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

¹ Oulu Center for Cell-Matrix Research, Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, ² Department of Clinical Chemistry, ³ Department of Pathology, ⁴ Biocenter Oulu and Department of Pathology, and ⁵ Biocenter Oulu, University of Oulu, Oulu, Finland; ⁶ Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; and ⁷ Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland

Requests for reprints: Taina Pihlajaniemi, Oulu Center for Cell-Matrix Research, Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, FIN-90014 Oulu, Finland. Phone: 358-8-5375800; E-mail: taina.pihlajaniemi{at}oulu.fi or Herbert C. Morse III, Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland. E-mail: hm16c{at}nih.gov.

Key Words: Collagen • extracellular matrix • lymphoma • immune response

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):10324–31]