Autoantibodies targeting type I interferons: Prevalence, mechanisms of induction, and association with viral disease susceptibility

The type I IFN (IFN-I) system is essential to limit severe viral disease in humans. Thus, IFN-I deficiencies are associated with serious life-threatening infections. Remarkably, some rare individuals with chronic autoimmune diseases develop neutralizing autoantibodies (autoAbs) against IFN-Is thereby compromising their own innate antiviral defenses. Furthermore, the prevalence of anti-IFN-I autoAbs in apparently healthy individuals increases with age, such that ∼4% of those over 70 years old are affected. Here, I review the literature on factors that may predispose individuals to develop anti-IFN-I autoAbs, such as reduced self-tolerance caused by defects in the genes AIRE, NFKB2, and FOXP3 (among others), or by generally impaired thymus function, including thymic involution in the elderly. In addition, I discuss the hypothesis that predisposed individuals develop anti-IFN-I autoAbs following "autoimmunization" with IFN-Is generated during some acute viral infections, systemic inflammatory events, or chronic IFN-I exposure. Finally, I highlight the enhanced susceptibility that individuals with anti-IFN-I autoAbs appear to have towards viral diseases such as severe COVID-19, influenza, or herpes (e.g., varicella-zoster virus, herpes simplex virus, cytomegalovirus), as well as adverse reactions to live-attenuated vaccines. Understanding the mechanisms underlying development and consequences of anti-IFN-I autoAbs will be key to implementing effective prophylactic and therapeutic measures

Human Genomics of COVID-19 Pneumonia: Contributions of Rare and Common Variants.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is silent or benign in most infected individuals, but causes hypoxemic COVID-19 pneumonia in about 10% of cases. We review studies of the human genetics of life-threatening COVID-19 pneumonia, focusing on both rare and common variants. Large-scale genome-wide association studies have identified more than 20 common loci robustly associated with COVID-19 pneumonia with modest effect sizes, some implicating genes expressed in the lungs or leukocytes. The most robust association, on chromosome 3, concerns a haplotype inherited from Neanderthals. Sequencing studies focusing on rare variants with a strong effect have been particularly successful, identifying inborn errors of type I interferon (IFN) immunity in 1-5% of unvaccinated patients with critical pneumonia, and their autoimmune phenocopy, autoantibodies against type I IFN, in another 15-20% of cases. Our growing understanding of the impact of human genetic variation on immunity to SARS-CoV-2 is enabling health systems to improve protection for individuals and populations

Type I interferon signaling deficiency results in dysregulated innate immune responses to SARS-CoV-2 in mice

SARS-CoV-2 is a newly emerged coronavirus, causing the global pandemic of respiratory coronavirus disease (COVID-19). The type I interferon (IFN) pathway is of particular importance for anti-viral defence and recent studies identified that type I IFNs drive early inflammatory responses to SARS-CoV-2. Here, we use a mouse model of SARS-CoV-2 infection, facilitating viral entry by intranasal recombinant Adeno-Associated Virus (rAAV) transduction of hACE2 in wildtype (WT) and type I IFN-signalling-deficient (Ifnar1-/- ) mice, to study type I IFN signalling deficiency and innate immune responses during SARS-CoV-2 infection. Our data show that type I IFN signaling is essential for inducing anti-viral effector responses to SARS-CoV-2, control of virus replication and to prevent enhanced disease. Furthermore, hACE2-Ifnar1-/- mice had increased gene expression of the chemokine Cxcl1 and airway infiltration of neutrophils as well as a reduced and delayed production of monocyte-recruiting chemokine CCL2. hACE2-Ifnar1-/- mice showed altered recruitment of inflammatory myeloid cells to the lung upon SARS-CoV-2 infection, with a shift from Ly6C+ to Ly6C- expressing cells. Together, our findings suggest that type I IFN deficiency results in a dysregulated innate immune response to SARS-CoV-2 infection. This article is protected by copyright. All rights reserved

Critically ill COVID-19 patients with neutralizing autoantibodies against type I interferons have increased risk of herpesvirus disease

