Antibodies from Autoimmune Polyendocrine Syndrome Type 1 Patients Protect Against Diabetes

Patients with autoimmune polyendocrine syndrome type 1 have defects in autoimmune regulator, a transcription factor that regulates the expression of tissue-specific antigens and promotes T cell central tolerance. These patients are known to develop autoantibodies against self-proteins, including type I IFNs and interleukin-17 (IL-17); however, no large-scale analysis of their autoantibody repertoire had ever been undertaken. Meyer et al. used a ProtoArray displaying ~9,000 human proteins to assess the self-reactivity shown by sera from 81 patients with autoimmune polyendocrine syndrome type 1. Collectively, patients showed strong reactivity against more than 40% of the proteins tested. The specific repertoires of proteins recognized by individual patients were highly variable, but cytokines were commonly targeted. Furthermore, 12 proteins were targeted by more than 60% of the patients, and these ‘public’ specificities included several type I IFNs and T helper 17 (TH17)-type cytokines. Additional analyses showed that all 13 IFNα subtypes and IFNω were common targets of the autoantibodies of patients with polyendocrine syndrome type 1, but IFNβ was rarely targeted.

To better understand the nature of the autoantibodies, the authors characterized nine IFNα-specific monoclonal antibodies derived from four patients with APS1. These IFNα-specific antibodies had highly mutated variable regions, appeared to bind epitopes shared by several IFN subtypes and showed extremely high affinity for their targets.

Reporter assays showed that 2 of the patient-derived antibodies (19D11 and 26B9) could neutralize IFN-dependent responses at lower doses than sifalimumab and rontalizumab anti-IFN monoclonal antibodies Interestingly 19D11 neutralized all IFNα subtypes tested. Patient-derived antibodies targeting IL-17F, IL-22, IL-32γ and IL-20 also showed neutralizing activity in vitro, so the authors assessed whether these autoantibodies could neutralize their targets in vivo. Indeed, intraperitoneal delivery of patient-derived monoclonal antibodies to mice protected against ear swelling induced by intradermal injection of the target cytokine. Furthermore, a patient-derived autoantibody targeting IL-22 significantly reduced pathology in a mouse model of psoriasis.

Given these findings, the authors were interested in determining how the autoantibodies produced by patients with autoimmune polyendocrine syndrome type 1 affect the patients themselves. Type I IFNs have been linked to the development of type 1 diabetes, and many patients with autoimmune polyendocrine syndrome type 1 have GAD65-reactive autoantibodies (which are also associated with type 1 diabetes) but do not present with this disease. To assess whether IFN-neutralizing autoantibodies may protect against type 1 diabetes development, the authors compared 8 patients with autoimmune polyendocrine syndrome type 1 who had presented with type 1 diabetes with a cohort of 13 patients with autoimmune polyendocrine syndrome type 1 who had not developed type 1 diabetes but showed strong GAD65 reactivity. All of the patients had autoantibodies to IFNα and IFNω; however, although the autoantibodies from the patients without type 1 diabetes effectively neutralized IFNs, the autoantibodies from patients with type 1 diabetes showed low or negligible neutralizing The authors concluded targeting type I IFNs may be effective against type 1 diabetes. The authors also suggest that further study of patients with APS1 could identify other protective autoantibodies with clinical applications