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Development of B cells producing natural autoantibodies to thymocytes and senescent erythrocytes

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Abstract

Natural antibodies produced by CD5+ B-1 B cells include those with specificity for senescent erythrocytes (anti-BrMRBC, anti-PtC) and for thymocytes (anti-thymocyte autoantibody, ATA). Here we describe work from our laboratories studying two prototypic examples, VH11Vκ9-encoded anti-BrMRBC and VH3609Vκ21c-encoded ATA. Using VH11-μ transgenic mice, we discovered that certain natural autoantibodies utilize VH genes that are selected against in bone marrow B cell development, but not fetal liver, effectively restricting their generation to fetal/neonatal life. Studies with ATA-μ transgenic mice demonstrated a critical requirement for self antigen in the accumulation of B cells with this specificity and for the production of high levels of serum ATA. Finally, analysis of B cell development in ATA-μκ transgenic mice revealed two distinct responses by B cells to expression of this B cell receptor (BCR): most developing B cells in spleen of adult mice were blocked at an immature stage and only escaped apoptosis by editing their BCR to eliminate the ATA specificity; nevertheless, high levels of serum ATA were observed, indicating that some B cells differentiated to antibody-forming cells without altering their specificity. Thus, our studies reveal mechanisms for restricting the generation of B cells producing natural autoantibodies, demonstrate a key positive selection step in their development, and show that most developing B cells in adult mice bearing such specificities fail to reach a mature stage.

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Acknowledgments

This work was supported by grants from the NIH to RRH (AI26782, AI40946) and KH (AI49335) and by an appropriation from the Commonwealth of Pennsylvania.

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  1. Division of Basic Sciences, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA, 19111, USA

    Richard R. Hardy & Kyoko Hayakawa

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  1. Richard R. Hardy
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  2. Kyoko Hayakawa
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Correspondence to Richard R. Hardy.

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Hardy, R.R., Hayakawa, K. Development of B cells producing natural autoantibodies to thymocytes and senescent erythrocytes. Springer Semin Immun 26, 363–375 (2005). https://doi.org/10.1007/s00281-004-0183-1

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