Autoantibodies neutralizing the antiviral action of type I interferons (IFNs) have been associated with predisposition to severe Coronavirus Disease 2019 (COVID-19). Here, we screened for such autoantibodies in 103 critically ill COVID-19 patients in a tertiary intensive care unit (ICU) in Switzerland. Eleven patients (10.7%), but no healthy donors, had neutralizing anti-IFNα or anti-IFNα/anti-IFNω IgG in plasma/serum, but anti-IFN IgM or IgA was rare. One patient had non-neutralizing anti-IFNα IgG. Strikingly, all patients with plasma anti-IFNα IgG also had anti-IFNα IgG in tracheobronchial secretions, identifying these autoantibodies at anatomical sites relevant for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Longitudinal analyses revealed patient heterogeneity in terms of increasing, decreasing, or stable anti-IFN IgG levels throughout the length of hospitalization. Notably, presence of anti-IFN autoantibodies in this critically ill COVID-19 cohort appeared to predict herpesvirus disease (caused by herpes simplex viruses types 1 and 2 (HSV-1/-2) and/or cytomegalovirus (CMV)), which has been linked to worse clinical outcomes. Indeed, all 7 tested COVID-19 patients with anti-IFN IgG in our cohort (100%) suffered from one or more herpesviruses, and analysis revealed that these patients were more likely to experience CMV than COVID-19 patients without anti-IFN autoantibodies, even when adjusting for age, gender, and systemic steroid treatment (odds ratio (OR) 7.28, 95% confidence interval (CI) 1.14 to 46.31, p = 0.036). As the IFN system deficiency caused by neutralizing anti-IFN autoantibodies likely directly and indirectly exacerbates the likelihood of latent herpesvirus reactivations in critically ill patients, early diagnosis of anti-IFN IgG could be rapidly used to inform risk-group stratification and treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT04410263

Decreased T‐cell response against latent cytomegalovirus infection does not correlate with anti‐IFN autoantibodies in patients with APECED

Autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy (APECED) is an inborn error of immunity affecting both multiple endocrine organs and susceptibility to candidiasis, each with an autoimmune basis. Recently, high titer neutralizing anti‐type I interferon (IFN) autoantibodies have been linked with increased severity of SARS‐CoV‐2 and varicella zoster virus infections in APECED patients. Examining immunity against cytomegalovirus (CMV), we found a higher prevalence of anti‐CMV IgG antibodies in patients with APECED (N = 19) than in 44 healthy controls (90% vs 64%, p = 0.04); the similar difference in their IgG levels did not achieve significance (95 ± 74 vs 64 ± 35 IU/mL, ns.). In contrast, the frequency of CMV‐specific T cells was lower (804 ± 718/million vs 1591 ± 972/million PBMC p = 0.03). We saw no correlations between levels of anti‐CMV IgG and anti‐IFN antibodies in APECED patients or in a separate cohort of patients with thymoma (n = 70), over 60% of whom also had anti‐IFN antibodies. Our results suggest a dysregulated response to CMV in APECED patients and highlight immunodeficiency to viral infections as part of the disease spectrum

Critically ill COVID-19 patients with neutralizing autoantibodies against type I interferons have increased risk of herpesvirus disease.

Autoantibodies neutralizing the antiviral action of type I interferons (IFNs) have been associated with predisposition to severe Coronavirus Disease 2019 (COVID-19). Here, we screened for such autoantibodies in 103 critically ill COVID-19 patients in a tertiary intensive care unit (ICU) in Switzerland. Eleven patients (10.7%), but no healthy donors, had neutralizing anti-IFNα or anti-IFNα/anti-IFNω IgG in plasma/serum, but anti-IFN IgM or IgA was rare. One patient had nonneutralizing anti-IFNα IgG. Strikingly, all patients with plasma anti-IFNα IgG also had anti-IFNα IgG in tracheobronchial secretions, identifying these autoantibodies at anatomical sites relevant for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Longitudinal analyses revealed patient heterogeneity in terms of increasing, decreasing, or stable anti-IFN IgG levels throughout the length of hospitalization. Notably, presence of anti-IFN autoantibodies in this critically ill COVID-19 cohort appeared to predict herpesvirus disease (caused by herpes simplex viruses types 1 and 2 (HSV-1/-2) and/or cytomegalovirus (CMV)), which has been linked to worse clinical outcomes. Indeed, all 7 tested COVID-19 patients with anti-IFN IgG in our cohort (100%) suffered from one or more herpesviruses, and analysis revealed that these patients were more likely to experience CMV than COVID-19 patients without anti-IFN autoantibodies, even when adjusting for age, gender, and systemic steroid treatment (odds ratio (OR) 7.28, 95% confidence interval (CI) 1.14 to 46.31, p = 0.036). As the IFN system deficiency caused by neutralizing anti-IFN autoantibodies likely directly and indirectly exacerbates the likelihood of latent herpesvirus reactivations in critically ill patients, early diagnosis of anti-IFN IgG could be rapidly used to inform risk-group stratification and treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT04410263

