Abstract

RA and SLE are B cell-mediated autoimmune diseases dominated by autoantibodies that affect over 1.5 million Americans. Together RA and SLE contribute to over 29 billion in healthcare costs, therefore due to the high financial burden and physical toll of these diseases on the population, there is a critical need to effectively and efficiently diagnose and treat RA and SLE patients. The aim of our studies was to identify biomarkers and drug targets to improve the identification and treatment of RA and SLE patients. As discussed above, APRIL, BAFF and TSLP have been implicated in the pathogenesis of RA and SLE. Current therapeutics used to treat RA and SLE provide sub-optimal response in a third of patients treated. Therefore, identifying subsets of patients based on their surface and soluble biomarkers and identifying which therapeutics that will provide the most benefit for these patient cohorts has the potential to rationalize the treatment of RA and SLE patients. The cytokine APRIL has been implicated as a potential disease mediator in B cell mediated autoimmune diseases. Our studies show that surface APRIL is expressed on circulating myeloid cells and on total CD19+ B cells and correlates with increased disease in RA patients. Our findings suggest that surface APRIL could provide an easily detectable biomarker and be a useful selection criterion for the administration of drugs that antagonize APRIL. Another cytokine, TSLP has been implicated in the pathogenesis of RA. We found that TSLP was elevated in the synovial fluid of RA and in the plasma of SLE patients compared to non-inflammatory OA patients indicating that TSLP may act locally in the joints of RA patients and systemically in SLE patients. These studies provide insight into the role of APRIL and TSLP in B cell mediated autoimmune diseases and provide a rationale to guide treatment strategies based upon the expression of APRIL and TSLP. This work is significant because it has the potential to provide clinicians with easily accessible biomarkers to identify the best treatment plan to target these cytokines and their function in pathways involved in RA and SLE pathogenesis.

LLU Discipline

Microbiology and Molecular Genetics

Department

Basic Sciences

School

School of Medicine

First Advisor

Payne, Kimberly J.

Second Advisor

Casiano, Carlos A.

Third Advisor

Duerksen-Hughes, Penelope J.

Fourth Advisor

Hernandez, Elvin A.

Fifth Advisor

Langridge, William

Sixth Advisor

Moldovan, Ioana

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2014

Date (Title Page)

12-2014

Language

English

Library of Congress/MESH Subject Headings

Autoimmune Diseases; Rheumatoid Arthritis; Systemic Lupus Erythematosus; Biomarkers

Subject - Local

B cell-mediated autoimmune diseases; Autoantibodies; Cytokines;

Type

Dissertation

Page Count

146

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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