Regulation of Mucosal Immune Responses and Induction of Autoimmune Arthritis

Ankylosing Spondylitis (AS) and Reactive Arthritis (ReA) are important members of a group of inflammatory arthritides collectively known as the seronegative spondyloarthropathies. Although the precise cause is unknown, ReA is thought to represent a form of autoimmunity. The pathways by which autoimmune diseases develop remain poorly understood, although many lines of evidence point towards a defect in correct regulation of the immune system that can lead to a breakdown of immunological tolerance. In addition it is recognised that an infectious component may also exist in different autoimmune diseases, whereby triggering of the immune system to specific pathogens can result in a cross reactivity between proteins carried by the infectious agent and those expressed by self tissues. Indeed, ReA is normally preceded by infection with certain strains of gastrointestinal and genitourinary bacteria such as Salmonella and Chlamydia. <P>
This has lead us and others to hypothesise that infection with such organisms and / or defects in normal immune regulation may constitute primary factors in the aetiology of ReA. We have generated novel animal models for arthritis which have allowed us to investigate specific aspects of immune function associated with this disease. In these animals novel genes are expressed within specialised cells of the joints called chondrocytes. The artificial induction of immune responses to the antigenic proteins encoded by these transgenes, allows a highly accessible means of studying the potential pathogenic effects that this may have on joint tissue. <P>In light of the close correlation between intestinal inflammation and infection with the incidence of ReA, we propose to investigate how immune responses towards joint antigens are influenced by the immunological environment within the intestine. To achieve this we will employ refined systems in which manipulation of peripheral and mucosal T cell sub-sets results in the development of a specific type of intestinal inflammation. <P>Altering the immunological climate within the intestine through these very specific means, will place us in a position to specifically address the role that intestinal immunity plays in the development of joint specific autoimmunity.