Periodontitis is a chronic inflammatory disease that is the leading cause of periodontal tissue destruction and tooth loss. The cost of treating periodontal diseases in the U.S. in 2011 was estimated at $50 billion. Severe periodontitis has been associated with Porphyromonas gingivalis (Pg) colonization of the oral mucosa and has been characterized as an immune-driven disease. The impact of mucosal oral Langerhans cells (oLCs) on the differentiation of pathogenic CD4+ T helper cells (Th) and alveolar bone destruction remains unresolved. Our current objective is to determine how oLCs drive a destructive Th17 response in the mouse periodontitis model. We hypothesize that oLCs produce a toll-like receptor/MyD88-dependent diffusible signal that conditions underlying lamina propria-resident dendritic cells (DCs) to a Th17 polarizing program in a manner independent of major histo-compatibility class II (MHC-II)-restricted antigen presentation by oLCs. To test our hypothesis we will pursue two specific aims using a novel antigen-specific tetramer to determine the kinetics of activation and phenotype of Pg-specific Th and regulatory CD4+ T cells in two mutant mouse strains.
Aim 1 : Determine the requirement of Ag:MHC-II presentation in oLCs to drive differentiation of antigen-specific Th17 cells after oral colonization of mice with Pg. We hypothesize that oLCs indirectly influence the polarization of nave CD4+ T cells by locally ?educating? lamina propria dendritic cells in the mucosae towards a polarization program that differentiates Th17 cells. We predict that cognate MHC-II:T cell receptor interaction between oLCs and nave CD4+ T cells is not required to drive polarization by lamina propria dendritic cells. Mice unable to present microbial MHC-II peptides on oLCs are, therefore, expected to differentiate a normal Th17 type response to Pg.
Aim 2 : Determine the requirement of MyD88-dependent signaling in oLCs to drive differentiation of antigen-specific Th17 cells after oral colonization of mice with Pg. We hypothesize that MyD88- dependent pathogen recognition signaling induces oLCs to express bystander inflammatory signal(s). These signals condition lamina propria dendritic cells to drive a Th17-biased polarization program. We predict that lamina propria dendritic cells will be unable to drive Th17 polarization in mice lack TLR/MyD88-dependent signals on oLC. The expected scenario in MyD88-deficient oLC mice will be a Th1 polarization when encountering Pg at mucosal surfaces. This Th1-differentiation scenario is expected to be identical to what we have discovered in mice that lack oLCs. Data from this R03 funding mechanism will support an R01 application to define the mechanism by which oLCs drive local conditioning of lamina propria dendritic cells. By understanding the role played by oLCs in directing periodontal disease comes the opportunity to manipulate this arm of immunity to achieve better disease outcomes through vaccine targeting or by using immunotherapy to interfere with signals emanating from oLCs.
It is estimated that gum disease will afflict one in three adults in the United States at some stage in their lifetime and was estimated to cost $50 billion in 2011. When gum disease persists it can lead to gum destruction and the loss of jawbone supporting the teeth. We know that gum disease is initiated by specific bacterial species that reside in our mouth and we know that the type of immune response triggered plays an important role in whether or not gum disease leads to tooth loss. Currently, we do not know the specific role in this disease of a number of immune cell types. Our long-term goal is to identify and characterize the components of the local immune response that leads to jawbone destruction when challenged with these bacterial pathogens. In this project, we will examine the role played by one specific cell type. This cell sits just beneath the gum surface and responds to the presence of bacterial pathogens by alerting other cell types and by specifically activating a specialized arm of the immune system. We are interested in how they do that. Working with an experimental mouse model of bone destruction around teeth, we will determine what functions are required by these key immune cells to activate this arm of the immune system. Identifying critical steps in this disease process opens the way to targeted therapeutic intervention and is key in our efforts to reduce the economical and personal burden of periodontal disease.
