Paradoxical sex-specific patterns of autoantibody response to SARS-CoV-2 infection

Abstract

Background Pronounced sex differences in the susceptibility and response to SARS-CoV-2 infection remain poorly understood. Emerging evidence has highlighted the potential importance of autoimmune activation in modulating the acute response and recovery trajectories following SARS-CoV-2 exposure. Given that immune-inflammatory activity can be sex-biased in the setting of severe COVID-19 illness, the aim of the study was to examine sex-specific autoimmune reactivity to SARS-CoV-2 in the absence of extreme clinical disease. Methods In this study, we assessed autoantibody (AAB) reactivity to 91 autoantigens previously linked to a range of classic autoimmune diseases in a cohort of 177 participants (65% women, 35% men, mean age of 35) with confirmed evidence of prior SARS-CoV-2 infection based on presence of antibody to the nucleocapsid protein of SARS-CoV-2. Data were compared to 53 pre-pandemic healthy controls (49% women, 51% men). For each participant, socio-demographic data, serological analyses, SARS-CoV-2 infection status and COVID-19 related symptoms were collected by an electronic survey of questions. The symptoms burden score was constructed based on the total number of reported symptoms (N = 21) experienced within 6 months prior to the blood draw, wherein a greater number of symptoms corresponded to a higher score and assigned as more severe burden. Results In multivariable analyses, we observed sex-specific patterns of autoreactivity associated with the presence or absence (as well as timing and clustering of symptoms) associated with prior COVID-19 illness. Whereas the overall AAB response was more prominent in women following asymptomatic infection, the breadth and extent of AAB reactivity was more prominent in men following at least mildly symptomatic infection. Notably, the observed reactivity included distinct antigens with molecular homology with SARS-CoV-2. Conclusion Our results reveal that prior SARS-CoV-2 infection, even in the absence of severe clinical disease, can lead to a broad AAB response that exhibits sex-specific patterns of prevalence and antigen selectivity. Further understanding of the nature of triggered AAB activation among men and women exposed to SARS-CoV-2 will be essential for developing effective interventions against immune-mediated sequelae of COVID-19.

Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: Assessing the long‐term outcomes in COVID‐19 patients

“…The underlying factors driving persistently raised markers of hemostasis and inflammation are yet to be established; these could include SARS‐CoV‐2 viral antigen persistence in tissues 26 and in monocytes 27 causing sustained endothelial activation, inflammation, and hypercoagulability. Other plausible mechanisms include immune dysregulation 28 with failure to return to baseline homeostasis, dysfunctional endothelium, 29 or acquired autoimmunity 30 …”

Autoimmunity is a hallmark of post-COVID syndrome

“…Autoantibodies may persist after COVID-19, and latent PolyA increases over time in PCS [ 1 ]. In a recent study by Liu et al [ 5 ], the authors observed that SARS-CoV-2 infection, even in the absence of severe clinical disease, can cause a broad autoantibody response exhibiting sex-specific patterns of prevalence and antigen specificity.…”

“…Herein we confirmed that most autoantibodies are correlated with anti-SARS-CoV-2 antibodies, as shown by Liu et al . [ 5 ]. In patients with PCS, a proinflammatory state is evident [ 1 ], suggesting that bystander activation contributes to the emergence of autoimmunity [ 10 ].…”

The immune response to COVID‐19: Does sex matter?

“… 101 Sex‐specific autoimmune responses may influence the course of recovery from COVID‐19. 104 , 105 A study found that, after asymptomatic infection, the overall autoantibody (AAB) response was greater in women. However, after ‘at least mildly symptomatic infection,’ the ‘breadth and extent of AAB reactivity’ was greater in men.…”

“…However, after ‘at least mildly symptomatic infection,’ the ‘breadth and extent of AAB reactivity’ was greater in men. 105 …”