Neutralizing Anti-interferon-γ Autoantibodies: an Ameliorating Factor in COVID-19 Infection?
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ABSTRACT:
SUBMITTER: Kacar M
PROVIDER: S-EPMC8311417 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC4880074 | biostudies-literature
Project description:Adult-onset immunodeficiency syndrome due to anti-interferon (IFN)-γ autoantibodies has attracted much attention in recent years. It usually occurs in previously healthy people and usually presents as chronic, recurrent, and hard-to-control infections that can be effectively treated with aggressive antibiotic therapy. Adult-onset immunodeficiency syndrome is also referred to as AIDS-like syndrome. Anti-type I IFN (IFN-I) autoantibodies have been reported to play a significant role in the pathogenesis of coronavirus disease 2019 (COVID-19) and preexisting anti-IFN-I autoantibodies are associated with an increased risk of severe COVID-19. This review summarizes the effects of anti-IFN autoantibodies on the susceptibility and severity of various infectious diseases, including SARS-CoV-2 infection. In addition, we discuss the role of anti-IFN autoantibodies in the pathogenesis of autoimmune diseases that are characterized by recurrent infections.
| S-EPMC8727472 | biostudies-literature
Project description:Purpose Autoantibodies (aAbs) to type I interferons (IFNs) have been found in <1% of individuals under the age of 60 in the general population, with the prevalence increasing among those over 65. Neutralizing autoantibodies (naAbs) to type I IFNs have been found in at least 15% of patients with life-threatening COVID-19 pneumonia in several cohorts of primarily European descent. We aimed to define the prevalence of aAbs to IFN-α2 in 3,456 Japanese controls aged 20-91 and of aAbs and naAbs to IFN-α2 and IFN-ω in 627 Japanese COVID-19 patients aged 0-104, among whom were 170 critical, 235 severe, 112 moderate, 105 mild, and 5 asymptomatic infections. Methods ELISA and ISRE reporter assays were used to detect aAbs and naAbs using E. coli-produced IFNs. Results In an uninfected general Japanese population aged 20-91, we found aAbs in 0.087% of individuals. naAbs to type I IFNs (IFN-α2 and/or IFN-ω, 100 pg/mL) were detected in 10.6% of patients with critical infections, 2.6% of patients with severe infections, and ≤1% of patients with asymptomatic to mild infections. They were higher in COVID-19 patients over 50 (5.8%) than in younger patients (0%) and higher in men (5.5%) than in women (1.1%). A significant but not strong correlation between aAbs and naAbs to IFN-α2 existed (r=-0.307, p-value<0.0001), stressing the importance of measuring naAbs. Conclusion In the largest study focusing on a single ethnic and geographic group, we show that Japanese individuals with pre-existing naAbs have a much higher risk of life-threatening COVID-19 pneumonia.
| S-EPMC8923117 | biostudies-literature
Project description:PurposeAutoantibodies (aAbs) to type I interferons (IFNs) have been found in less than 1% of individuals under the age of 60 in the general population, with the prevalence increasing among those over 65. Neutralizing autoantibodies (naAbs) to type I IFNs have been found in at least 15% of patients with life-threatening COVID-19 pneumonia in several cohorts of primarily European descent. We aimed to evaluate the prevalence of aAbs and naAbs to IFN-α2 or IFN-ω in Japanese patients who suffered from COVID-19 as well as in the general population.MethodsPatients who suffered from COVID-19 (n = 622, aged 0-104) and an uninfected healthy control population (n = 3,456, aged 20-91) were enrolled in this study. The severities of the COVID-19 patients were as follows: critical (n = 170), severe (n = 235), moderate (n = 112), and mild (n = 105). ELISA and ISRE reporter assays were used to detect aAbs and naAbs to IFN-α2 and IFN-ω using E. coli-produced IFNs.ResultsIn an uninfected general Japanese population aged 20-91, aAbs to IFNs were detected in 0.087% of individuals. By contrast, naAbs to type I IFNs (IFN-α2 and/or IFN-ω, 100 pg/mL) were detected in 10.6% of patients with critical infections, 2.6% of patients with severe infections, and 1% of patients with mild infections. The presence of naAbs to IFNs was significantly associated with critical disease (P = 0.0012), age over 50 (P = 0.0002), and male sex (P = 0.137). A significant but not strong correlation between aAbs and naAbs to IFN-α2 existed (r = - 0.307, p value < 0.0001) reinforced the importance of measuring naAbs in COVID-19 patients, including those of Japanese ancestry.ConclusionIn this study, we revealed that patients with pre-existing naAbs have a much higher risk of life-threatening COVID-19 pneumonia in Japanese population.
| S-EPMC9243824 | biostudies-literature
Project description:Adult-onset immunodeficiency (AOID) with anti-interferon-γ (IFN-γ) autoantibodies (autoAbs) is an emerging immunodeficiency syndrome in Asian countries. The presence of neutralizing anti-IFN-γ autoAbs are significantly associated with severe disseminated opportunistic infections. However, the characteristics of the neutralizing antibodies in patients are poorly defined. To better understand the properties of the anti-IFN-γ autoAbs in patients with opportunistic infections, a simplified competitive-binding ELISA was developed. The domains recognized by anti-IFN-γ autoAbs were assessed based on their competition with commercial neutralizing mouse anti-IFN-γ monoclonal antibodies (mAbs). First, the binding affinity and neutralizing capacity of these mAbs (clones B27, B133.5, and MD-1) were characterized. Kinetic analysis and epitope binning using bio-layer interferometry showed the comparable binding affinity of these mAbs to full-length IFN-γ and to the adjacent binding region. These mAbs did not recognize the synthetic 20-mer peptides and inhibited IFN-γ-mediated functions differently. In a competitive-binding ELISA, the anti-IFN-γ autoAbs in AOID serum blocked B27, B133.5, and MD-1 mAb binding. This evidence suggested that the autoAbs that competed with neutralizing mouse anti-IFN-γ mAbs recognized a discontinuous epitope of homodimeric IFN-γ as these mAbs. The patient autoAbs that recognized the B27 epitope exhibited strong neutralizing activity that was determined by the functional analysis. Our results demonstrated the heterogeneity of the autoAbs against IFN-γ in AOID patients and the different patterns among individuals. These data expand upon the fundamental knowledge of neutralizing anti-IFN-γ autoAbs in AOID patients.
