AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies

Abstract

SummaryAPS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

“…TYK2, a candidate gene for type 1 diabetes, regulates both PIC-(a mimic of double-stranded RNA produced during viral infection) and IFNα-induced MHC class I expression and inflammation in human beta cells [23]. Furthermore, histological analysis and other approaches have identified higher expression of type I IFNs in islets from patients with type 1 diabetes [7][8][9][10], and self-reactive antibodies targeting type I IFNs are associated with protection against type 1 diabetes in patients with an autoimmune syndrome [20]. Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I [1,2], ER stress [3,37] and beta cell apoptosis [6], and we presently show that IFNα induces or contributes to these three phenomena in human beta cells.…”

“…Laser-captured islets obtained from living donors with recent onset type 1 diabetes showed a significant increase in nearly 50% of the IFN-stimulated genes (ISGs) evaluated [18]. Neutralisation of the IFNα/β receptor (IFNAR1) with monoclonal antibodies prevents diabetes in NOD mice [13,19] and self-reactive antibodies targeting type I IFNs-particularly IFNα-are associated with protection against type 1 diabetes in patients with mutations in the thymus transcription factor autoimmune regulator (AIRE) [20]. It is surprising that very few studies have investigated the direct effects of this cytokine in pancreatic beta cells [21][22][23].…”

Progression of type 1 diabetes from the prediabetic stage is controlled by interferon-α signaling

“…Third, we provided evidence that type I IFN-α, and not IFN-β, was essential for entry of autoreactive T cells into the islets. Of interest is the report by Meyer et al (25) on humans with autoimmune T1D due to mutations in autoimmune regulator (AIRE). A subset of patients with AIRE deficiency that generated self-reactive neutralizing antibodies specific for type I IFN-α1, IFN-α2, IFN-α5, IFN-α8, and IFN-α14 were protected from T1D whereas, in contrast, those not possessing anti-IFN-α antibodies developed T1D.…”

Insights into immune tolerance from AIRE deficiency

“…While Type 1 interferon autoantibodies are virtually diagnostic for APS-1, it is unclear whether they have a pathogenic role. Recently, investigators with the APECED patient collaborative described a broad spectrum of autoantibodies targeting >40% of the proteome in a cohort of 81 patients with notable prevalence of high-affinity, neutralizing anti-cytokine antibodies [43]. Based on the inverse correlation of type-I interferon autoantibodies with Type 1 diabetes, such antibodies may protect from diabetes in APS-1 patients [43].…”

“…Recently, investigators with the APECED patient collaborative described a broad spectrum of autoantibodies targeting >40% of the proteome in a cohort of 81 patients with notable prevalence of high-affinity, neutralizing anti-cytokine antibodies [43]. Based on the inverse correlation of type-I interferon autoantibodies with Type 1 diabetes, such antibodies may protect from diabetes in APS-1 patients [43]. In contrast, another recent study demonstrated that only a very limited portion of the proteome becomes targeted in APS-1 patients [44].…”