Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19,Science Translational Medicine

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Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19
Science Translational Medicine ( IF 15.8 ) Pub Date : 2021-09-22 , DOI: 10.1126/scitranslmed.abh2624
Monique G P van der Wijst _{1,

2,

3} , Sara E Vazquez _{4,

5,

6,

7} , George C Hartoularos _{2,

3} , Paul Bastard _{8,

9,

10} , Tianna Grant _{2,

3} , Raymund Bueno _{2,

3} , David S Lee _{2,

3,

11} , John R Greenland ₁₂ , Yang Sun _{2,

3,

11} , Richard Perez _{2,

13} , Anton Ogorodnikov _{2,

3} , Alyssa Ward _{2,

3} , Sabrina A Mann _{7,

14} , Kara L Lynch _{15,

16} , Cassandra Yun _{15,

16} , Diane V Havlir ₁₇ , Gabriel Chamie ₁₇ , Carina Marquez ₁₇ , Bryan Greenhouse ₁₇ , Michail S Lionakis ₁₈ , Philip J Norris _{15,

16,

19} , Larry J Dumont _{20,

21,

22} , Kathleen Kelly ₂₀ , Peng Zhang ₁₀ , Qian Zhang ₁₀ , Adrian Gervais _{9,

10} , Tom Le Voyer _{9,

10} , Alexander Whatley ₂₃ , Yichen Si ₂₄ , Ashley Byrne ₁₄ , Alexis J Combes _{11,

25,

26} , Arjun Arkal Rao _{11,

25,

26} , Yun S Song _{14,

23,

27} , Gabriela K Fragiadakis _{3,

11,

26} , Kirsten Kangelaris ₂₈ , Carolyn S Calfee ₂₉ , David J Erle _{2,

11,

15} , Carolyn Hendrickson ₂₉ , Matthew F Krummel _{11,

25} , Prescott G Woodruff _{11,

29} , Charles R Langelier ₃₀ , Jean-Laurent Casanova _{8,

9,

10,

31} , Joseph L Derisi _{7,

14} , Mark S Anderson _{6,

32} , Chun Jimmie Ye _{2,

3,

11,

14,

33,

34,

35} ,

Affiliation

Department of Genetics, University of Groningen, University Medical Center Groningen, 9713AV Groningen, Netherlands.
Institute of Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France.
University of Paris, Imagine Institute, 75015 Paris, France.
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA.
ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Medicine, University of California, San Francisco, San Francisco Medical Service, San Francisco Veterans Affairs Health Care System, San Francisco, CA 94121, USA.
School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
Zuckerberg San Francisco General, San Francisco, CA 94110, USA.
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Division of HIV, Infectious Disease and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20814, USA.
Vitalant Research Institute, San Francisco, CA 94118, USA.
Vitalant Research Institute, Denver, CO 80230, USA.
University of Colorado School of Medicine, Aurora, CO 80045, USA.
Geisel School of Medicine at Dartmouth, Lebanon, NH 03755, USA.
Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA.
Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA.
Division of Hospital Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Division of Infectious Disease, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Howard Hughes Medical Institute, New York, NY 10065, USA.
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Departments of Epidemiology and Biostatistics and Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA.

Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN–specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non–COVID-19 controls revealed a lack of type I IFN–stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN–specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN–specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.

中文翻译：

I 型干扰素自身抗体与 COVID-19 患者的全身免疫改变有关

在一些患有严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的严重急性呼吸系统综合症冠状病毒病 2019 (COVID-19) 患者中发现了针对 I 型干扰素 (IFN) 的中和性自身抗体。然而，这些抗体的流行、它们在疾病严重程度范围内的纵向动态以及它们对循环白细胞的功能影响仍然未知。在 284 名 COVID-19 患者中，我们在 19% 的重症患者和 6% 的重症患者的外周血样本中发现了 I 型 IFN 特异性自身抗体。我们在患有中度疾病的个体中未发现 I 型干扰素自身抗体。超过600的纵向剖析，使用来自 54 名 COVID-19 患者和 26 名非 COVID-19 对照的多重单细胞表位和转录组测序的 000 个外周血单核细胞显示，患者的骨髓细胞缺乏 I 型干扰素刺激基因 (ISG-I) 反应患有危重疾病。这在从产生 I 型干扰素特异性自身抗体的危重疾病患者中分离出来的树突状细胞群中尤为明显。此外，我们发现在病程早期从危重病患者分离的单核细胞表面抑制性受体白细胞相关免疫球蛋白样受体 1 (LAIR1) 的表达升高。LAIR1 表达与 COVID-19 患者的 ISG-I 表达反应呈负相关，但在健康对照中不表达。

更新日期：2021-09-23

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