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