Generation of autoantibodies is a hallmark of autoimmune diseases. Recent data in humans and mice show that overrepresentation of T follicular helper (Tfh) cells, a CD4+ T cell subset specialized in helping B cells in germinal centers (GCs), is associated with autoimmunity. Yet, the immune mechanisms that cause exaggerated Tfh response in human autoimmune diseases remain largely unknown. Our preliminary studies suggest a common mechanism associated with exaggerated Tfh responses in human autoimmune disease. We identified two candidate factors derived from antigen-presenting cells promoting Tfh responses. Altered Tfh response in autoimmune diseases might be also associated with dysregulated of T follicular regulatory (Tfr) cells that originate from thymus-derived regulatory T cells (Tregs). In this Collaborative Project, we hypothesize that Altered APCs promotes Tfh response while suppressing Tfr response thereby contributing to the pathogenesis of human autoimmune diseases. We will share our established methods for the studies of human Tfh cells to other Centers, so that newly diagnosed untreated patients with a broad range of autoimmune diseases can be analyzed across the Centers.
The specific aims are AIM 1: To determine the alteration in Tfh cell subsets in blood in autoimmune diseases.
AIM 2 : To determine the alteration in Tfh cells and CD11c+ APCs in inflammatory tissues in autoimmune diseases.
AIM 3 : To determine whether APCs in inflammatory tissues are capable of inducing naive and memory CD4+ T cells to differentiate into Tfh cells, and AIM 4: To determine whether and how Tfr response is altered in autoimmune diseases. In conclusion, we might be able to reveal immunological pathways that cause altered Tfh/GC response shared by different autoimmune diseases as well as unique one to each disease.

Public Health Relevance

Autoimmune patients, especially with SLE, continue to have unmet medical needs, necessitating in-depth studies enabling increased understanding of disease pathophysiology and identification of novel therapeutic targets. Our long-term goal is to discover novel target(s) for treatment/prevention of human autoimmune diseases by elucidating the immunological mechanisms associate with dysregulated Tfh/GC responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI082715-06
Application #
8732917
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Baylor Research Institute
Department
Type
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75204
Caielli, Simone; Veiga, Diogo Troggian; Balasubramanian, Preetha et al. (2018) A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate. Nat Med :
Horiuchi, Shu; Ueno, Hideki (2018) Potential Pathways Associated With Exaggerated T Follicular Helper Response in Human Autoimmune Diseases. Front Immunol 9:1630
Gu, Jinghua; Wang, Xuan; Chan, Jinyan et al. (2017) Phantom: investigating heterogeneous gene sets in time-course data. Bioinformatics 33:2957-2959
Cepika, Alma-Martina; Banchereau, Romain; Segura, Elodie et al. (2017) A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis. J Exp Med 214:3449-3466
Banchereau, Romain; Cepika, Alma-Martina; Banchereau, Jacques et al. (2017) Understanding Human Autoimmunity and Autoinflammation Through Transcriptomics. Annu Rev Immunol 35:337-370
Schmitt, Nathalie; Liu, Yang; Bentebibel, Salah-Eddine et al. (2016) Molecular Mechanisms Regulating T Helper 1 versus T Follicular Helper Cell Differentiation in Humans. Cell Rep 16:1082-1095
Blanco, Patrick; Ueno, Hideki; Schmitt, Nathalie (2016) T follicular helper (Tfh) cells in lupus: Activation and involvement in SLE pathogenesis. Eur J Immunol 46:281-90
Caielli, Simone; Athale, Shruti; Domic, Bojana et al. (2016) Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J Exp Med 213:697-713
Ueno, Hideki (2016) T follicular helper cells in human autoimmunity. Curr Opin Immunol 43:24-31
Banchereau, Romain; Hong, Seunghee; Cantarel, Brandi et al. (2016) Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients. Cell 165:551-65

Showing the most recent 10 out of 41 publications