The goal is to determine how B cells regulate development of autoimmune diseases in a model of spontaneous autoimmune thyroiditis (SAT). All wild-type (WT) NOD.H-2h4 mice given 0.05% NaI water develop SAT, with T and B cell infiltration of the thyroid and production of autoantibody. B cell-deficient (B-/-) mice are resistant to SAT. SAT resistance is due to activity of CD4+CD25+ regulatory T cells (T reg), since B-/- mice develop SAT after transient depletion of T reg. We hypothesize that autoantigen-specific B cells are critical antigen-presenting cells (APC) for activation of effector T cells (Teff) for SAT. If B cells are absent or cannot present autoantigen, other APC preferentially activate T reg and SAT does not develop. After T reg depletion, non B cells can present antigen to Teff, and SAT develops. Anti-CD20 depletes B cells and has beneficial effects on some autoimmune diseases including SAT, but the underlying mechanisms are unclear. The proposed studies will test the hypothesis that B cell depletion by anti-CD20 in young WT mice before T eff activation inhibits SAT because T reg are preferentially activated. B cell depletion is nearly complete, and SAT remains suppressed after B cell repopulation. When anti-CD20 is given to adult mice, most marginal zone (MZ) B cells are not depleted. SAT is suppressed but continuous B cell depletion is required to maintain suppression. We hypothesize that MZ B cells produce IL-10 that plays a role in suppression of SAT in adult mice given anti-CD20. MZ B cells will be selectively depleted using mAb HMD1-5. Another aim will determine if WT and B -/- T reg differ functionally and if Teff activated by B cell APC can be suppressed by T reg. GFP+Foxp3+ cells from Foxp3 GFP knockin WT or B-/- mice will be transferred with T eff to TCR1-/- recipients to assess their ability to suppress SAT. Transfer experiments will be done to determine if activated Teff can be suppressed by T reg, and if Teff activated in the absence of B cells and T reg differ from T eff activated in the presence of B cells and T reg. Finally, the characteristics of the B cells that function as APC will be determined using bone marrow (BM) chimeras with B-/- BM and BM or B cells from mice lacking specific molecules on their B cells. NP-thyroglobulin will be used to promote uptake of thyroid antigen by NP-specific B cells to test the hypothesis that concentration of thyroid antigen by specific B cells is required for optimal activation of T eff. Insights gained in these studies will increase our understanding of mechanisms by which B cells regulate autoimmune diseases, and may provide novel strategies t modulate T reg to inhibit autoimmune diseases.

Public Health Relevance

Drugs such as Rituximab that selectively deplete B cells are currently used to treat several autoimmune diseases in man. Although these drugs are very effective, there are large gaps in knowledge of the mechanisms by which B cell depletion inhibits autoimmune diseases, primarily because versions of the drugs able to deplete B cells in animal models were not available until recently. Our studies use a well characterized animal model of autoimmune disease to test the hypothesis that one mechanism of inhibition of autoimmune disease following B cell depletion involves activation of a subset of T cells called regulatory T cells that function to suppress autoimmune diseases. These studies will also determine if disease remission is maintained after the drug is stopped and B cells have returned, or if continued injections of the drug are required to maintain disease remission.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Johnson, David R
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University of Missouri-Columbia
Internal Medicine/Medicine
Schools of Medicine
United States
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