Mikobakteriyel hastalıklara mendel duyarlılığı hastalarının genetik ve klinik profili; tek merkez deneyimi

Objective: Mendelian susceptibility to mycobacterial disease (MSMD) is a subgroup of primary immunodeficiencies which develops with the Bacille Calmette–Guérin (BCG) vaccine or non-tuberculous mycobacterial infections. The clinical symptoms have a broad spectrum, from localized to disseminated infections. Materials and Methods: Herein, we performed whole-exome sequencing (WES) on 13 patients with MSMD phenotype. All variants were confirmed by Sanger sequencing. The mean age was 8.41 years (min 3 – max 14 years), and the mean age of symptom onset was 4.6 years in our cohort. Results: We found previously identified IFNGR1 (n=1), IFNGR2 (n=1), TYK2 (n=1), IL12RB1 (n=1), and CYBB (n=1) gene variants in nine patients. Our patients mostly suffered from lymphadenitis (61.5%), osteomyelitis (38%), and miliary tuberculosis (31%). All patients except one had had the BCG vaccination. Two patients developed BCGitis after vaccination. Three patients suffered from disseminated BCG infection (BCGosis). Conclusion: Our findings show the importance of molecular diagnosis in patients with severe infections as an approach for understanding the genetic basis of infectious diseases and deciding on treatment options. The deficiency of IFN-mediated immunity genes plays a crucial role in the pathogenesis of MSMD and must be considered in pediatric patients with BCGitis.Amaç: Mikobakteriyel hastalığa (MSMD) Mendel duyarlılığı, Bacille Calmette-Guérin (BCG) aşısı veya tüberküloz dışı mikobakteriyel enfeksiyonlarla gelişen primer immün yetmezliklerin bir alt grubudur. Klinik semptomlar, lokalize enfeksiyondan yayılmış enfeksiyona kadar geniş bir spektruma sahiptir. Gereç ve Yöntem: Bu çalışmada; MSMD fenotipli 13 hastada tüm ekzom dizileme (WES) yaptık. Tüm varyantlar Sanger dizileme ile doğrulandı. Bizim kohortumuzda ortalama yaş 8.41 yıl (en az 3 – en fazla 14 yıl) ve ortalama semptom başlangıç yaşı 4.6 idi. Bulgular: Dokuz hastada; IFNGR1 (n=2), IFNGR2 (n=1), TYK2 (n=1), IL12RB1 (n=1) ve CYBB (n=1) gen varyantları bulduk. Hastalarımızda en çok lenfadenit (%61,5), osteomiyelit (%38) ve miliyer tüberküloz (%31) mevcuttu. Biri hariç tüm hastalara BCG aşısı yapıldı. İki hastada aşılamadan sonra BCGitis gelişti. Üç hasta, yayılmış BCG enfeksiyonundan (BCGosis) muzdaripti. Sonuç: Bulgularımız, enfeksiyon hastalıklarının genetik temelinin anlaşılmasında ve tedavi seçeneklerine karar verilmesinde bir yaklaşım olarak ağır enfeksiyonlu hastalarda moleküler tanının önemini göstermektedir. IFN aracılı bağışıklık genlerinin eksikliği, MSMD’nin patogenezinde çok önemli bir rol oynar ve BCGitis’li pediatrik hastalarda düşünülmelidir

