The Role of Foxo3 in B Cell Tolerance

Date

2017-01-17

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Abstract

B cells secrete antibodies in order to help defend the body against pathogens. Due to the enormous diversity of B cell receptors required to recognize pathogens, some self-reactive receptors are generated. It is important for the immune system to prevent autoimmune cells from attacking one's self. This can be done at the immature B cell stage through receptor editing, deletion of the B cell, or anergy (inactivation) of the B cell. During editing, the receptor recombines its components in order to generate a new receptor, which is tested for auto-reactivity. If the receptor is strongly auto-reactive after editing, the cell dies by apoptosis. Foxo3 is a transcription factor that participates in pro-apoptotic pathways in several cell types. Previous work in our lab showed that apoptosis is reduced in immature B cells from Foxo3-/- mice, and others have observed decreased levels of Foxo3 in B cells from mouse models of lupus (an autoimmune disease in which B cells produce antibodies reactive against the body's own DNA). It is hypothesized that edited cells that remain auto-reactive may survive inappropriately in the absence of Foxo3. B cells that have undergone receptor editing are more likely to express the Igλ light chain and to have undergone a process called "RS recombination." Foxo3-/- mice were found by flow cytometry to exhibit increased Igλ+ B cells in the immature B cells of the bone marrow, as well as in the transitional B cells of the spleen. PCR demonstrated increased RS recombination in Igλ+ B cells from Foxo3-/- mice compared to wild-type mice. Anti-double-stranded DNA ELISAs were run on supernatants from total B cells stimulated by LPS to secrete antibodies. These showed no difference in auto-reactivity between wild-type mice and Foxo3-/- mice. Thus, there appears to be an increase in receptor editing in the knockout mice, but not an overall increase in the auto-reactivity of the total population of B cells. This suggests that the reduced apoptosis of Foxo3-/- immature B cells allows cells that were originally auto-reactive a longer window of time in which to edit their receptors away from auto-reactivity.

General Notes

The 55th Annual Medical Student Research Forum at UT Southwestern Medical Center (Monday, January 17, 2017, 2-5 p.m., D1.600)
Each year the Medical Student Research Program awards students for the best oral presentation and the best poster presentation as judged by faculty across campus. This author received an award as one of the best poster presentations at this forum.

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Subjects

Basic Research and Disease Models, B-Lymphocytes, Forkhead Box Protein O3, Receptors, Antigen, B-Cell, Best Poster Presentation Award

Citation

Barrios, E., Ottens, K., Hinman, R., Skaug, B., Castrillion, D., & Satterthwaite, A. (2017, January 17). The role of Foxo3 in B cell tolerance. Poster session presented at the 55th Annual Medical Student Research Forum, Dallas, TX. Retrieved from https://hdl.handle.net/2152.5/4027

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