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Emily K Moser, Jennifer Roof, Joseph Dybas, Lynn Spruce, Stephen Seeholzer, Michael P Cancro, Paula M Oliver, The E3 Ubiquitin Ligase Itch Restricts the Magnitude of Antigen-Driven B Cell responses, The Journal of Immunology, Volume 204, Issue 1_Supplement, May 2020, Page 218.1, https://doi.org/10.4049/jimmunol.204.Supp.218.1
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Abstract
More than 23 million Americans suffer from autoimmune disease, driven in large part by germinal center (GC)-derived autoantibodies. In GC B cells, somatic hypermutation of immunoglobulin (Ig) genes can render autoreactivity, but cells bearing autoreactive Ig receptors are eliminated due to strict selection of GC B cells by mechanisms that are still poorly defined. The E3 ubiquitin ligase Itch prevents the emergence of autoimmune disease and autoantibodies in humans and mice, and patients lacking Itch develop debilitating, multi-faceted, potentially fatal, autoimmune disease; yet how Itch regulates GC B cell fate or function has not previously been explored. By studying spontaneous and immunization-induced GC B cell responses in Itch deficient mice, we now show that Itch directly limits B cell activity to shape antibody responses. While Itch-deficient mice displayed normal numbers of pre-immune B cell populations, they showed elevated numbers of antigen-experienced B cells. Mixed bone marrow chimeras revealed that Itch acts within B cells to limit follicular and GC B cell numbers. Proteomic profiling of acutely activated B cells uncovered that Itch limited abundance of a subset of proteins involved in cell cycle and mTORC1 activity. We next found that B cells lacking Itch showed increased proliferation, glycolytic capacity, and mTORC1 activation in vitro and in vivo. Moreover, stimulation of these cells by in vivo immunization resulted in elevated numbers of GC B cells, plasma cells, and serum IgG. These results support a novel role for Itch in limiting B cell metabolism and proliferation to suppress GC B cell responses, supporting the idea that overly-exuberant GC B cell responses may contribute to autoimmunity in Itch deficiency.
