Importance of CD44 variant isoforms in mouse models for inflammatory bowel disease

A major part of immune surveillance is controlled by cell surface molecules. Defined changes in the cellular communication are features of haemopoiesis, immune pathology, embryonic development and neoplastic transformation. The transmembrane glycoprotein CD44 and its many isoforms is one of these adhesion molecules (reviewed in Günthert 1996). Experimental evidence has pointed out the involvement of CD44 isoforms in lymphocyte activation and homing into inflamed tissues, haemopoiesis, tumour dissemination and pattern formation in embryogenesis (as reviewed in Kincade et al. 1997; Lesley et al. 1997; Günthert 1996; Stauder and Günthert 1995; Ruiz et al. 1995; Günthert et al. 1995). This multipurpose nature of CD44 can possibly be explained by the enormous number of isoforms. Although only encoded by one gene, CD44 isoforms represent a large family of molecules which differ in the primary structure. These differences are produced by alternative splicing of at least ten unique exons, encoding extracellular regions out of a total of twenty exons. The function of specific variant isoforms (CD44v) has been a matter of debate for a long time. With the availability of genetically modified mice a clearer picture is emerging now. The purpose of this article is to give an overview on our current knowledge of the role of CD44 isoforms in autoimmune diseases and inflammation, with special emphasis on inflammatory bowel disease. Inflammatory bowel disease (IBD) is regarded as a dysregulated immune response to components of the normal intestinal flora (reviewed in MacDonald, 1999). In humans, Crohn’s disease and ulcerative colitis are most severe chronic inflammations with a devastating presentation. The lamina propria is massively infiltrated by activated lymphocytes, plasma cells and macrophages. The lymphocytes are mostly of T helper 1 subsets (Th1), secreting pro-inflammatory cytokines, such as IL-2 and IFN-g, whereas the macrophages secrete IL-1, IL-6, IL-8, IL-12 and TNF-a. Activated human and mouse lymphocytes are known to upregulate CD44v isoforms (reviewed in Stauder and Günthert, 1995) and hence we were interested to find out whether CD44v is of importance for the disease process in mouse models for inflammatory bowel disease. Whether the data on mouse models also apply to humans still has to be further analysed. Consistent in the two species is an exaggerated Th1 response in the lamina propria, accompanied by injury of the mucosa.