Etiology of Inflammatory Bowel Disease

Inflammatory bowel disease appears to result from a dysregulated immune response to intestinal contents. Inflammatory cells are always present in normal mucosa poised to protect us from potentially harmful luminal agents. In patients with Crohn disease (CD) or ulcerative colitis, the normal tightly controlled activity of the mucosal immune system becomes excessive resulting in profound tissue damage. To prevent this tissue damage, patients with IBD are placed on potent medications (glucocorticoids, azathioprine, infliximab, cyclosporine, and/or methotrexate) that suppress cellular immunity.

Animal models of IBD show that immune dysregulation results in intestinal inflammation and provide insight into the circuits that prevent excessive activity. Immune-deficient mice develop colitis when given a segregated population of naïve CD4+ T cells (CD45RBHigh). The colitis can be prevented by cotransfer of CD45RBLow-expressing T cells. The cytokines transforming growth factor β (TGF-β) and interleukin (IL)-10 are required for this regulation.[1,2] IL-10 is a regulatory cytokine that inhibits macrophage and dendritic cell activation and suppresses production of proinflammatory mediators such as tumor necrosis factor a, IL-12, IL-1, nitric oxide, and several chemokines.[3] Mice that lack IL-10 develop spontaneous colitis.[4] TGF-β has many actions[5] including inhibition of T-cell proliferation. TGF-β prevents naïve T cells from expressing transcription factors (T-bet, Gata-3) that drive their development into effector T cells.[6,7] Instead, TGF-β induces T cells to express the transcription factor Foxp3 (scurfin) that drives their development into a regulatory phenotype.[8**] Mice engineered to have T cells that cannot sense TGF-β develop spontaneous colitis.[9]

In most animal models of IBD, inflammation results from an excessive T helper (Th) 1 response. Cellular immune responses often polarize into the Th1 type, characterized by cells that make IL-12, interferon gamma (IFN-γ), or tumor necrosis factor a and the Th2 type, characterized by cells that make IL-4, IL-5, and IL-13.[10] When unbridled, either polarized Th1 or Th2 responses can cause disease. Diseases associated with polarized Th1 responses include CD, multiple sclerosis, insulin-dependent diabetes, rheumatoid arthritis, and psoriasis. Diseases associated with polarized Th2 responses include atopic dermatitis, allergic rhinitis, and asthma. Ulcerative colitis has features of both Th1 (IFN-γ) and Th2 (IL-4) responses.

Normally, the immune response is appropriately restrained by multiple homeostatic mechanisms (Fig. 1). IFN-γ made by Th1 cells inhibits development and proliferation of Th2 cells, whereas IL-4, IL-13, and IL-10 made by Th2 cells inhibit generation of Th1 cells. Thus, the Th1 and Th2 responses are counterregulatory. More recently identified are at least three phenotypes of T cells with predominant regulatory function (Treg) called the natural T regulatory, Th3, and Tr1 subtypes. Natural CD4+CD25+ regulatory T cells, differentiated in the thymus, inhibit proliferation of other T cells by cell contact.[11] Mice that lack natural regulator T cells develop autoimmune diseases. Regulatory CD4+CD25+ T cells may also develop outside the thymus.[12*] A transcription factor that drives development of CD4+CD25+ Tregs is FoxP3.[13**,14**] Animals and patients lacking Foxp3 develop severe, fatal multiorgan autoimmune disease.[15,16] Th3 cells make TGF-β[17] that inhibits development of both Th1 and Th2 cells. Tr1 cells make copious amounts of IL-10 that inhibits both Th1 and Th2 responses.[3]

Pathways of Immune Regulation

What causes the immune dysregulation in IBD is unknown. A mutation in Card15 ( Nod2 ) accounts for some of the risk of developing CD in Western populations.[18,19] Card15 is a protein expressed in Paneth cells and monocytes that senses muramyl dipeptide, a component of all bacteria.[20**,21] Although Card15 mutations confer risk, they are neither required nor sufficient for developing CD. Most patients with CD do not have Card15 mutations and most people with Card15 mutations do not have CD. This shows that the interaction of multiple genes contributes to developing CD.

Although genes contribute, environmental factors also affect the development of IBD. Studies of monozygotic (genetically identical) twins show a concordance rate for IBD in 50% of twins with CD (observed for an average of 27.4 years) and 18.8% of twins with ulcerative colitis (observed for an average of 32.2 years).[22**] Concordance rates would be much higher for identical twins if genes alone predestined IBD.