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Investigations of APRIL, its receptors TACI and BCMA, and EBI2, in the deregulation of B cells and plasma cells in a lupus animal model

English title Investigations of APRIL, its receptors TACI and BCMA, and EBI2, in the deregulation of B cells and plasma cells in a lupus animal model
Applicant Santiago-Raber Marie-Laure
Number 138338
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.10.2011 - 31.12.2014
Approved amount 328'680.00
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Keywords (4)

Systemic Lupus Erythematosus; Autoantibody; APRIL, BCMA and TACI, EBI2; B cells

Lay Summary (English)

Lead
Lay summary

Investigations of APRIL, its receptors TACI and BCMA, and EBI2, in the deregulation of B cells and plasma cells in a lupus animal model.

Systemic lupus erythematosus (SLE) is a disorder of systemic autoimmunity characterized by the production of a variety of autoantibodies (antibodies directed against self-components) and subsequent development of immune complex glomerulonephritis. Several mouse strains with different genetic backgrounds spontaneously develop an autoimmune syndrome resembling human SLE. This allows to study the immunological and genetic basis underlying the pathogenesis of SLE and to evaluate various therapeutic approaches. In SLE, B cell (B lymphocyte, the plasma cell precursor. Plasma cells produce autoantibodies) hyperactivity leads to the production of various autoantibodies mainly directed against nuclear constituents such as chromatin, double-stranded and single-stranded DNA (dsDNA and ssDNA), and RNA-related antigens. B cell defects encountered in lupus mice may originate from several altered pathways, such as B cell differentiation and plasma cell survival. We herein propose to study the potential implication of molecules involved in B cells and plasma cell generation that would be relevant in B cell and antibody-mediated autoimmunity such as SLE.

Among these molecules, APRIL (A proliferation inducing ligand), is known to play a crucial role for the control of plasma-cell survival and for the late stages of B-cell differentiation. In this respect, we have shown a beneficial effect on anti-APRIL therapy in a mouse lupus model. In addition, lymphocytes mobility is modulated by the chemoattractant receptor EBI2 (Epstein-Barr virus (EBV)-induced gene 2) which is upregulated during B cell maturation in the bone marrow. EBI2 increases in expression early after activation, before being downregulated during plasma cell differentiation for antibody secretion.

In order to understanding the combined effect of APRIL-receptors TACI and BCMA on B cells and plasma cells during SLE, we plan to study the effect of APRIL-deficiency and APRIL-receptors (BCMA and TACI)-deficiency on the development of the disease in a lupus mice.

The important role for EBI2 in positioning B cells appropriately in order to mount T-dependent antibody response makes it an interesting receptor to be studied in murine lupus context where altered T-dependant autoantibody response is observed. For this reason we intend to investigate the effect of EBI2 deficiency in a spontaneous murine lupus model.

The proposed studies should clarify the potential contribution of APRIL and its receptors, and of EBI2 in deregulated development and/or activation of B cells and plasma cells in the pathogenesis of SLE, thus providing a possible explanation for the mechanism responsible for the break of self-tolerance in SLE. It will be then legitimate to consider these signaling pathways as potential new targets for therapeutic approaches in B cells and antibody-mediated autoimmunity.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Collaboration

Group / person Country
Types of collaboration
Dr. Andreas Sailer, Novartis Pharma AG, Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
P. Schneider / University of Lausanne Switzerland (Europe)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
The 9th European Lupus Meeting, Athens, Greece. 2014 Talk given at a conference TACI-dependent APRIL signaling is critical for the generation of autoreactive B cells in SLE 23.04.2014 Athens, Greece Santiago-Raber Marie-Laure;
The 9th Congress of Autoimmunity, Nice, France, 2014 Talk given at a conference APRIL is critical for the persistence of autoreactive B cells in SLE 26.03.2014 Nice, France Santiago-Raber Marie-Laure;
The 15th International Congress of Immunology, Milan, Italy. 2013 Poster Reduced disease severity in an APRIL-deficient lupus mouse model 22.08.2013 Milan, Italy Santiago-Raber Marie-Laure; Tran Ngoc Lan;


Abstract

1.1. Background Systemic lupus erythematosus (SLE) pathogenesis is complex, but it is now widely accepted that autoantibodies play a key role in the process by forming excessive immune complexes; their deposits within tissues leading to inflammation and functional damages. The availability of mouse strains, which spontaneously develop an autoimmune syndrome resembling human SLE, offers the opportunity to investigate immune deregulation leading to the break of self-tolerance and to evaluate new therapeutic approaches. Recently, we and others contributed to the discovery that anti-nuclear immune complexes could stimulate autoantibody production in mice by engagement of endosomal toll-like receptors (TLR) (Santiago-Raber et al, J Immunol. 2008; Santiago-Raber et al, J Autoimmun. 2010. Study of new pathways involved in the regulation of B and plasma cells activation and differentiation, respectively, would be of great interest in lupus. Among these molecules, APRIL (A proliferation inducing ligand), a member of the TNF superfamily, is known to play a crucial role for the control of plasma-cell survival and for the late stages of B-cell differentiation. In this respect, we have shown a beneficial effect on anti-APRIL therapy in a mouse lupus model (Huard et al, submitted). Furthermore, studies strongly suggest cooperation between TLR activation and APRIL production as well as its receptors expression, TACI (calcium modulator and cyclophilin ligand interactor) and BCMA (B-cell maturation antigen). In addition, lymphocytes mobility is modulated by the chemoattractant receptor subfamily of G protein-coupled receptors (GPCRs). EBI2 (Epstein-Barr virus (EBV)-induced gene 2) is a GPCR which is upregulated during B cell maturation in the bone marrow. EBI2 increases in expression early after activation, before being downregulated in germinal center B cells preceding plasmablasts differentiation and antibody secretion.1.2. Working hypothesis The role of autoreactive B cells and plasma cell, which constitute key players involved in autoreactivity in lupus, needs to be better understood. This proposal, based on previous publication of my research group and solid preliminary data, is aimed at exploring in depth the role of key molecules involved in B cell differentiation and plasma cell survival, including APRIL and its receptors (BCMA and TACI), as well as EBI2. In the first Aim we plan to study the effect of the plasma cell survival factor APRIL-deficiency on the development of SLE. In the second Aim, we will investigate the effect of APRIL-receptors BCMA- and TACI-deficiency on the development of SLE. The Aim 3 would concentrate on the cross-talk between APRIL-receptors and endosomal TLR engagements in autoreactive B cells. Finally in the fourth Aim, we propose to explore the effect of EBI2 deficiency on the development of SLE in lupus-prone mice.1.3. RationaleThe proposed studies should clarify the potential contribution of APRIL and its receptors, and of EBI2 in deregulated development and/or activation of B cells and plasma cells in the pathogenesis of SLE, thus providing a possible explanation for the mechanism responsible for the break of self-tolerance in SLE. It will be then legitimate to consider these signaling pathways as potential new targets for therapeutic approaches in B cells and antibody-mediated autoimmunity.
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