Pathogenic mechanisms of IgE-mediated inflammation in self-destructive autoimmune responses

Autoantibodies of the IgG subclass are pathogenic in a number of autoimmune disorders such as systemic lupus erythomatosus. The presence of circulating IgE autoantibodies in autoimmune patients has also been known for almost 40 years. Despite their role in allergies, IgE autoantibodies are not associated with a higher rate of atopy in these patients. However, recently they have been recognized as active drivers of autoimmunity through mechanisms involving the secretion of Type I interferons by plasmacytoid dendritic cells (pDC), the recruitment of basophils to lymph nodes, and the activation of adaptive immune responses through B and T cells. Here, we will review the formation, prevalence, affinity, and roles of the IgE autoantibodies that have been described in autoimmunity. We also present novel evidence supporting that triggering of IgE receptors in pDC induces LC3-associated phagocytosis, a cellular process also known as LAP that is associated with interferon responses. The activation of pDC with immune complexes formed by DNA-specific IgE antibodies also induce potent B-cell differentiation and plasma cell formation, which further define IgE’s role in autoimmune humoral responses

Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes.

Toll-like receptor-9 (TLR9) is largely responsible for discriminating self from pathogenic DNA. However, association of host DNA with autoantibodies activates TLR9, inducing the pathogenic secretion of type I interferons (IFNs) from plasmacytoid dendritic cells (pDCs). Here, we found that in response to DNA-containing immune complexes (DNA-IC), but not to soluble ligands, IFN-α production depended upon the convergence of the phagocytic and autophagic pathways, a process called microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP). LAP was required for TLR9 trafficking into a specialized interferon signaling compartment by a mechanism that involved autophagy-related proteins, but not the conventional autophagic preinitiation complex, or adaptor protein-3 (AP-3). Our findings unveil a new role for nonconventional autophagy in inflammation and provide one mechanism by which anti-DNA autoantibodies, such as those found in several autoimmune disorders, bypass the controls that normally restrict the apportionment of pathogenic DNA and TLR9 to the interferon signaling compartment