Type 1 diabetes (T1D) results from a complex cascade of events that breaks immune tolerance and culminates in the destruction of islet cells. B lymphocytes (B cells) play a critical role in disease. This project focuses on the role ofa central B cell signaling protein, Bruton's tyrosine kinase (BTK). We have defined the role of BTK in supporting autoreactive B cells that present antigen to autoreactive T cells, and shown that BTK can be targeted to protect against development of T1D. We now extend those findings to mucosal immunity, and have discovered that BTK-deficient nonobese diabetic (NOD) mice have greatly reduced numbers of Peyer's Patch B cells, important for production of IgA. Accordingly, IgA is also reduced. We therefore tested the hypothesis that IgA in gut mucosa selects the resident microbes. Genetic sequencing of intestinal microbiota showed that Btk-/-/NOD mice have strikingly altered microbial populations compared with wild type NOD mice. Furthermore, exposure to different microbes in the neonatal period abrogated disease protection in Btk-/-/NOD mice. The hypothesis underlying this proposal is that B cell signaling via BTK supports production of IgA, which shapes a microbiome that promotes T1D in genetically susceptible hosts. To understand BTK contributions to the microbiome in relationship to T1D, we propose to: 1) determine the mechanisms by which BTK regulates the microbiome, by using cell-specific targeted deletion to define the effects on gut immune structures including Peyer's Patches. The impact of BTK actions on IgA production and gut immune responses will be investigated and effects of BTK inhibitors on mucosal immunity assessed, 2) determine the kinetics of BTK-targeting in modifying the microbiome. The developmental stages from neonate to adult when the microbiome is sensitive to the functions of BTK will be identified. Timed excision of BTK or drug administration will assess the potential to halt the progression of T1D in the NOD model and determine if microbiome modification is required for a successful outcome. Experiments will also determine how reconstitution with PP B cells affects microbial modification and disease outcome, and 3) determine disease contributions of the microbiome that is supported by BTK. Btk-/-/NOD mice will be rederived into a germ-free facility to separate autoimmune disease effects of BTK-signaling from that of the microbiome. Fecal transfer will be used to directly test microbiome contributions to T1D. This project has direct clinical importance in understanding how BCR-signaling supports the selection of commensal flora that influences the outcome of T1D as a necessary step in developing therapeutic interventions.
Bruton's tyrosine kinase (BTK)-deficiency decreases autoreactive B cells and prevents type 1 diabetes (T1D). We have now discovered that BTK-deficiency also promotes the growth of intestinal bacteria (microbiome) that may prevent T1D. The overall goal of this project is to understand how BTK-mediated signaling influences microbiome contributions to T1D in order to provide new avenues of therapeutic intervention.
| Wilfong, Erin M; Lentz, Robert J; Guttentag, Adam et al. (2018) Interstitial Pneumonia With Autoimmune Features: An Emerging Challenge at the Intersection of Rheumatology and Pulmonology. Arthritis Rheumatol 70:1901-1913 |
| Bahnan, Wael; Boucher, Justin C; Gayle, Petoria et al. (2018) The eIF2? Kinase Heme-Regulated Inhibitor Protects the Host from Infection by Regulating Intracellular Pathogen Trafficking. Infect Immun 86: |
| Nyhoff, Lindsay E; Clark, Emily S; Barron, Bridgette L et al. (2018) Bruton's Tyrosine Kinase Is Not Essential for B Cell Survival beyond Early Developmental Stages. J Immunol 200:2352-2361 |
| Nyhoff, Lindsay E; Crofford, Leslie J; Kendall, Peggy L (2017) Reply. Arthritis Rheumatol 69:475-477 |
| Nyhoff, Lindsay E; Barron, Bridgette L; Johnson, Elizabeth M et al. (2016) Bruton's Tyrosine Kinase Deficiency Inhibits Autoimmune Arthritis in Mice but Fails to Block Immune Complex-Mediated Inflammatory Arthritis. Arthritis Rheumatol 68:1856-68 |
| Kendall, Peggy L (2016) New Players in the Field of T1D: Anti-Peripherin B Lymphocytes. Diabetes 65:1794-6 |
| Crofford, Leslie J; Nyhoff, Lindsay E; Sheehan, Jonathan H et al. (2016) The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy. Expert Rev Clin Immunol 12:763-73 |
| Hemler, Jonathan A; Phillips, Elizabeth J; Mallal, Simon A et al. (2015) The evolving story of human leukocyte antigen and the immunogenetics of peanut allergy. Ann Allergy Asthma Immunol 115:471-6 |
| Case, James B; Bonami, Rachel H; Nyhoff, Lindsay E et al. (2015) Bruton's Tyrosine Kinase Synergizes with Notch2 To Govern Marginal Zone B Cells in Nonobese Diabetic Mice. J Immunol 195:61-70 |
| Bonami, Rachel H; Wolfle, William T; Thomas, James W et al. (2014) NFATc2 (NFAT1) assists BCR-mediated anergy in anti-insulin B cells. Mol Immunol 62:321-8 |
Showing the most recent 10 out of 17 publications
