All ETDs from UAB

Advisory Committee Chair

John D Mountz

Advisory Committee Members

Huma Fatima

Hui-Chen Hsu

Jan Novak

Chander Raman

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Objective: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by production of autoantibodies (autoAbs) and cytokines. Moreover, lupus nephritis (LN) occurs in approximately 50% of SLE patients. AutoAb and cytokine levels produced by B and T cells are high in LN patients, although their relationship with histological patterns requires investigation. Methods: We analyzed the relationship between B cell cytokines and major T cell cyto-kines, including their association with autoAbs, and the clinical manifestations of SLE, especially LN. We also analyzed endogenous intracellular interferon beta (IFNβ) expression in the peripheral blood mononuclear cells and serum circulating nephritogenic autoAbs from patients with SLE (n = 80) and healthy controls (n = 16). Subsequently, plasma levels of T-helper cell cy-tokines and autoAbs were determined in patients with SLE (n = 60) and healthy controls (n = 11). Results: IFNβ expression was significantly higher in patients with SLE than in healthy controls (HC; P < 0.001) and positively associated with LN (P = 0.008) but not cutaneous manifestations. Additionally, it was associated with increased circulating IgG anti-DNA and IgG anti- ii Smith autoAbs (P = 0.0130, P = 0.0010, respectively), and elevated urinary protein/creatinine ratio (P = 0.064). Histopathological evaluation of kidney biopsies revealed that higher IFNβ levels correlated with severe LN—higher degree of activity and chronicity (P < 0.0001, P = 0.0225 and P = 0.0327, respectively). Immune complex deposition in the kidney was not associated with in-creased IFNβ. Interferon gamma (IFNɣ) and interleukin (IL)-17 were generalized features in pa-tients with SLE. However, higher IL-10 levels occurred in patients with LN. IL-17 levels were significantly higher in patients with LN class V and discoid lupus (P = 0.0055 and P = 0.0238, respectively). IFNɣ was positively correlated with anti-double stranded DNA and anti-Sjogren's syndrome A (P = 0.0355 and p = 0.0402, respectively), while IL-17 was correlated with anti-Ro/SSA (P = 0.0130). Conclusions: IFNβ represents a potential biomarker for LN, while IL-10 and IL-17 could be used in combination with other diagnostic markers. Our results show the pathogenic mechanisms underlying LN to guide diagnosis and therapy.

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