Evidence of a Sjögren’s disease–like phenotype following COVID-19 in mice and humans
Yiran Shen, Alexandria Voigt, Laura Goranova, Mehdi Abed, David E. Kleiner, Jose O. Maldonado, Margaret Beach, Eileen Pelayo, John A. Chiorini, William F. Craft, David A. Ostrov, Vijay Ramiya, Sukesh Sukumaran, Ashley N. Brown, Kaley C. Hanrahan, Apichai Tuanyok, Blake M. Warner, Cuong Q. Nguyen
Yiran Shen, Alexandria Voigt, Laura Goranova, Mehdi Abed, David E. Kleiner, Jose O. Maldonado, Margaret Beach, Eileen Pelayo, John A. Chiorini, William F. Craft, David A. Ostrov, Vijay Ramiya, Sukesh Sukumaran, Ashley N. Brown, Kaley C. Hanrahan, Apichai Tuanyok, Blake M. Warner, Cuong Q. Nguyen
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Research Article COVID-19

Evidence of a Sjögren’s disease–like phenotype following COVID-19 in mice and humans

Abstract

Sjögren’s Disease (SjD) is a systemic autoimmune disease characterized by lymphocytic inflammation of the lacrimal and salivary glands (SG), dry eyes and mouth, and systemic symptoms. SARS-CoV-2 may trigger the development or progression of autoimmune diseases. To test this, we used a mouse model of SARS-CoV-2 infection and convalescent patients’ blood and SG in order to understand the development of SjD-like autoimmunity after infection. First, SARS-CoV-2–infected human angiotensin-converting enzyme 2 (ACE2) transgenic mice exhibited decreased salivation, elevated antinuclear antibodies (ANA), and lymphocytic infiltration in the lacrimal and SG. The sera from patients with COVID-19 sera showed increased ANA (i.e., anti-SSA [Sjögren’s-syndrome-related antigen A]/anti-Ro52 and anti-SSB [SS-antigen B]/anti-La). Male patients showed elevated anti-SSA compared with female patients, and female patients exhibited diverse ANA patterns. SG biopsies from convalescent COVID-19 patients were microscopically similar to SjD SG with focal lymphocytic infiltrates in 4 of 6 patients and 2 of 6 patients exhibiting focus scores of at least 2. Lastly, monoclonal antibodies produced in recovered patients blocked ACE2/spike interaction and cross-reacted with nuclear antigens. Our study shows a direct association between SARS-CoV-2 and SjD. Hallmark features of SjD-affected SGs were histologically indistinguishable from convalescent COVID-19 patients. The results implicate that SARS-CoV-2 could be an environmental trigger for SjD.

Authors

Yiran Shen, Alexandria Voigt, Laura Goranova, Mehdi Abed, David E. Kleiner, Jose O. Maldonado, Margaret Beach, Eileen Pelayo, John A. Chiorini, William F. Craft, David A. Ostrov, Vijay Ramiya, Sukesh Sukumaran, Ashley N. Brown, Kaley C. Hanrahan, Apichai Tuanyok, Blake M. Warner, Cuong Q. Nguyen

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Figure 3

Increase in inflammation and apoptosis detected in SGs and LGs of infected mice.

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Increase in inflammation and apoptosis detected in SGs and LGs of infect...
(A) Representative H&E staining of the SGs and LGs of the control and SARS-CoV-2–infected mice with caspase-3+ cells. Yellow arrows indicate lymphocytic infiltrates in the interstitium. (B) Larger areas of lymphocytic infiltration are present in the exocrine glands of infected mice. The lymphocytic focal areas of 52 LGs and 26 SGs were counted using Aperio ImageScope (v12.4.6.5003), with each point representing 1 countable focus in the SG or LG (control, n = 5 females; infected, n = 26, 13 males, 13 females). (C) Elevated glandular apoptosis detected by TUNEL staining (SGs: control males n = 5, control females n = 4, infected males n = 4, and infected females n = 5; LGs: control males n = 10, control females n = 5, infected males n = 7, and infected females n = 8). (D) Elevated glandular apoptosis detected by caspase-3 staining (SGs: control males n = 5, control females n = 4, infected males n = 4, and infected females n = 5; LGs: control males n = 10, control females n = 5, infected males n = 7, and infected females n = 8). (E) Increase in CD68+ macrophage frequency in SGs and (F) LGs of the infected mice. Representative immunofluorescence staining of CD68+ macrophages are displayed in green with blue DAPI nuclei staining. Original magnification, ×40. The statistical significance was calculated using 1-tailed Mann-Whitney U tests where error bars indicate SEM; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. M, male; F, female.