Autoantikörper gegen Typ-I-Interferone bei SARS-CoV-2 Infektion

Severe-acute-respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), rapidly became a pandemic and has caused 6.6 million deaths since the outbreak started. Although the development and administration of vaccines provided a substantial improvement by decreasing both the number of transmission events and disease severity of infected individuals, emerging viral variants still pose a threat due to their potentially increased transmissibility, immune evasion and virulence. Therefore, there is an ongoing need to better characterize SARS-CoV-2 pathogenicity and the underlying mechanisms to develop alternative strategies for prevention and treatment of COVID-19. This dissertation is based on two publications investigating interferon (IFN) autoantibodies in patients with autoimmune polyendocrine type I (APS-1) and hospitalized COVID-19 patients, respectively. Despite the known production of neutralizing IFN autoantibodies (IFN-AABs) by patients with autoimmune disorders -like APS-1- and well-characterized, key role of IFNs in immune responses during viral infections, the contribution of IFN-AABs to disease in viral infections have been rarely addressed. With the emergence of the COVID-19 pandemic, several studies revealed presence of IFN-AABs in a proportion of patients with severe COVID-19 and pointed towards a link between IFN-AABs and disease severity. Firstly, we conducted a prospective study on a small cohort of patients with APS-1. We hypothesized that these patients have a disposition to develop severe COVID-19 in case of a SARS-CoV-2 infection due to pre-existing IFN-AABs. Contrary to our hypothesis, patients within our cohort that reported an infection with SARS-CoV-2, reported mild disease, showing an incomplete clinical penetrance of IFN-AABs to severe COVID-19. Secondly, we performed a large scale, cross-sectional, multi-cohort study on hospitalized patients with COVID-19. Here, we aimed to identify clinical parameters that co-present with neutralizing IFN-AABs. We propose a novel clinical algorithm for rapid identification of neutralizing IFN-AAB-positive patients that can benefit from specific alternative therapies.Das schwere akute respiratorische Syndrom Coronavirus 2 (SARS-CoV-2), der Erreger der Coronavirus-Krankheit 2019 (COVID-19), wurde schnell zu einer Pandemie und hat seit Beginn des Ausbruchs 6,6 Millionen Todesfälle verursacht. Obwohl die Entwicklung und Verabreichung von Impfstoffen eine wesentliche Verbesserung gebracht hat, indem sowohl die Zahl der Übertragungsereignisse als auch die Schwere der Erkrankung bei infizierten Personen verringert wurden, stellen neu auftretende Virusvarianten aufgrund ihrer potenziell erhöhten Übertragbarkeit, Immunflucht und Virulenz immer noch eine Bedrohung dar. Daher besteht ein anhaltender Bedarf, die Pathogenität von SARS-CoV-2 und die zugrunde liegenden Mechanismen besser zu charakterisieren, um alternative Strategien und zur Prävention und Behandlung von COVID-19 zu entwickeln. Diese Dissertation basiert auf zwei Publikationen, die Interferon (IFN)-Autoantikörper bei Patienten mit autoimmunem polyendokrinem Typ I (APS-1) bzw. bei hospitalisierten COVID-19-Patienten untersuchen. Trotz der bekannten Produktion von neutralisierenden IFN-Autoantikörpern (IFN-AABs) in Patienten mit Autoimmunerkrankungen – wie APS-1 – und einer gut charakterisierten Schlüsselrolle von IFNs bei Immunantworten während Virusinfektionen, wurde der Beitrag von IFN-AABs zur Erkrankung im Kontext von Virusinfektionen selten untersucht. Mit dem Aufkommen der COVID-19-Pandemie zeigten mehrere Studien die Präsenz von IFN-AABs bei einigen Patienten mit schwerem COVID-19 und wiesen auf einen Zusammenhang zwischen IFN-AABs und der Schwere der Erkrankung hin. Zunächst führten wir eine prospektive Studie (1) an einer kleinen Kohorte von Patienten mit APS-1 durch. Wir stellten die Hypothese auf, dass diese Patienten eine Neigung haben, im Falle einer Infektion mit SARS-CoV-2 aufgrund prä-existierender IFN-AABs eine schwere COVID-19 Erkrankung zu entwickeln. Entgegen unserer Hypothese berichteten Patienten in unserer Kohorte, die eine Infektion mit SARS-CoV-2 berichteten, von einer leichten Erkrankung, die eine unvollständige klinische Penetranz von IFN-AABs in Bezug auf schwerem COVID-19 zeigte. Zweitens führten wir eine groß angelegte Querschnittsstudie mit mehreren Kohorten (2) von hospitalisierten Patienten mit COVID-19 durch. Hier zielten wir darauf ab, klinische Parameter zu identifizieren, die mit neutralisierenden IFN-AABs assoziieren. Wir schlagen einen neuartigen klinischen Algorithmus zur schnellen Identifizierung neutralisierender IFN-AAB-positiver Patienten vor, die von spezifischen alternativen Therapien profitieren können

Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria.

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