Date of Award

January 2013

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Joseph Craft

Subject Area(s)

Medicine, Immunology

Abstract

Autoreactive B cells in Systemic Lupus Erythematosus (SLE) undergo autoantigen selection, suggesting a requirement for germinal center follicular helper T (Tfh) cells in their maturation. However, evidence for dysregulation of Tfh cells in SLE and their contribution to disease activity remains unclear. Recently, blood CXCR5hi CD4 T cells, a heterogeneous pool consisting of functionally distinct Th1-, Th2-, Th17-like subsets, have been proposed to be the circulating counterpart of Tfh cells. The purpose of this study was to examine the hypothesis that Tfh dysregulation, as reflected in altered phenotype of blood CXCR5hi population, was associated with SLE disease activity. Blood samples from 49 clinically well-characterized SLE patients, 28 Behçet's disease (BD) patients as autoimmune disease control and 16 healthy controls were included. Expression of key Tfh surface receptors (ICOS, inducible T-cell co-stimulator; PD-1, programmed cell death protein-1) as well as composition of T helper subtypes within the circulating CXCR5hi compartment were enumerated by flow-cytometry. The phenotype of blood CXCR5hi cells was correlated with clinical history and B cell phenotype. SLE patients had significant expansion of circulating Tfh-like CD4 T cells (CXCR5hiICOShiPD-1hi) when compared to controls (p < 0.001). Interestingly, PD-1 mean florescence intensity (MFI) was markedly elevated in blood CXCR5hi subset of SLE patients when compared to controls (p < 0.001). PD-1 MFI in the CXCR5hi population correlated significantly with SLE disease activity index (SLEDAI; Spearman r = 0.43, p = 0.03), blood plasmablast expansion (Spearman r = 0.34, p = 0.02), and high anti-dsDNA antibody titers (p = 0.004). Blood CXCR5hiPD-1hi cells phenotypically resembled pre- or post-germinal center Tfh cells, with increased percentage of IL-21 producers (p = 0.02), lower CCR7 MFI (p = 0.03) when compared to CXCR5hiPD-1lo subset, and low Bcl-6 expression. Compared to BD patients, SLE patients had an increase in the CXCR5hi Th2 subset (p < 0.05) and a decrease in the Th17 (p < 0.001) subsets. The expansion of the CXCR5hi Th2 subset was also positively associated with SLEDAI scores. Our results demonstrate that altered phenotype and subset composition of blood Tfh-like cells is correlated with disease activity in lupus patients, suggesting a potential role of GC Tfh dysregulation in the pathogenesis of human SLE.

Comments

This is an Open Access Thesis.

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