Introduction
Autoimmunity is defined by a break of tolerance to self-antigens leading to either organ-specific or systemic diseases. This reactivity to self is driven by autoreactive B and/or T cells that escaped negative selection processes through mechanisms that are not yet fully characterized. Several models explaining the loss of tolerance to some self-antigens have been proposed concerning the expansion of both autoreactive B and T cells1-6. Some autoimmune diseases (AID) are characterized by the presence of pathogenic autoreactive antibodies (AAb) produced by plasmablast and/or plasma cells resulting from T cell-dependent and/or T cell-independent B cell differentiation from both follicular and extrafollicular areas of secondary or tertiary lymphoid organs3,7. Pathogenic antibodies drive the development of organ injury in these antibody-mediated AID (AbAID) through mechanisms involving Fc receptor bearing cells and/or complement pathways8.
In organ-specific AbAID, AAb target tissue-expressed self-antigens which leads to the development of signs and symptoms. For instance, in bullous pemphigoid, AAb against BP-180 and BP-230 (BP Ag2 and BP Ag1, respectively, key dermis-epidermis junction molecules) are responsible for blister formation9. In systemic diseases, AAb target non-organ specific antigens. In systemic lupus erythematosus (SLE), for instance, AAb to nuclear antigens form circulating immune complexes (CIC) that induce chronic and systemic inflammation by depositing in target organs and by activating complement and innate immune cells that amplify AAb production through various mechanisms7.
AAb are prevalent in the general population and are thus not systematically associated with clinical symptoms10. However, in some individuals, through genetic, environmental and/or hormonal mechanisms, a pro-inflammatory trigger can amplify their production and modify their isotypes and glycosylation. Toll-like receptors (TLR) and intracellular nucleic acid sensing molecules engagement, through inflammatory signals, can lead to autoreactive B and T cells proliferation and maturation1,3,10-12. Some of these immune signals also initiate class switch recombination (CSR) allowing B cells to switch the constant region of their BCR from IgM to another isotype13,14.
While AAb of IgM isotype may generally be protective against AbAID, IgG AAb are mostly pathogenic. IgG subclasses differ in the activation of complement pathways and in engaging inhibitory and/or activating Fc receptors for IgG (FcγR), and differences in post-translational modifications influence their pro- or anti-inflammatory properties8,10. The pathogenicity of IgA and IgD AAb still needs further characterization, but recent evidence points to the pathogenicity of IgE AAb and highlights IgE as a potent therapeutic target in a number of AbAID15. Interleukin 4 (IL-4) and IL-13 are the main cytokines promoting IgE CSR and the generation of IgE-producing antibody-secreting cells14,16.
IgE binds with high affinity to FcεRI (Kd≈10-9 M), which is expressed in its tetrameric form αβγ2 by mast cells and basophils and, in humans, in its αγ2 trimeric form mainly by some dendritic cell subsets, Langerhans cells, eosinophils and some monocytes (either constitutively or induced)17. FcεRI-mediated activation of mast cells and basophils leads to the immediate release of granular pro-inflammatory preformed mediators and to neosynthesis and release of arachidonic derivatives, cytokines, and chemokines18. These effects can be toned down through co-engagement of FcγRIIB (CD32B) or other inhibitory receptors that can block degranulation and decrease cytokine production19,20.
The lower affinity IgE receptor FcεRII (CD23, Kd≈10-7-10-8 M) is mainly expressed by some subsets of B cells and monocytes and is involved in the regulation of IgE synthesis and, together with FcεRI, in IgE-mediated facilitated antigen presentation14. Beyond its effects on IgE synthesis, little is known about CD23-mediated pathogenicity of IgE in AbAID. Its involvement in the regulation of allergic responses has been recently reviewed14,21.
Autoreactive IgE can drive cellular activation of mast cells, basophils and other types of FcεRI-bearing cells15 without necessarily inducing their degranulation due to other factors influencing their functional outcomes. Indeed, AbAID-affected patients do not have chronic anaphylactic symptoms and systematically develop pathogenic antibodies of multiple isotypes including IgG. Depending on their subclass and their affinity to the autoantigen, autoreactive IgG can induce inhibitory signals that will be integrated to FcεRI-mediated activating signals leading to a specific cellular activation (or inhibition) pattern of the targeted cell. This may result in mast cell or basophil activation without degranulation but with the production of cytokines, chemokines or other inflammation-related compounds22 and may potentiate the TLR9-dependent activation of dendritic cells23. Therefore, the term autoallergy (or allergy to self) should be used cautiously when referring to diseases where mast cell and basophil degranulation are not induced by IgE AAb.
The present review summarizes the current knowledge on the pathogenicity of autoreactive IgE in AbAID and will discuss the role of IgE as a therapeutic target in these conditions. We will also highlight the need to develop better assays for IgE AAb to validate their diagnostic and prognostic values and allow further study of their pathophysiological contribution to AbAID.