Neutralizing Anti-Cytokine Autoantibodies Against Interferon-α in Immunodysregulation Polyendocrinopathy Enteropathy X-Linked

Abstract

Anti-cytokine autoantibodies (ACAAs) have been described in a growing number of primary immunodeficiencies with autoimmune features, including autoimmune polyendocrine syndrome type I (APS-1), a prototypical disease of defective T cell-mediated central tolerance. Whether defects in peripheral tolerance lead to similar ACAAs is unknown. Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) is caused by mutations in FOXP3, a master regulator of T regulatory cells (Treg), and consequently results in defective T cell-mediated peripheral tolerance. Unique autoantibodies have previously been described in IPEX. To test the hypothesis that ACAAs are present in IPEX, we designed and fabricated antigen microarrays. We discovered elevated levels of IgG ACAAs against interferon-α (IFN-α) in a cohort of IPEX patients. Serum from IPEX patients blocked IFN-α signaling in vitro and blocking activity was tightly correlated with ACAA titer. To show that blocking activity was mediated by IgG and not other serum factors, we purified IgG and showed that blocking activity was contained entirely in the immunoglobulin fraction. We also screened for ACAAs against IFN-α in a second geographically distinct cohort. In these samples, ACAAs against IFN-α were elevated in a post hoc analysis. In summary, we report the discovery of ACAAs against IFN-α in IPEX, an experiment of nature demonstrating the important role of peripheral T cell tolerance.

New-Onset IgG Autoantibodies in Hospitalized Patients with COVID-19

“…Pre-existing IFN-α autoantibodies were recently identified in 4/10 (40%) SLE patients from NIH’s SLE cohort who later became infected with SARS-CoV-2 32 . We have identified ACA in SLE (including anti-BAFF blocking antibodies and anti- IFN α) 18 , systemic sclerosis 30 , and a variety of immunodeficiency disorders 18,19,31 , suggesting that ACA are probably more common than previously appreciated in immune-mediated diseases. Taken together, these earlier studies are consistent with the notion that pre-existing ACA are pathogenic and may place such individuals at increased risk of developing severe COVID-19.…”

“…Both groups showed that a subset of ACA prevent binding of soluble factors to their cognate cell surface receptors and have been postulated to play a pathogenic role by thwarting protective immune responses to COVID-19. We created a 41-plex array comprising secreted proteins and cell surface receptors, modeled on arrays we and others have used previously to characterize “secretome” antibodies in immunodeficiency disorders 18, 19 , SLE 18 , and systemic sclerosis patients 20 ( Supplementary Table 2 ). We observed even more striking results with the secretome array, which revealed that serum antibodies in 41/51 (80%) of hospitalized COVID-19 patients recognized at least one secreted or cell surface autoantigen ( Fig.…”

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

“…61 Antibodies against type I interferons capable of blocking interferon signaling can also be found, but their clinical relevance is not yet understood. 62 Notably, anti-interferon antibodies in patients with IPEX syndrome are detected at lower levels and are less biologically potent than anti-interferon antibodies detected in patients with autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy syndrome (also known as autoimmune polyendocrine syndrome type 1, caused by a deleterious mutation of the AIRE gene), 62 in which their presence is linked to resistance to T1D. 63 Antibodies against platelets, neutrophils, and liver and pancreatic islet proteins and others have also been described in relation to the target organs affected.…”

The autoimmune targets in IPEX are dominated by gut epithelial proteins

“…Our group recently demonstrated that the microbiome induces MC maturation in the skin because it induces stem cell factor (SCF) production in keratinocytes, which is essential for MC survival. 6,7 Therefore we hypothesized that changes in the skin microbiome caused by hair loss could be an important factor in increasing the number of MCs present in the skin of hairless mice.…”

“…Given that our laboratory previously demonstrated that MC maturation and migration can be promoted by using skin commensal gram-positive bacteria through the Toll-like receptor 2 (TLR2)-SCF pathway in keratinocytes, 6,7 we investigated the composition of the skin microbiome in C57 HR and C57 WT mice. Skin microbiome composition was assessed by using 16S rRNA sequencing performed on 14 samples, including 8 C57 WT mice, 4 C57 HR mice, and two 1-week-old C57 HR mice.…”