Autoantibodies are highly prevalent in non–SARS-CoV-2 respiratory infections and critical illness
Allan Feng, et al.
Allan Feng, et al.
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Research Article Infectious disease

Autoantibodies are highly prevalent in non–SARS-CoV-2 respiratory infections and critical illness

Abstract

The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non–SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non–SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness.

Authors

Allan Feng, Emily Y. Yang, Andrew Reese Moore, Shaurya Dhingra, Sarah Esther Chang, Xihui Yin, Ruoxi Pi, Elisabeth K.M. Mack, Sara Völkel, Reinhard Geßner, Margrit Gündisch, Andreas Neubauer, Harald Renz, Sotirios Tsiodras, Paraskevi C. Fragkou, Adijat A. Asuni, Joseph E. Levitt, Jennifer G. Wilson, Michelle Leong, Jennifer H. Lumb, Rong Mao, Kassandra Pinedo, Jonasel Roque, Christopher M. Richards, Mikayla Stabile, Gayathri Swaminathan, Maria L. Salagianni, Vasiliki Triantafyllia, Wilhelm Bertrams, Catherine A. Blish, Jan E. Carette, Jennifer Frankovich, Eric Meffre, Kari Christine Nadeau, Upinder Singh, Taia T. Wang, Eline T. Luning Prak, Susanne Herold, Evangelos Andreakos, Bernd Schmeck, Chrysanthi Skevaki, Angela J. Rogers, Paul J. Utz

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Figure 4

Cell-based cytokine receptor-blocking assays.

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Cell-based cytokine receptor-blocking assays. (A) FACS plots of IFN-α2, ...
(A) FACS plots of IFN-α2, IL-6, and GM-CSF signaling assays. Cells were treated with media only; commercial blocking antibody or 10% positive control serum from a patient with atypical mycobacterial infection (AMI); 10% healthy control serum; or 10% test serum. Cells were treated with patient serum or a control in the unstimulated condition and with both cytokine and patient serum or a control in the stimulated condition. (B) Blocking activity of patient serum on cells in cytokine signaling assays, reported as percentage of pSTAT+ cells in the unstimulated and stimulated condition. Patient sera were from patients with influenza (nMarburg = 4, nAthens = 5), Stanford ICU (ninfected = 19, nnoninfected = 2), or ARDS (n = 8) . For IFN-α2 and IFN-α8, results shown represent 2 independent experiments (Supplemental Figure 7). HC and positive controls (PC; commercially available antibody or prototype patient serum with known blocking activity) are also included. (C) Neutralization activity to IFN-α2, IFN-γ, and IFN-λ3 in the serum samples of 2 patients. IFN-α2, IFN-γ, and IFN-λ3 were incubated with heat-inactivated serum from donor AMI (PC) and donor SU047 (infected Stanford ICU cohort) and added to HAP1 reporter cells. The serum samples were prepared and tested with a 5-fold serial dilution on HAP1 reporter cells. Final concentrations of IFN-α2, IFN-γ, and IFN-λ3 in the culture were 40 U/mL, 8 U/mL, and 1 ng/mL, respectively (Supplemental Figure 8). The percentages of GFP+ HAP1 reporter cells were evaluated 22–24 hours after the incubation with flow cytometry.