| S-EPMC6702949 | biostudies-literature
Project description:A hallmark of patients with autoimmune polyendocrine syndrome type 1 (APS-1) is serological neutralizing autoantibodies against type 1 interferons (IFN-I). The presence of these antibodies has been associated with severe course of COVID-19. The aims of this study were to investigate SARS-CoV-2 vaccine tolerability and immune responses in a large cohort of patients with APS-1 (N = 33) and how these vaccinated patients coped with subsequent infections. We report that adult patients with APS-1 were able to mount adequate SARS-CoV-2 spike-specific antibody responses after vaccination and observed no signs of decreased tolerability. Compared with age- and gender-matched healthy controls, patients with APS-1 had considerably lower peak antibody responses resembling elderly persons, but antibody decline was more rapid in the elderly. We demonstrate that vaccination protected patients with APS-1 from severe illness when infected with SARS-CoV-2 virus, overriding the systemic danger of IFN-I autoantibodies observed in previous studies.
| S-EPMC10251722 | biostudies-literature
Project description: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-? (IFN-?) in a cohort of IPEX patients. Serum from IPEX patients blocked IFN-? 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-? in a second geographically distinct cohort. In these samples, ACAAs against IFN-? were elevated in a post hoc analysis. In summary, we report the discovery of ACAAs against IFN-? in IPEX, an experiment of nature demonstrating the important role of peripheral T cell tolerance.
| S-EPMC5885158 | biostudies-literature
Project description:BackgroundHigh-titer anti-interferon (IFN)-γ autoantibodies are strongly associated with intracellular pathogens such as nontuberculous mycobacteria and Talaromyces marneffei, but they are not as commonly associated with Talaromyces marneffei co-infected with Mycobacterium tuberculosis.Case presentationHerein, we report a case of an HIV-negative Chinese man with a severe, disseminated co-infection of Talaromyces marneffei and Mycobacterium tuberculosis, who had a high-titer of anti IFN-γ autoantibodies and a CFI heterozygous nonsense gene mutation. The patient rapidly developed sepsis and died. Through by flow cytometry for CD4+ T cells' intracellular phosphorylated STAT-1 and Th1 cells (CD4+ IFN-γ+ cells), we found that the patient's serum can inhibited IFN γ-induced CD4+ T cells' STAT-1 phosphorylation and Th1 cell differentiation in normal peripheral blood mononuclear cells, but this phenomenon was not observed in normal control's serum. In addition, the higher serum concentration in the culture medium, the more obvious inhibition of Th1 cell differentiation.ConclusionsFor HIV-negative individuals with relapsing, refractory, fatal double or multiple intracellular pathogen infections, especially Talaromyces marneffei, clinicians should be aware that if they might be dealing with adult-onset immunodeficiency syndrome due to high-titer anti-IFN-γ autoantibodies. Systematic genetic and immunological investigations should also be performed.
| S-EPMC8796477 | biostudies-literature
Project description:Interferon-γ autoantibodies increase the risk of disseminated nontuberculous mycobacterial infections. Addition of rituximab to antibiotics accelerates and improves outcomes, but refractory infections can occur due to persistent production of autoantibodies. We combined bortezomib with rituximab to reduce autoantibodies leading to clinical and radiographic improvement in infection.
| S-EPMC8141761 | biostudies-literature
Project description:IntroductionAnti-interferon-gamma (anti-IFN-γ) autoantibody increases susceptibility to lower-virulence pathogens and causes immunodeficiency syndrome in HIV-negative patients.Patient concernsA 69-year-old Chinese man presented with a 2-month history of pruritic skin lesions on his forearms, trunk, and legs. He was diagnosed with 5 opportunistic infections without conventional immunosuppression-associated factors in past. The most conspicuous characteristics were recurrent pulmonary infection, persistent immunoglobulin E elevation and eosinophilia during the whole disease course.DiagnosisEnzyme-linked immunosorbent assay showed anti-IFN-γ autoantibody positive. The final diagnosis for the patient was adult-onset immunodeficiency due to anti-IFN-γ autoantibody, non-tuberculous mycobacterial (NTM) infection and reactive dermatosis.InterventionsThe patient underwent long-term anti-NTM and corticosteroid maintenance treatment.OutcomesThe patient was followed for 2 years during which opportunistic infection no longer happened, the immunoglobulin E level and eosinophil count reduced, the autoantibody levels remained largely steady and lung lesions absorbed.ConclusionClinicians should be vigilant for NTM infection in patients with anti-IFN-γ autoantibodies, even when culture results are negative. Long-term anti-non-tuberculous mycobacteria and glucocorticoid regimens were effective.
| S-EPMC7478425 | biostudies-literature