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. 2026 Mar 2;223(3):e20251760.
doi: 10.1084/jem.20251760. Epub 2025 Dec 5.

Autoantibodies neutralizing type I IFNs in patients with fulminant herpes simplex virus hepatitis

Adrian Gervais  1   2 , Astrid Marchal  1   2 , Soraya Boucherit  1   2 , Anthony Abi Haidar  1   2 , Lucy Bizien  1   2 , Ahmet Yalcinkaya  3   4 , Ella Sandström  3 , Xiao-Fei Kong  5   6 , Emmanuel Jacquemin  7 , Olivier Bernard  7 , Dominique Debray  8 , Florence Lacaille  9 , Philippe Ichai  10 , Cigdem Arikan  11 , Etienne Javouhey  12 , Bertrand Roquelaure  13 , Frédéric Gottrand  14 , Francesca Trespidi  15 , Veronica Codullo  16 , Lorenzo Cavagna  16   17 , Nicolas Schleinitz  18 , Mohamed Bousfiha  19   20 , Naima Amenzoui  19   20 , Ahmed Aziz Bousfiha  19   20 , Sofie E Jørgensen  21   22 , Nanna Mørk  21   22 , Trine H Mogensen  21   22 , Paul Bastard  1   2   23   24 , Anne Puel  1   2   23 , Alessandro Borghesi  15   25   26   27 , Jody A Rule  5 , William M Lee  5 , Nils Landegren  3 , Aurélie Cobat #  1   2   23 , Jean-Laurent Casanova #  1   2   23   28   29 , Emmanuelle Jouanguy #  1   2   23
Affiliations

Autoantibodies neutralizing type I IFNs in patients with fulminant herpes simplex virus hepatitis

Adrian Gervais et al. J Exp Med. .

Abstract

Fulminant viral hepatitis (FVH) is a devastating condition caused by hepatotropic viruses such as hepatitis A virus (HAV), hepatitis B virus (HBV), and HSV-1/2. We studied 149 FVH patients (73 males and 76 females, aged 1-76) for blood autoantibodies (auto-Abs) neutralizing type I interferons (IFNs; IFN-α2, -β, -ω). Six of 16 (37.5%) HSV-triggered FVH patients carried such auto-Abs on admission, including three with a previously known autoimmune disease. These patients contrasted with 133 HAV- (n = 46) or HBV-triggered (n = 87) patients, none of whom had such detectable auto-Abs. Odds ratios for HSV-triggered FVH in individuals with auto-Abs ranged from 35.3 (95% CI: 13.0-96.2; P < 10-7) for those neutralizing only 100 pg/ml IFN-α/ω to 1,895 (CI: 448.5-8,002; P < 10-12) for those neutralizing both IFN-α and IFN-ω at 10 ng/ml. Over one third of HSV-triggered FVH cases in this international cohort were due to preexisting auto-Abs. This finding highlights auto-Abs against type I IFNs as a major determinant of HSV-FVH and paves the way for targeted preventive or therapeutic interventions.

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Conflict of interest statement

Disclosures: E. Javouhey reported personal fees from Sanofi, GSK, and MSD outside the submitted work. B. Roquelaure reported grants from Ipsen and personal fees from Mirum outside the submitted work. W.M. Lee reported personal fees from BMS, GSK, RAPT, Seagen, and Genentech; and grants from Akero, Camurus, and Madrigal outside the submitted work. J.-L. Casanova reported a patent to PCT/US2021/042741 pending. No other disclosures were reported.

Figures

Figure 1.
Figure 1.
Description of the FVH cohort. (A) Distribution of the viruses implicated in FVH in these FVH patients. (B) Sex distribution of the FVH patients according to the infecting virus. (C) Anti-HSV-1 IgG titers in the plasma of HSV-FVH patients, as determined by ELISA.
Figure 2.
Figure 2.
AAN-I-IFNs in patients with FVH and associated OR. (A) Luciferase-based neutralization assay to detect auto-Abs neutralizing 10 ng/ml IFN-α2, IFN-ω, or IFN-β. Samples with a RLA <15% are considered neutralizing. (B) Luciferase-based neutralization assay to detect auto-Abs neutralizing 100 pg/ml IFN-α2 or IFN-ω or 1 ng/ml IFN-β. (C) Proportion of type I IFNs neutralized in the patients, in individuals with HAV-HBV FVH and in individuals with HSV-FVH. (D) OR for the presence of AAN-I-IFNs in all individuals with FVH, relative to the general population, with adjustment for age by logistic regression. The horizontal bars indicate the upper and lower limits of the 95% CI. IFN-α, auto-Abs neutralizing IFN-α2 (regardless of their effects on other IFNs); IFN-ω, auto-Abs neutralizing IFN-ω (regardless of their effects on other IFNs); IFN-α ± ω ± β, auto-Abs neutralizing IFN-α2 and/or IFN-ω and/or IFN-β; IFN-α + ω, auto-Abs neutralizing both IFN-α2 and IFN-ω. (E) OR for the presence of AAN-I-IFNs in individuals with HSV-FVH vs. HAV/HBV-FVH.
Figure S1.
Figure S1.
Detection of auto-Abs by ELISA and HuProt. (A) Correlation between ELISA and neutralization assay results for the detection auto-Abs. (B) Detection of auto-Abs by HuProt in the six HSV-triggered FVH with AAN-I-IFNs FVH vs. healthy donors.
Figure 3.
Figure 3.
AAN-I-IFNs in longitudinal samples, as determined with the luciferase-based neutralization assay in P2 and P6 samples. (A–C) Plasma samples were diluted 1:10 and incubated with 10 ng/ml (A), 1 ng/ml (B), or 100 pg/ml (C) IFNs. Plasma samples from the APS-1 patients and the healthy donor were not longitudinal and were only used as control for type I IFNs neutralization. APS-1, autoimmune polyendocrinopathy syndrome type 1.
See this image and copyright information in PMC

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