A mutant collagen XIII alters intestinal expression of immune response genes and predisposes transgenic mice to develop B-cell lymphomas.
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.
Tuomisto
Anne
A
Department of Medical Biochemistry, Oulu Center for Cell-Matrix Research, Institute of Biomedicine, University of Oulu, Oulu, Finland.
Sund
Malin
M
Tahkola
Jenni
J
Latvanlehto
Anne
A
Savolainen
Eeva-Riitta
ER
Autio-Harmainen
Helena
H
Liakka
Annikki
A
Sormunen
Raija
R
Vuoristo
Jussi
J
West
Anne
A
Lahesmaa
Riitta
R
Morse
Herbert C
HC
Pihlajaniemi
Taina
T
D000818:Animals; D001485:Basement Membrane / Q000276:immunology; D024181:Collagen Type XIII / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D018928:Immunity, Mucosal / Q000235:genetics; D007421:Intestine, Small / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction
D024181:Collagen Type XIII