This study demonstrates that most of mouse HC IgEs react with multiple autoantigens. Since some of the autoantigens, e.g., HRF and dsDNA and ssDNA, have multivalency in terms of the IgE-binding ability, it seems reasonable to assume that such an autoantigen can trigger cross-linking of IgE-bound receptors, thus activation of mast cells and basophils, eventually leading to allergic reactions. Indeed, HRF was shown to amplify allergic inflammation by this mechanism in passive cutaneous anaphylaxis and airway inflammation in mice.24
Similar to HRF, dsDNA and ssDNA released from damaged tissues during allergic reactions may contribute to exacerbate allergic inflammation by interacting with HC IgE bound to FcεRI on mast cells and basophils. One of the eight mouse IgE mAbs tested failed to react with autoantigens. This negative result might be due to the fact that the number of autoantigens tested was not exhaustive enough or appropriate autoantigens were not tested.
As encountered by western blotting or other immunoassays on a daily basis, immunologists have long known that an antibody recognizes more than one antigen.35
Particularly, monoclonal antibodies were shown to have multispecificity.36
Conformational diversity of antigen recognition, whereby one antibody (e.g., IgE) sequence adopts multiple structures, can increase the effective size of the antibody repertoire and may lead to autoimmunity.28
Autoimmunity underlies allergic diseases.34
Epidemiological data indicate that the prevalence of allergies and autoimmune diseases have increased in parallel.37,38
Recent studies support the concept that IgE autoreactivity may play a pathogenic role in severe and chronic forms of atopy.34,39
While acute allergic reactions following exposure to exogenous allergens are understood as immediate type inflammation triggered by degranulation of mast cells via allergen-IgE-FcεRI interactions, chronic allergic inflammation with Th1 characteristics can occur and persist in the absence of exogenous allergens. IgE-mediated presentation of autoallergens may activate autoreactive Th1 cells to release proinflammatory cytokines.40,41
Several environmental allergens have striking structural and immunologic similarities with human proteins.42-46
A broad spectrum (≥140 proteins) of IgE-reactive autoantigens were found in AD patients and some of them were shown to have the ability to activate basophils.47
As shown in this study, some AD patients who had high levels of ssDNA- (or dsDNA-) and/or β-galactosidase-reactive IgEs also had high levels of HRF-reactive IgEs, the autoimmune mechanism could be an important part of the disease pathogenesis in this subset of patients. This observation also suggests the heterogeneity of AD pathogenesis, as not all AD patients have increased IgE reactivity to autoantigens. Interestingly, NC/Nga mice spontaneously develop AD-like skin lesions48
and IgE autoantibodies including anti-histone H3 IgE;49
this age-dependent increase in the serum anti-histone H3 IgE was in parallel with the onset of dermatitis, and correlated well with dermatitis severity at 12-16 weeks of age. As global gene expression patterns are similar in lesional skin between NC/Nga mice and human AD patients (Ando et al., in preparation), these data and our present study support the notion that IgE autoreactivity may play a pathogenic role in AD. Thus, further characterization of the role of IgE autoantibodies in the NC/Nga model will be interesting.
This study also demonstrates that human IgE molecules exhibit heterogeneity in the ability to induce cytokine production and survival promotion in human mast cells in a similar way that mouse HC versus PC IgE molecules exhibit differences in inducing various activation events in mouse mast cells.19,50
Thus, a human HC IgE induces cytokine/chemokine production more strongly than do human PC IgEs. However, there are some differences between human and mouse systems. For example, significant survival promotion was seen only with a human HC IgE, in contrast with mouse IgE effects showing that even PC IgEs can promote mast cell survival albeit with weak potency.7,10
Degranulation could not be induced by either type of human IgE. These results could be due to the type of human mast cells used in this study. Indeed, even IgE+anti-IgE-stimulated human CBMCs degranulate only 10%-20% of the granule content (data not shown). This low responsiveness may be related to low expression levels of FcεRI in CBMCs, which can be enhanced by IL-4 stimulation.29
Unlike CBMCs pretreated or not with IL-4, human monomeric myeloma IgE induced dose-dependent histamine release, leukotriene C4 production, and IL-8 synthesis in cultured human lung mast cells.22
That study suggests that cultured human lung mast cells are more responsive to IgE than human CBMCs, although this and our studies were performed using different IgE molecules. Despite the above-mentioned minor differences in monomeric IgE effects between mouse and human, a human HC IgE bound autoantigens such as dsDNA, ssDNA and HRF, like mouse HC IgEs.
In conclusion, HC, but not PC, IgEs exhibit reactivity to various autoantigens. Some of the autoantigens are multivalent, thus potentially capable of activating HC IgE-bound mast cells and basophils. Therefore, these results indicate an autoimmune component in the pathogenic mechanisms of allergic diseases.