The role of TL1A and DR3 in autoimmune and inflammatory diseases.

TNF-like ligand 1A (TL1A), which binds its cognate receptor DR3 and the decoy receptor DcR3, is an identified member of the TNF superfamily. TL1A exerts pleiotropic effects on cell proliferation, activation, and differentiation of immune cells, including helper T cells and regulatory T cells. TL1A and its two receptors expression is increased in both serum and inflamed tissues in autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). Polymorphisms of the TNFSF15 gene that encodes TL1A are associated with the pathogenesis of irritable bowel syndrome, leprosy, and autoimmune diseases, including IBD, AS, and primary biliary cirrhosis (PBC). In mice, blocking of TL1A-DR3 interaction by either antagonistic antibodies or deletion of the DR3 gene attenuates the severity of multiple autoimmune diseases, whereas sustained TL1A expression on T cells or dendritic cells induces IL-13-dependent small intestinal inflammation. This suggests that modulation of TL1A-DR3 interaction may be a potential therapeutic target in several autoimmune diseases, including IBD, RA, AS, and PBC.

An experimental animal model of granulomatous bowel disease.

A study has been undertaken of the granulomatous response induced in the ascending colon and terminal ileum of the guinea pig by the direct inoculation of mycobacterial antigens. Live BCG (Pasteur) 2 x 10(7) at two weeks induced epithelioid cell granulomas in both large and small bowel and in the draining lymph nodes. The area of infiltration was significantly greater for a given inoculum in the large bowel. Acid fast bacilli were present on Ziehl Neelson stained sections of the large bowel infiltrate, but only rarely in sections from the small bowel lesions. The response to skin testing with a standardised amount of purified protein derivative was less in animals inoculated in the small bowel. Inoculation with 2 x 10(9) cobalt irradiated BCG gave rise, at five weeks, to granulomas containing lesser numbers of epithelioid cells and caseation was sometimes evident. There was a similar but smaller difference in the degree of infiltration at the two inoculation sites. Ziehl Neelson staining failed to reveal the presence of acid fast bacilli in any sections of the bowel infiltrates. Skin testing with purified protein derivative gave a response which was greater in animals inoculated in the small bowel. An identical dose of Cobalt irradiated M leprae induced at five weeks a predominantly macrophage granuloma in both the large and small bowel, with no significant difference in the degree of infiltration at the two sites. No acid fast bacilli were seen in Ziehl Neelson stained sections of the bowel and skin testing with purified protein derivative was reduced. These findings and their relevance to studies of the aetiology of Crohn's disease are discussed.