Grant number: 220006
Principal Investigator: Hideki Ueno, MD, PhD
Funding Organization: Alliance for Lupus Research
Project Start: February 1, 2012
Project End: January 31, 2014
Abstract:
Uncontrolled generation of autoantibodies is a hallmark of systematic lupus erythematosus (SLE). Several recent mouse studies with lupus models have demonstrated the contribution of T follicular helper (Tfh) cells, a CXCR5-expressing CD4+ T cell subset specialized for the help of antibody responses, to disease pathogenesis. Yet, very little is known regarding the contribution of Tfh cells in human lupus. Recent studies including ours show that human blood CXCR5+ CD4+ T cells represent a circulating pool of memory Tfh cells and thus can be used as surrogates to determine the type of systemic Tfh responses in vivo.
Importantly, we reported that blood CXCR5+ CD4+ T cells are composed of Th1, Th2, and Th17-committed cells, which show distinct abilities to help B cell responses. While CXCR5+ Th2 and Th17 cells efficiently help B cells via IL-21 secretion, CXCR5+ Th1 cells fail to do so. The main hypothesis of this proposal is that Tfh subsets including Th1-type cells are functionally altered in pediatric SLE patients and differentially promote the generation of autoantibodies. Aim 1 will determine whether alterations in the phenotypes of SLE blood CXCR5+ CD4+ T cell subsets correlate with disease severity and/or specific organ damage. The phenotype of blood CXCR5+ CD4+ T cell subsets from SLE patients will be analyzed by multicolor flow cytometry. We will analyze these subsets from newly diagnosed patients and well-controlled patients, as well as healthy matched controls. Aim 2 will establish whether and how cytokine production of SLE blood CXCR5+ CD4+ T cell subsets are altered. Aim 3 will establish whether and how the gene expression profiles of SLE CXCR5+ CD4+ T subset are altered. In Aims 2 and 3, blood CXCR5+ CD4+ T cell subsets will be isolated from newly diagnosed untreated patients, well-controlled patients, and control subjects for comparison.
Altogether, our study will reveal how Tfh cell responses are altered in pediatric SLE. Thus, this project will establish a cornerstone for our long-term goal, which is to develop novel therapeutic approaches for pediatric SLE aiming at the reprogramming of altered Tfh responses.