IgE in the Pathogenesis of SLE: From Pathogenic Role to Therapeutic Target

Abstract

Systemic lupus erythematosus (SLE) is a multifactorial chronic autoimmune disease, marked by the presence of autoantibodies to nuclear antigens belonging to different isotype classes. For several years, IgE antibodies have been incriminated in the development of allergic diseases and parasitic infections and different anti-IgE therapies have been developed to encounter the pathogenic role of IgE in these pathologies. Recently, multiple studies showed the presence of elevated total IgE levels and demonstrated a pathogenic role of autoreactive IgE in SLE. This review aims to summarize the findings incriminating IgE and autoreactive IgE in the pathophysiology of SLE, to describe their functional outcomes on their targeted cells as well as to discuss different IgE-related therapeutic modalities that emerged and that may be beneficial for SLE patient care.

Keywords: Fc receptors; IgE; SLE; autoantibodies; basophils; isotypes; lupus; plasmacytoid dendritic cells.

Figure 1

Autoreactive and non-autoreactive IgE effects on basophils and pDC in SLE. 1: The binding of the autoreactive IgE to dsDNA induces the crosslinking of the high affinity receptor for IgE (FcεRI) at the surface of basophils, which can lead to their degranulation and the secretion of lipid mediators and cytokines, such as: IL-4, IL-6 and BAFF. The secreted cytokines promote plasma cells differentiation and amplifies the secretion of autoreactive and non-autoreactive IgE/IgG. 2: In immune complexes, IgE and IgG autoreactive antibodies, together with the autoantigens, can aggregate both activating Fc receptors (FcεRI and FcγRIIA, respectively) and inhibiting Fc receptors, (FcγRIIB on basophils). This can modulate (enhance or inhibit) the activation signal mediated by autoreactive IgE through FcεRI and results in suboptimal activation where basophils do not degranulate but migrate to secondary lymphoid organs where they secrete cytokines influencing autoreactive B and T cell functions. 3: Non-autoreactive IgE can compete with autoreactive IgE for the binding of FcεRI, hence preventing the activation of basophils or pDC. 4,6: The binding of autoreactive IgE and IgG, respectively, to FcεRI and FcγRIIA on the surface of pDC, is followed by the delivery of these immune complexes to the phagolysosome where TLR9 is engaged and leads to the secretion of IFNα which promote B cell differentiation. 5: The crosslinking of FcεRI by non-autoreactive IgE inhibits the pDC activation by decreasing the FcεRI surface expression such as TLR7 and TLR9 expression and trafficking to phagolysosomes.