Multistep Regulation of Rheumatoid Factor B Cell Activation in the NZM2410 Mouse Model of Lupus

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Material Information

Title:
Multistep Regulation of Rheumatoid Factor B Cell Activation in the NZM2410 Mouse Model of Lupus
Physical Description:
1 online resource (130 p.)
Language:
english
Creator:
Sang, Allison L
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Medical Sciences, Immunology and Microbiology (IDP)
Committee Chair:
MOREL,LAURENCE MARGUERITE
Committee Co-Chair:
MATHEWS,CLAYTON ELWOOD
Committee Members:
SOBEL,ERIC S
HARRISON,JEFFREY K

Subjects

Subjects / Keywords:
autoimmunity -- bcell -- lupus -- tolerance
Immunology and Microbiology (IDP) -- Dissertations, Academic -- UF
Genre:
Medical Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the dysregulation of self-reactive B cells resulting in the secretion of pathogenic autoantibodies (autoAb).  Recent SLE therapies have focused on targeting B cells but additional understanding of B cell tolerance mechanisms is required to benefit a broader spectrum of patients.  The goal of our lab is to understand the breakdown in B cell tolerance in the lupus-prone B6.Sle1.Sle2.Sle3 (TC) strain,which contains three major NZM2410-derived lupus susceptibility loci.  To study tolerance in a well characterized study system we crossed the AM14 heavy chain (HC) to the TC lupus background.  The AM14 HC when combined to endogenous Vk8 light chain produces a rheumatoid factor (RF) specific forIgG2aa.    The TC genetic background is sufficient to induce spontaneous RF B cell activation in the presence of the autoantigen(autoAg).  Activated RF B cells differentiated into short-lived Ab secreting plasmablasts and underwent somatic hypermutation (SHM) preferentially at extrafollicular (EF) sites.  Dual B cell receptor (BCR) and TLR9 ligation could induce RF activation in the TC autoimmune background but not in the B6non-autoimmune background.  Additionally,TLR9 ligation is essential for RF activation in the lupus-prone TC mice as in vitro studies showed that it could compensate for the absence of the autoAg and induce RF Ab secretion.   All three Sle loci are required to break RF tolerance as single congenic Sle1 or Sle2 mice resulted in an intermediate phenotype as the presence of the autoAg was sufficient to activate RF B cells and promote their differentiation, but not to levels significantly higher than healthy controls.  Furthermore, RF activation could not be induced by dual BCR and TLR9 ligation in Sle1.AM14 and Sle2.AM14mice.  Dysregulation in cytokine networks may play a role in the breakdown of B cell tolerance in the TC background as TC dendritic cells (DC) enhanced B cell proliferation and secreted high levels of inflammatory cytokines after TLR7/TLR9 stimulation. In addition, TC B cells inefficiently downregulated inflammatory cytokines under anti-inflammatory conditions.  Therefore, multiple factors affect B cell tolerance and this must be taken into consideration to develop effective SLE therapies.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Allison L Sang.
Thesis:
Thesis (Ph.D.)--University of Florida, 2013.
Local:
Adviser: MOREL,LAURENCE MARGUERITE.
Local:
Co-adviser: MATHEWS,CLAYTON ELWOOD.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2014-12-31

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2013
System ID:
UFE0046088:00001