Autoreactive IgE in systemic lupus erythematosus and other autoimmune connective tissue diseases
Systemic autoimmune rheumatic (or connective tissue) AbAID include, but are not limited to, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Gougerot-Sjogren syndrome (GS), systemic sclerosis (SSc or scleroderma) and mixed connective tissue disease (MCTD). In these diseases, AAb are pathogenic drivers and diagnostic markers. They form circulating immune complexes (CIC) once engaged by their target autoantigen, complement components, and eventually rheumatoid factors. These CIC deposit in the targeted organs and activate innate immune cells that drive tissue injury and amplify AAb production7. All of these AbAID come with IgG AAb against nuclear antigens with established pathogenic properties2. The main specificities of the AAb in these diseases and their prevalence for IgG isotype are summarized in Table 1.
Nearly five decades ago, the presence and prevalence of IgE AAb against nuclear antigens were established for RA and SLE24,25and extended to other rheumatic diseases along with their abilities to drive basophil activation26. More recent studies characterized the prevalence of autoreactive IgE in these AbAID and their association with disease activity and particular organ damage, especially in SLE where autoreactive IgE titers are clearly associated with lupus nephritis23,27-29 (Table 1). In lupus-like mouse models, IgE deficiency prevents, dampens, or delays the development of the disease27,30. The pathogenic role of autoreactive IgE in the pathophysiology of SLE includes effects on two main FcεRI-bearing cell types, namely plasmacytoid dendritic cells (pDC) and basophils23,27,29,31 (Figure 1).
In a non-autoimmune context, IgE is known to downregulate TLR7 and TLR9 function and expression on pDCs, reducing their ability to produce IFNα32. However, once aggregated to nucleic acids, IgE AAb amplify IFNα production by pDC. Indeed, in human SLE, through Fcγ receptor-, FcεRI- and TLR7/9-mediated activation, pDC are responsible for the production of high levels of type I interferons that promote autoantibody production and other pro-inflammatory pathways. Anti-DNA IgG can strongly induce pDC IFNα production by facilitating the addressing of DNA (TLR9 ligand) to the TLR9 bearing endosomal compartment. Anti-DNA IgE does the same, and the presence of anti-DNA IgE and IgG in the same immune complexes enhances the induced IFNα production23,29,32.
Basophil activation status correlates with SLE disease activity and is directly associated with the presence of IgE AAb in the circulation of SLE patients23,27-31. Sera from SLE patients induce basophil activation and IL-4 production, features that are lost after IgE depletion from the serum26,31,33. In SLE patients and lupus-like mouse models, activated basophils accumulate in secondary lymphoid organs (SLO) by prostaglandin D2- and CXCR4-dependent mechanisms22,27,33, and this accumulation is lost in IgE-deficient lupus-like mouse models27,30. In SLO, basophils promote plasmablast accumulation and AAb production most probably through their production of IL-4 that acts on both B and T cells and their expression of membrane-bound B cell activating factor of the TNF superfamily (BAFF)22,27,33,34 (Figure 1).
Because of their effects on pDC and basophils, IgE AAb are considered as a pathogenic factor in SLE, and IgE depletion in SLE patients may constitute a valuable therapeutic strategy (see below). Other FcεRI-bearing cells are involved in SLE pathophysiology such as Langerhans cells in photosensitivity35 or mast cells that accumulate in kidneys from lupus nephritis patients36, but their IgE-dependent contribution is not established. Of note, mast cell deficiency in lupus-like mouse models does not affect disease development27,37.
In MCTD, the main autoantigen is the 70kDa subunit of the U1-snRNP (small nuclear ribonucleoprotein). Most MCTD patients (78%) have IgE against U1-snRNP, and this is associated with an activation of their basophils38. In a mouse model of MCTD, IgE deficiency fully prevented the development of the associated lung disease38. In RA, increased blood IgE levels, prevalence of anti-nuclear IgE (49%), and IgE-containing immune complexes in synovial fluid are associated with disease activity, as is the activation of mast cells in synovium15,39. Whether the latter is FcεRI- and/or IgE-mediated still needs to be investigated39.
As indicated in Table 1, the prevalence of IgE AAb in other autoimmune connective tissue diseases suggests that they may have a pathogenic role in these conditions (Table 1). Indeed, several FcεRI-bearing cells are involved in the pathogenesis of these conditions (for instance: mast cells in RA and SSc; pDC in RA, GS, and SSc)15. A high prevalence of IgE AAb has been reported as well in some organ-specific autoimmune diseases affecting the thyroid, with anti-thyroid peroxidase (TPO) IgE in Graves disease (72%) and Hashimoto disease (70%)40, the eyes, with anti-retinal S antigen IgE in autoimmune uveitis (68%)41, and the nervous system, with anti-myelin IgE in multiple sclerosis (100%)42. Further studies will be required to determine the relevance of autoreactive IgE in the pathophysiology of these diseases and their value as a putative therapeutic target.
Table 1: Prevalence of anti-nuclear autoreactive IgG and IgE in some autoimmune connective tissue diseases