The present study showed that JSLE patients have an increased serum IgE concentration regardless of the presence of atopic manifestations or parasitic disease.
SLE pathogenesis is complex, and there remain controversies concerning the involvement of immunoglobulin E in the pathogenesis of the disease (1
). The dysregulation of immune tolerance results in aberrant Th2 responses and polyclonal activation of B lymphocytes along with the production of autoantibodies, including those of IgE isotype (1-5
). The human Th2 immune response, characterized by the significant production of IL-4, IL-5, IL-10, and IgE, is mainly observed in atopic diseases and in some parasitic infections; however, elevated IgE production has also been observed in patients with partial T cell immunodeficiencies and autoimmune diseases (5
Although IgE synthesis is tightly controlled by regulatory T cells, B cells, and cytokines, the role of immunoglobulin E in autoimmune diseases has not been fully elucidated (11
). The most striking observation reported in the literature is that elevated IgE production and allergic and autoimmune manifestations frequently occur in patients with partial T cell immunodeficiencies even though elevated IgE levels and autoimmune and inflammatory diseases are traditionally associated with hyperactivity of the adaptive immune system (5
). Moreover, mouse models have recently highlighted that an increased IgE level frequently accompanies different partial T cell immunodeficiencies that result in autoimmunity (5
). Taken together, these observations suggest that IgE levels increase when there is an imbalance between the immunogenic and tolerogenic signals in effector T cells; thus, elevated IgE levels can be considered a biomarker of immune dysregulation (5
Although some authors have postulated that IgE is not related to connective tissue disease pathogenesis, others have claimed that IgE plays an essential role in connective tissue disorders (7
). The latter authors state that, through the release of vasoactive mediators from basophils and mast cells, IgE can cause increased vasopermeability, which may be important in causing the deposition of circulating immune complexes in glomerulonephritis pathogenesis (28
). The demonstration of increased IgE serum levels in SLE patients with renal involvement and the detection of IgE immune complex deposition in renal biopsies further implicate IgE in the pathogenesis of lupus nephritis (13
). High IgE levels have also been reported in adult SLE patients without nephritis, suggesting that IgE may have a role in SLE disease and not only in nephritis (4
). Furthermore, antinuclear and anti-DNA autoantibodies of the IgE isotype were observed in adult SLE patients, and these IgE autoantibodies did not correlate with the serum IgE concentration (4
). Anti-IgE IgG autoantibodies have also been observed in SLE patients with lymphoadenopathy, articular involvement and anti-DNA antibodies (9
). In addition, increased IgE serum levels were observed in children of mothers with lupus, regardless of the presence of allergic disease in the mothers (34
). Another study showed elevated IgE levels in male SLE patients compared with female patients (35
). To the best of our knowledge, this was the first study to demonstrate increased IgE levels in JSLE patients.
SLE and allergic disorders share certain immunological abnormalities (6
) because the prevalence of IgE-mediated and/or IgE-associated disorders, such as allergic reactions to drugs, atopic dermatitis, asthma, allergic rhinitis and allergic conjunctivitis, has been reported to be elevated in patients with lupus (6
). In contrast, recent studies observed a similar prevalence of IgE-related disorders in SLE subjects compared with patients without SLE (30
In our study, 15 (21.7%) JSLE patients had at least one respiratory and/or cutaneous allergic manifestation, which is similar to the rate of atopic disorders found in healthy subjects (40
The current study showed that JSLE patients harbor higher IgE concentrations in a manner independent of the presence of allergic disease. Our observations are in line with recent reports stating that patients with lupus are not at an increased risk of IgE-mediated allergic disorders. However, our observations differ from those of previous studies reporting evidence of an increased incidence of atopic conditions in SLE patients (12
We also observed increased IgE serum levels in JSLE patients independent of the presence of parasitic infections. However, the IgE serum concentrations varied widely, which may be due to differences in environment- and patient-specific factors, such as contact with antigens, race, gender and age. Witting et al. (24
) showed that an IgE level of 100 IU/ml is the upper-limit cutoff for elevated IgE diagnostic sensitivity and specificity for all patient cohorts. Thus, one possible limitation of this study is the lack of comparison with age- and gender-matched healthy controls.
Regarding lupus activity, patients with severe active disease (SLEDAI 2K ≥10) had IgE levels at least two times higher than the IgE levels of patients with inactive disease, although this difference was not statistically significant. Interestingly, IgE concentrations correlated inversely with C4 levels, which could suggest that the complement cascade was activated and its components were consumed, as shown by the reduction of C4 levels, which is also considered a marker of disease activity. The latter statement that IgE levels could be a marker of disease activity requires further investigation because the correlation between IgE and C4 levels was relatively weak. Although serum IgE levels have been reported to vary according to disease activity in adult SLE patients (14
), our findings could not confirm this correlation in a definitive manner in patients with JSLE.
Interestingly, IgE serum concentrations were inversely correlated with SLICC/ACR-DI scores, suggesting a protective role for increased IgE levels. This finding is contrary to current knowledge that patients with active disease have high IgE levels and are consequently at a higher risk of organ damage. In addition to the observed direct correlation between IgE and IgA serum levels, the inverse relationship between IgE levels and SLICC/ACR-DI scores supports the hypothesis that increased IgE levels can be considered a marker of immune dysregulation, which may be important in the generation of immune complexes.
Lupus nephritis, which has various histological patterns and variable clinical outcomes, is one of the most important SLE-associated morbidities. Although the pathogenic mechanism in each histological type of nephritis remains unclear, some findings point to a role for both Th1 and Th2 immune responses in renal damage (7
). Th1 cytokines have been related to diffuse lupus nephritis, while Th2 cytokines have been associated with membranous lupus nephritis (7
). In the present study, 81.2% of the JSLE patients had lupus nephritis, and IgE levels ≥100 UI/ml were observed in 36.2% of these patients. However, the mean IgE levels were similar in patients with and without nephritis, as well as in patients with severe renal disease. This observation is in contrast with the published works with adult SLE patients, which showed a significant correlation between serum IgE concentration and nephritis activity, and previous reports, which showed that IgE renal deposits in lupus patients correlate with a poor prognosis (13
All patients with JSLE were taking glucocorticoids, and the down-regulation of allergic inflammation could have been associated with the use of this medication, as glucocorticoids can increase IL-10 gene transcription and decrease both IL-4 and IL-5 gene transcription (43
Finally, despite the variety of factors that can influence IgE production, the present study demonstrated for the first time that JSLE patients have higher IgE concentrations, suggesting that increased IgE levels could play a role in lupus pathogenesis. However, the specific mechanisms underlying the elevation of IgE levels in children with lupus remain to be clarified, and further studies are needed.