune diseases can be broadly divided into organ-specific and systemic autoimmune diseases. Sytemic autoimmune diseases include diseases such as systemic lupus erythematosus (SLE), scleroderma and polymyositis. The feature of these diseases is that the targeted antigens are located throughout the body. As the name implies, organ-specific autoimmune diseases involve specific organs of the body in which the target auto-antigen is found. Examples of organ-specific autoimmune diseases include type 1 or insulin-dependant diabetes (insulin secreting cells of the pancreas), thyroiditis (thyroid), multiple sclerosis (myelin sheath of the nervous system; brain) and autoimmune gastritis; which is the underlying cause of pernicious anaemia (acid secreting cells of the stomach). Collectively, autoimmune diseases affect up to 6% of the population and represents the 3rd greatest health issue behind heart disease and cancer. As such, much research is directed towards understanding the mechanisms associated with the development and pathology of autoimmune diseases. Ultimately, this is aimed at providing new and better treatment and developing cures for these diseases.

Mouse model of Experimental Autoimmune Gastritis

Our research group is interested in the autoimmune response associated with autoimmune gastritis. Much of our studies revolve around an experimental mouse model of autoimmune gastritis (EAG). Experimental autoimmune gastritis can be induced by a number of procedures which include neonatal thymectomy, immunisation with autoantigen, repeated low dose irradiation and transgenic expression of GM-CSF in the stomach. Regardless of the induction protocol, the characteristics associated with EAG are similar. They are characterised by induction of autoantibodies to gastric parietal cells in which the target antigens are the alpha and beta subunits of the gastric H/K ATPase, a mononuclear cell infiltrate within the gastric mucosa and cellular destruction within the gastric mucosa. The components of the stomach that are the target areas in autoimmune gastritis humans and the animal model are illustrated in Figure 1 below

Figure 1. Schematic diagram showing the organization of the gastric mucosa, gastric gland, gastric parietal cell and the gastric H/K ATPase

Figure 1. Schematic diagram showing the organization of the gastric mucosa, gastric gland, gastric parietal cell and the gastric H/K ATPase.

Using these models, we are exploring important aspects of autoimmunity. Some of these important aspects are illustrated in Figure 2 below.

Key features associated with the autoimmune response in models of EAG

Figure 2. Key features associated with the autoimmune response in models of EAG. These focus on (1) Initial triggers of autoimmunity such as perturbation of immune regulation or local inflammation. (2) Ingestion of abundant local H/K ATPase together with activation of APCs results in enhanced presentation of gastric autoantigens. (3) Activated APCs migrate to the draining paragastric lymph node where they are instrumental in (4), activation of H+/K+ ATPase specific T cells within the draining lymph node and overriding of local tolerance mechanisms. (5) Activated CD4+ T cells migrate through homing and chemokine receptors from the draining lymph node to the gastric mucosa where they (6) initiate and propagate the cellular destruction associated with EAG.