A Mutant Collagen XIII Alters Intestinal Expression of Immune Response Genes and Predisposes Transgenic Mice to Develop B-Cell Lymphomas

Abstract

Epithelial cells of mucosal surfaces are critical for maintaining immune homeostasis by aiding in the discrimination of pathogenic and commensal microorganisms and modulating the activities of antigen-presenting cells and lymphocytes. Functional breakdowns resulting in chronic infection and inflammation are associated with the development of hematologic and solid neoplasms for which detailed pathogenetic mechanisms are poorly understood. Mice heterozygous for a transgene Col13a1 del expressing a mutant collagen XIII developed clonal mature B-cell lineage lymphomas originating in mesenteric lymph nodes (MLN). The tumors were associated with T cells and macrophages. The incidence of disease was reduced 2-fold in transgenic mice raised under specific pathogen-free conditions, suggesting a role for infectious agents. The lymphomas did not express the mutant collagen XIII, indicating that its influence on tumorigenesis was B-cell extrinsic and likely to be associated with collagen XIII-positive tissues drained by the MLN. Studies of the small intestines of transgenic mice showed that the subepithelial basement membranes (BM) were highly abnormal and that they exhibited heightened expression of genes involved in immune responses. These results define collagen XIII-dependent maintenance of the intestinal BM as a previously unappreciated component of immune responses and a critical determinant of cancer susceptibility. [Cancer Res 2008;68(24):10324-32]

Genome-Wide Association Study Identifies Variants Associated With Histologic Features of Nonalcoholic Fatty Liver Disease

“…LTBP3 secretion is known to be dependent upon co-expression of TGF-beta24 which is a key pro-fibrogenic cytokine that is activated in chronic inflammation and leads to collagen deposition 25,26. COL13A1 has been previously linked with modifying inflammatory response genes in intestine 27. A recent GWAS study showed that EFCAB4B is associated with hypertension in Chinese population 28.…”

Collagen XIII: A type II transmembrane protein with relevance to musculoskeletal tissues, microvessels and inflammation

“…Vascular functions have also been implicated in a mouse model for Alport syndrome, where collagen XIII expression was found to be induced in the inflamed kidney endothelium, mediating selective recruitment of ␣1␤1 integrin-positive monocytes to the kidney (Dennis et al, 2010). Furthermore, collagen XIII affects the immune system, as shown with mice expressing a low dose of the truncated dominant-negative minigene mentioned above, which develop B-cell lymphomas and present heightened expression of immune response genes in the gastrointestinal tract (Tuomisto et al, 2008). Interestingly, COL13A1 was classified as a prognostically favourable molecule in large-B-cell lymphomas (Lenz et al, 2008).…”

“…Being derived mostly from mesenchymal cells, collagen XIII is found in practically all tissues studied, often in association with BMs, e.g. in blood vessels or junctional structures such as myotendinous and neuromuscular junctions (MTJ and NMJ) and the periosteum Sund et al, 2001a;Tuomisto et al, 2008;Kvist et al, 2001;Latvanlehto et al, 2010;Ylönen et al, 2005). The highest local concentrations of collagen XIII identified in a ␤-galactosidase reporter mouse model generated by homologous recombination were in the postnatal NMJ and the periosteum (Latvanlehto et al, 2010).…”

“…The transcripts encoded by the collagen XIII gene were found to undergo complex alternative splicing (Pihlajaniemi et al, 1987;Pihlajaniemi and Tamminen, 1990;Peltonen et al, 1997), and the structure and processing of the resulting protein have been described in numerous studies (Hägg et al, 1998Snellman et al, 2000aSnellman et al, ,b, 2007Tu et al, 2002;Väisänen et al, 2004Väisänen et al, , 2006a. Collagen XIII is broadly expressed in mesenchymal tissues, albeit at low levels Sund et al, 2001a;Ylönen et al, 2005;Tuomisto et al, 2008;Latvanlehto et al, 2010). Expression profiling has identified changes in collagen XIII levels in certain human pathological conditions, and it is thought to have a protective role against cancer development (Väisänen et al, 2005;Määttä et al, 2006;Lenz et al, 2008).…”

Microarray Analysis Identifies a Unique Molecular Signature of Human Thyroid Cancer Stem Cells

“…For example, COL13A1 is the most highly down-regulated in thyrospheres, which express 521-fold lower levels than do monolayer cells (p=0.0000207). It encodes the alpha chain of one of the nonfibrillar collagens [20]. The function of this gene product in ATC is unknown.…”