Bonnie N. Dittel, PhD
Blood Research Institute, BloodCenter of Wisconsin
Assistant Professor, Microbiology and Molecular Genetics
Medical College of Wisconsin
Research Focus: Immune regulation and homeostasis
University of Minnesota, Minneapolis (1994) Pathobiology
One goal of my research program is to investigate the cellular and molecular mechanisms involved in the regulation of the autoimmune immune response. Broadly, we are studying how the immune system regulates inflammation associated with the central nervous system autoimmune disease multiple sclerosis (MS). These studies are largely conducted using the animal model of MS experimental autoimmune encephalomyelitis (EAE). Specific areas of interest are regulatory mechanisms of B cells, immune-mediated neuronal damage and myeloperoxidase as a therapeutic target in CNS autoimmunity.
Regulatory B Cells (Breg)
B cell regulation of autoimmunity was first demonstrated in the EAE model, where it was demonstrated that mice deficient in B cells were unable to recover from the clinical signs of EAE. We have discovered that B cells promote recovery from EAE by maintenance of CD4+Foxp3+ T regulatory (Treg) cell numbers in a GITRL-dependent manner. Our current studies focus on the identification Breg:Treg cell interactions required for Treg proliferation. In addition, we have identified a novel Breg phenotype that induces Treg proliferation that we are now studying in humans.
Immune-Mediated Neuronal Damage
Although both EAE and MS are demyelinating diseases not all of the clinical symptoms can be explained by just the loss of the myelin sheath in localized lesions. Indeed, it is known that damage to neurons occurs in both EAE and MS. We have discovered that T cells with cytolytic potential upon activation secrete a protein that induces axonal damage by destabilization of microtubules. Intact microtubules are essential to the function and health of neurons. Furthermore, we found that microtubule destabilization is driven by a protein component of lytic granules. In our current studies, we are using a variety of methods to identify the lytic granule protein and to determine the cellular and biochemical signals that lead to axonal damage.
Myeloperoxidase is a potent pro-oxidative enzyme that converts H2O2 into highly reactive oxidants and free radicals that cause cellular injury. Using a novel MPO inhibitor developed by Dr. Dittel’s collaborators, we have been able to demonstrate that inhibition of MPO significantly attenuates EAE disease severity. Our current studies focus on the mechanism whereby MPO induces cellular damage in EAE.
Regulatory B and T cells
Ray, A., S. Basu, C. Williams, N. Salzman and B.N. Dittel. 2012. A novel IL-10-independent regulatory role
for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITRL. J. Immunol.
Ray, A., S. Basu, N.M. Miller, A.M. Chan and B.N. Dittel. 2014. An increase in tolerogenic dendritic cells and
natural T regulatory cell numbers during EAE in Rras-/- mice results in attenuated disease. J. Immunol.
Wang, L., A. Ray, X. Jiang, J-Y. Wang, S. Basu, X. Liu, T. Qian, B.N. Dittel* and Y. Chu*. 2015. T regulatory
cells and B cells cooperate to form a regulatory loop that maintains gut homeostasis and suppresses dextran
sulfate sodium-induced colitis. Mucosal Immunol. doi: 10.1038/mi.2015.20. Epub ahead of print.
Ray, A., L. Wang, and B.N. Dittel. 2015. IL-10-independent regulatory B cell subsets and mechanism of action. Int. Immunol. doi: 10.1093/intimm/dxv033. Epub ahead of print.
Immune-Mediated Neuronal Damage
Shriver, L.P. and B.N. Dittel. 2006. T cell-mediated disruption of the neuronal microtubule network:
Correlation with early reversible axonal dysfunction in acute experimental autoimmune encephalomyelitis.
Amer. J. Path. 169:999-1011.
Miller, N., L.P. Shriver, V.L. Bodiga, A. Ray, S. Basu, R. Ahuja, A. Jana, K. Pahan and B.N. Dittel. 2013. Lymphocytes with cytotoxic activity induce rapid microtubule axonal destabilization independently and before signs of neuronal death. ASN NEURO. e00105. doi:10.1042/AN20120087
View a complete list of my publications