Date of Award

2019

Embargo Period

6-25-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Wei Jiang

Second Advisor

Gary Gilkeson

Third Advisor

Alexander Alekseyenko

Fourth Advisor

Azizul Haque

Fifth Advisor

Diane Kamen

Sixth Advisor

Gregg Silverman

Abstract

Objective – Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by loss of tolerance to self-antigens and production of autoantibodies. Growing evidence suggests that autoimmune diseases may arise or worsen due to increased intestinal permeability allowing passage of antigens into the systemic circulation. Translocation of microbes or microbial components into the systemic circulation can result in consequences including alteration of microbiota composition and immune system activation. In SLE disease, the extent of intestinal permeability and microbial translocation and their effect on SLE disease pathogenesis is yet to be defined. We hypothesized that increased gut permeability resulting in increased magnitude of microbial translocation and alteration of microbiota composition are contributors to SLE disease pathogenesis. Methods – In a cohort of 50 healthy controls and 80 SLE patients, we determined the magnitude of gut permeability and microbial translocation and assessed associations between markers of permeability, translocation and SLE disease markers. We investigated innate and adaptive immune cells and their contributions to intestinal permeability and microbial translocation in SLE disease. We profiled the circulating microbiome in SLE patients compared to healthy controls and first-degree relatives of SLE patients compared to unrelated healthy controls, and assessed relationships between the circulating microbiome profile of SLE patients and markers of intestinal permeability, microbial translocation, and autoantibodies. Results – Gut permeability and microbial translocation markers were elevated in SLE patients and directly associated with each other. Increases in gut permeability and microbial translocation positively correlated with pathogenic autoantibodies in SLE patients. Abnormal monocyte response to LPS signaling emerged as a potential mechanism for increased microbial translocation and persistent autoantibody production in SLE patients. Profiling of the circulating microbiome revealed novel relationships between the microbiome and markers of gut permeability, microbial translocation, and autoantibodies in SLE patients and their first-degree relatives. 14 Conclusion – Increases in gut permeability and microbial translocation and alterations in the circulating microbiome composition of SLE patients correlate with autoantibody levels, which may contribute to SLE disease pathogenesis.

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