Final Progress Report

Proposal No. IBD-0104
Principal Investigator:  Edward H. Leiter, Ph.D.
Applicant Organization:  The Jackson Laboratory (Bar Harbor, Maine, U.S.A.)
Project Title:  Functional genomics of colitis susceptibility in IL-10 deficient mice
Period of Award:  March 1, 2004 – June 30, 2006

Lay Summary

Because of they are genetically well-defined, mouse models provide valuable insights into the causes of colitis.  Our Broad Medical Research Program-funded research has focused on the genetic basis for the colitis resistance of C57BL/6J (B6) mice versus the high colitis susceptibility of C3H/HeJBir (C3Bir) mice.  The genetic manipulation used to induce the clinical disease was the introduction of a mutation in the gene encoding the cytokine, IL-10.  IL-10 is an important molecule for maintaining immunologic homeostasis in the large intestine.  When the gene is mutated so that IL-10 is no longer made, severe colitis develops in C3Bir, but not B6.  Inflammatory damage in the C3Bir-IL10 deficient mouse model is the result of a hyper-reactive immune response against bacterial products.  Hence, up to the time that we initiated our Broad-funded study, the genes predisposing the gut immune system to colitis were assumed to hyperactivate what is termed the adaptive immune system (T lymphocytes and antibody-producing B lymphocytes).  Our Broad Research Program funding has led to a paradigm shift in our understanding of this model.  We found that the major genetic contributor (termed Cdcs1 on mouse Chromosome 3) controlling how a mouse responds to the colitis stress imposed by the absence of IL-10 did not impart hyper-responsiveness to the effector cells of the adaptive immune system.  On the contrary, the Cdcs1 gene acted to impair responses at the level of antigen presenting cells of the innate immune system.  Such cells include macrophages and dendritic cells that have specialized receptors to “sense” the presence of bacterial products in gut tissues and send “danger signals” to the effector cells of the adaptive immune system.   We found that the C3Bir susceptibility allele at Cdcs1 impaired this signaling function.  Thus, the hyper-responsiveness of the adaptive immune system reflects an overly strong compensatory mechanism because of a weakness in the first line of defense against microbes, the cells of the innate immune system.  This is an important conceptual advance because it falls into place with the recent finding that the human IBD1 gene (designated NOD2) is a member of a bacterial recognition pathway in cells of the innate immune system.  The human IBD1/NOD2 susceptibility alleles have been associated with an impaired ability to signal “danger” when compared to the alleles associated with resistance to Crohn’s disease.  This indicates that in both humans and in mouse models, colitis can result from an immunodeficiency state wherein communication between the innate and adaptive arms of the immune system are subnormal such that the adaptive arm becomes dysregulated and mediates inflammatory damage.