Scientific Report 2006

Immunology

Autoimmune Mechanisms and Compensatory Responses

N. Sarvetnick, M. Cleary, S. Dabernat, S. Datta, D. Dietz, C. Fine, N. Hill, H. Hua, M. Kritzik, A. Marleau, P. Secrest, A. Stotland, D. Yadav, Y.Q. Zhang

Type 1 diabetes occurs when self-reactive T cells destroy the insulin-producing beta cells in the islets in the pancreas. The assumption has been that the fault lies exclusively in the immune system, but increasingly findings suggest that the targets of autoimmunity, the islets, may also be defective. Genetic linkage analysis of nonobese diabetic mice has led to the identification of critical intervals that confer susceptibility to diabetes. One of these regions, Idd9, is associated with strong protection from disease when it is replaced with the B10 allele. Interestingly, we found that genes at the Idd9 locus associated with susceptibility to diabetes control islet resilience to CD8⁺ T cell–mediated autoimmunity.

Susceptible islets are hyperresponsive to the cytokines TNF and IFN-γ, resulting in increased expression of the death receptor Fas. Fas upregulation in beta cells is mediated by TNF receptor 2 (TNFR2), and in nonobese diabetic mice, colocalization of the receptor with the adaptor TNF receptor–associated factor 2 in beta cells is altered. The gene for TNFR2 lies within the candidate Idd9 interval, and the diabetes-associated variant contains a mutation adjacent to the binding site for TNF receptor–associated factor 2. A component of diabetes susceptibility is therefore determined by the target of the autoimmune response, and protective TNFR2 signaling in islets may inhibit early cytokine-induced damage required for the development of destructive autoimmunity.

Because insulin-dependent diabetes mellitus is due to selective destruction of insulin-producing cells, strategies that promote growth of beta cells provide a means to prevent or reverse this type of diabetes. One approach is to replace insulin-producing cells by using genetic engineering or by guiding stem cells (pancreas progenitors) to differentiate into beta cells. The progression of pancreatic progenitor cells to beta cells is governed by basic helix-loop-helix transcription factors, which are regulated by inhibitor of differentiation proteins that bind to and inhibit the function of the factors. Transcription of inhibitor of differentiation proteins is induced by bone morphogenetic proteins (BMPs).

We showed that BMP signaling is necessary and sufficient for proliferation of pancreatic progenitor cells and that this signaling is correlated with an increase in the expression of inhibitor of differentiation proteins. Using a mouse model of regenerating pancreas, we found that injection of an antibody that inhibits BMP4 significantly reduced cell proliferation and caused an increase in NeuroD, a basic helix-loop-helix factor required for the differentiation of pancreatic islet cells. Therefore, our results indicate that stimulation by BMP4 blocks the differentiation of endocrine progenitor cells and instead promotes their expansion, thereby revealing a novel model of signaling that explains the balance between expansion and differentiation of pancreatic duct epithelial progenitors.

Publications

Flodstrom-Tullberg, M., Hultcrantz, M., Stotland, A., Maday, A., Tsai, D., Fine, C., Williams, B., Silverman, R., Sarvetnick, N. RNase L and double-stranded RNA-dependent protein kinase exert complementary roles in islet cell defense during coxsackievirus infection. J. Immunol. 174:1171, 2005.

Horwitz, M.S., Ilic, A., Fine, C., Sarvetnick, N. Induction of antigen specific peripheral humoral tolerance to cardiac myosin does not prevent CB3-mediated autoimmune myocarditis. J. Autoimmun. 25:102, 2005.

Hua, H., Zhang, Y.Q., Dabernat, S., Kritzik, M.N., Dietz, D., Sterling, L., Sarvetnick, N. BMP4 regulates pancreatic progenitor cell expansion through Id2. J. Biol. Chem. 281:13574, 2006.

Kayali, A.G., Stotland, A., Gunst, K.V., Kritzik, M., Liu, G., Dabernat, S., Zhang, Y.Q., Wu, W., Sarvetnick, N. Growth factor-induced signaling of the pancreatic epithelium. J. Endocrinol. 185:45, 2005.

Kim, S.H., Gunst, K.V., Sarvetnick, N. STAT4/6-dependent differential regulation of chemokine receptors. Clin. Immunol. 118:250, 2006.

Marleau, A.M., Sarvetnick, N. T cell homeostasis in tolerance and immunity. J. Leukoc. Biol. 78:575, 2005.

Martinez, X., Kreuwel, H.T., Redmond, W.L., Trenney, R., Hunter, K., Rosen, H., Sarvetnick, N., Wicker, L.S., Sherman, L.A. CD8⁺ T cell tolerance in nonobese diabetic mice is restored by insulin-dependent diabetes resistance alleles. J. Immunol. 175:1677, 2005.

Solomon, M., Flodstrom-Tullberg, M., Sarvetnick, N. Differences in suppressor of cytokine signaling-1 (SOCS-1) expressing islet allograft destruction in normal BALB/c and spontaneously-diabetic NOD recipient mice. Transplantation 15:1104, 2005.

Zhang, Y.Q., Kritzik, M., Sarvetnick, N. Identification and expansion of pancreatic stem/progenitor cells. J. Cell. Mol. Med. 9:331, 2005.