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Antigen-Driven B Cell Responses in ra and Sars-Cov-2 Vaccination.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Antigen-Driven B Cell Responses in ra and Sars-Cov-2 Vaccination./
作者:	Brewer, Rebeccah Camille.
面頁冊數:	1 online resource (144 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-05, Section: B.
Contained By:	Dissertations Abstracts International84-05B.
標題:	Infections. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29755966click for full text (PQDT)
ISBN:	9798357510853

Antigen-Driven B Cell Responses in ra and Sars-Cov-2 Vaccination.
Brewer, Rebeccah Camille.

Antigen-Driven B Cell Responses in ra and Sars-Cov-2 Vaccination. - 1 online resource (144 pages)

Source: Dissertations Abstracts International, Volume: 84-05, Section: B.

Thesis (Ph.D.)--Stanford University, 2022.

Includes bibliographical references

B cells play a central role in protective immunity by secreting antibodies directed against antigens from pathogens, and by activating T cells via antigen presentation of the cognate antigen. Conversely, in autoimmunity, B cells play a pathogenic role by secreting autoantibodies against self-antigens and triggering autoreactive T cells. However, the exact mechanisms mediating the development of antigen specific B cell responses in autoimmunity and vaccination warrant further investigation. Here, we characterize the B cell responses in patients with seropositive rheumatoid arthritis (RA) and in individuals who received the BNT162b2 mRNA vaccine against SARS-CoV-2.By sequencing the plasmablasts repertoire of RA patients, we demonstrate that extensively somatically hypermutated RA blood plasmablasts encode anti-citrullinated protein antibodies (ACPA) that target both citrullinated human autoantigens and in situ citrullinated epitopes from oral bacteria. In RA patients with periodontitis, oral bacteremias result in systemic translocation of these citrullinated oral bacteria into blood activating ISG15+ inflammatory monocytes, a myeloid population associated with clinical arthritis flares and present in RA synovium. Our findings indicate that repeated oral bacterial mucosal breaks mediate autoimmunity by driving activation and epitope spreading of the ACPA response to target both citrullinated bacterial and human antigen(s) via molecular mimicry.Additionally, we characterize the B cell response to the novel BNT162b2 mRNA vaccine against SARS-CoV-2 spike (S). The first vaccine dose elicits IgA+ plasmablasts against S protein subunit S2 (S2) on day 7, consistent with a secondary memory response derived from prior infections with betacoronaviruses that cause the common cold. On day 21, we observed an influx of minimally mutated IgG+ switched memory B cells against the S protein subunit S1 (S1) that contains the receptor binding domain (RBD), representing a primary response of recently matured naive B cells. The second vaccine dose boosted the anti-S1 and anti-RBD B cell response and produced high titers of antibodies that potently neutralize Wuhan-Hu-1 SARSCoV-2 pseudovirus and partially neutralize novel variants. Taken together, our results demonstrate how B cell responses continuously evolve to contribute to health and autoimmunity.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798357510853Subjects--Topical Terms:

1621997
Infections.
Index Terms--Genre/Form:

542853
Electronic books.

Antigen-Driven B Cell Responses in ra and Sars-Cov-2 Vaccination.
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100 1 $a Brewer, Rebeccah Camille. $3 3700474
245 1 0 $a Antigen-Driven B Cell Responses in ra and Sars-Cov-2 Vaccination.
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300 $a 1 online resource (144 pages)
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500 $a Source: Dissertations Abstracts International, Volume: 84-05, Section: B.
500 $a Advisor: Davis, Mark M. ; Engleman, Edgar G.; Kim, Peter; Robinson, Bill.
502 $a Thesis (Ph.D.)--Stanford University, 2022.
504 $a Includes bibliographical references
520 $a B cells play a central role in protective immunity by secreting antibodies directed against antigens from pathogens, and by activating T cells via antigen presentation of the cognate antigen. Conversely, in autoimmunity, B cells play a pathogenic role by secreting autoantibodies against self-antigens and triggering autoreactive T cells. However, the exact mechanisms mediating the development of antigen specific B cell responses in autoimmunity and vaccination warrant further investigation. Here, we characterize the B cell responses in patients with seropositive rheumatoid arthritis (RA) and in individuals who received the BNT162b2 mRNA vaccine against SARS-CoV-2.By sequencing the plasmablasts repertoire of RA patients, we demonstrate that extensively somatically hypermutated RA blood plasmablasts encode anti-citrullinated protein antibodies (ACPA) that target both citrullinated human autoantigens and in situ citrullinated epitopes from oral bacteria. In RA patients with periodontitis, oral bacteremias result in systemic translocation of these citrullinated oral bacteria into blood activating ISG15+ inflammatory monocytes, a myeloid population associated with clinical arthritis flares and present in RA synovium. Our findings indicate that repeated oral bacterial mucosal breaks mediate autoimmunity by driving activation and epitope spreading of the ACPA response to target both citrullinated bacterial and human antigen(s) via molecular mimicry.Additionally, we characterize the B cell response to the novel BNT162b2 mRNA vaccine against SARS-CoV-2 spike (S). The first vaccine dose elicits IgA+ plasmablasts against S protein subunit S2 (S2) on day 7, consistent with a secondary memory response derived from prior infections with betacoronaviruses that cause the common cold. On day 21, we observed an influx of minimally mutated IgG+ switched memory B cells against the S protein subunit S1 (S1) that contains the receptor binding domain (RBD), representing a primary response of recently matured naive B cells. The second vaccine dose boosted the anti-S1 and anti-RBD B cell response and produced high titers of antibodies that potently neutralize Wuhan-Hu-1 SARSCoV-2 pseudovirus and partially neutralize novel variants. Taken together, our results demonstrate how B cell responses continuously evolve to contribute to health and autoimmunity.
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538 $a Mode of access: World Wide Web
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650 4 $a T cell receptors. $3 3561758
650 4 $a Monoclonal antibodies. $3 603890
650 4 $a Plasma. $3 877619
650 4 $a Pathogens. $3 3540520
650 4 $a Vaccines. $3 684854
650 4 $a Gene expression. $3 643979
650 4 $a Chemokines. $3 702040
650 4 $a Disease. $3 705846
650 4 $a Rheumatoid arthritis. $3 930157
650 4 $a Autoimmune diseases. $3 872484
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650 4 $a Lymphocytes. $3 895384
650 4 $a Genomes. $3 592593
650 4 $a Bone marrow. $3 1621080
650 4 $a Antigens. $3 700737
650 4 $a Peptides. $3 605772
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650 4 $a Cellular biology. $3 3172791
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650 4 $a Immunology. $3 611031
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773 0 $t Dissertations Abstracts International $g 84-05B.
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