Regulation of anti-dsDNA B-cells in mice transgenic for the heavy and light chains of an anti-dsDNA antibody
Item
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Title
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Regulation of anti-dsDNA B-cells in mice transgenic for the heavy and light chains of an anti-dsDNA antibody
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Identifier
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d_2009_2013:2a969d6a3f1c:10619
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identifier
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10955
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Creator
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Lewis, Rita Hazel,
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Contributor
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Linda A. Spatz
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Date
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2010
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Language
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English
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Publisher
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City University of New York.
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Subject
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Molecular biology | Cellular biology | Immunology | allelic inclusion | Anergy | anti-dsDNA | B-cell regulation
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Abstract
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The diversity of the B-cell repertoire is important for the development of antibodies to a multitude of pathogens. However, in the process of generating antibody diversity, B-cells arise that produce antibodies to self-antigens. These autoreactive B-cells must be kept in check lest they secrete autoantibodies that can induce autoimmune disease. There are several mechanisms inherent in the immune system for regulating autoreactive B-cells. I have been using a transgenic mouse model, in which mice were made transgenic for the R4A IgM heavy and Vkappa1 light chain genes of an anti-double stranded DNA (anti-dsDNA) antibody, to study the regulation of anti-dsDNA B cells. Anti-dsDNA antibodies are the hallmark of the autoimmune disease Systemic Lupus Erythematosus (SLE). I observed that the transgenic anti-dsDNA B cells are targeted to anergy in the R4A-Cmu/Vkappa1 mice as evidenced by arrested development, receptor down modulation, and functional unresponsiveness and reduced calcium flux in response to B-cell receptor stimulation. I also observed a relatively high frequency of transgenic B cells in the T1 but not the T2 or mature stages of development. In addition, transgenic T1 B cells were observed to display features of anergy suggesting that the T1 stage may be a regulatory checkpoint where anti-dsDNA B cells are anergized and subsequently eliminated. Interestingly, transgenic B-cells that were able to transition to the T2 and T3 stages of development tended to co-express an endogenous heavy chain while the majority of mature B cells in these mice expressed the endogenous heavy chain only. Surprisingly, however, B-cells expressing only the endogenous heavy chain on their membrane were also observed to express transgenic heavy chain transcripts. These results have led me to propose a model whereby autoreactive B cells can escape a regulatory checkpoint if they express more than one heavy chain. These dual receptor expressing B-cells may have diminished autoreactivity if the level of membrane expression of the transgenic heavy chain is low relative to the level of expression of the endogenous heavy chain. Subsequent down-regulation of the transgenic heavy chain as a B-cell matures in the periphery may be a novel mechanism for averting autoreactivity.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biology
