Our research program is focused on studying the immune alterations in systemic lupus erythematosus (SLE), a potentially life threatening multisystem chronic inflammatory disease that primarily affects women of reproductive age. One of the main features of SLE is a breakdown of tolerance, leading to abberant responses of both the adaptive and innate immune system. As a result, multiple autoantibodies and self-reactive cells are produced that infiltrate peripheral tissues and promote organ damage.
Our goal is to decipher the altered phenotype and function of SLE immune cells by analyzing peripheral blood mononuclear cells (PBMC) from patients included in the Swiss SLE Cohort Study (SSCS) in order to understand the alterations leading to the loss of immune tolerance and the development of autoimmunity.
The role of Signaling Lymphocyte Activation Molecule Family (SLAMF) in SLE immunopathogenesis
Aberrant activation of immune cells is a key feature of SLE development. In this context, we aim to decipher the role of SLAMF receptors, a family of 9 cell surface receptors belonging to the CD2 superfamily, in SLE pathogenesis. In T and B cells, SLAMF molecules play a role as co-receptor in cell activation and differentiation, through the modulation of the T-cell receptor (TCR) or B-cell receptor (BCR) signal. We have already shown in previous work that monoclonal antibodies directed against specific SLAMF receptors may modify cell activation status. For instance, ligation of SLAMF3 on naïve CD4+ T cells has been shown to enhance their response to IL-2 and promote their differentiation toward a regulatory phenotype (Treg), while inhibiting Th1, Th2 and Th17 differentiation. This feature is of particular interest in SLE, a disease in which immune regulation is disrupted and suggests that SLAMF receptors may represent novel therapeutic targets in SLE.
The role of NK cells and cytotoxic CD8+ T cells cells in SLE was long disregarded, as compared to other cells involved in the SLE pathogenesis such as B or CD4+ T cells, and few studies examined their specific role in the immune alteration of the disease.
Alteration in cytotoxic cells phenotype and function contributes to important features that characterize patients with SLE: increased rate and more severe infection, as well as increased prevalence of cancer (lymphoma and solid neoplasms) compared to healthy subjects. Recent data also suggest a possible link between NK cells and the development of autoreactive T and B cells in autoimmune diseases. The mechanisms responsible for SLE NK cells alteration are largely unknown and no studies have evaluated potential alterations in NK’s cellular metabolism.
In this context, one of our research aims is to examine the phenotypic, functional and metabolic alterations of SLE cytotoxic, using advanced techniques, such as mass cytometry.