In this study, comprehensive profiling of AAB activation in 177 HCs with prior SARS-CoV-2 infection revealed several important sex-specific findings of interest. First, a surprisingly large number of the diverse autoantibodies assayed were differentially activated in males compared to females. Among previously infected individuals who were asymptomatic, the breadth of AABs response was more prominent in women than in men; by contrast, among previously infected individuals who experienced at least a mild burden of symptoms, the extent of antibody response was far more pronounced in men. Second, we found AAB responses to symptom clusters were also sex-specific, with certain associations seen more prominently in men compared to women, across the range of symptom burden. Third, we found that several autoantibodies, including ACE2, CSF2, LYZ, MDA5, MOV10, SNRPB, SOX13 and SRP19 significantly associated with higher overall symptom timing score, which may indicate that synthesis of these AABs is triggered at the beginning of the infections and correlated to symptoms that were reported closer to the blood draw. Finally, we observed these sex-specific AABs associations up to 6 months following symptomatology, indicating that SARS-CoV-2 triggers a complement of AABs responses that persists over time – in a sex-specific manner and irrespective of illness severity.

The current study expands from prior work in several ways. Extending from previous studies reporting on presence of post-COVID-19 autoimmunity [3, 23], we employed a broad array of antibodies to 91 distinct antigens previously linked to classic autoimmune conditions. Our results reveal a remarkable sex-specific prevalence and selectivity of the AABs response to SARS-CoV-2. Confirming and extending from the findings from prior reports, we found that a majority of our previously infected study participants had detectable circulating AABs against antigens such as ACE2, AQP4, C3, CHD4, CHGA, CXCL8, DBT, ECE1, ELANE, EXOSC10, HARS, HIST1H4A, IGF1R, INS, MOV10, MX1, PRTN3, RNF41, RPLP2, S100A9, SET, SNRPD1, SOX13, TG, TGFB1, TOP1, UBTF. Intriguingly, a distinct set of AABs to 59 antigens were highly correlated with reported symptoms in the male population, while another set of AABs to only 38 antigens were associated with symptoms in females. Notably, in males, we observed AABs associated with symptoms at a high frequency (≥ 6 symptoms) as well as at a moderate frequency (≥ 4 symptoms). The high frequency associated AABs included SNRPB, a ribonucleoprotein that is widely prevalent in human SLE [24]. The moderate frequency associated AABs included MOV10, CHGA, CHD4, HIST1H4A, ACE2, IFNA6, LYZ, RNF41. Importantly, both MOV10 and IFNA6 have been reported in patients infected with COVID-19 [21, 25]. In females, we observed an overall lower frequency of significant symptoms associated AABs when compared to males. The 3 most prominent symptoms in females were associated with AABs to DBT and ROS1. Interestingly, AABs to DBT have been associated with lung cancer [26]. Importantly, a number of AABs can be classified as implicated more frequently with systemic disease traits (i.e., multi-organ or multi-system) which may be particularly relevant to the more non-specific symptoms such as fatigue, fever, rashes, cold or allergy-type symptoms, weight loss, and muscular weakness.

Intriguingly, despite greater co-occurrence of distinct symptoms in females and overall between-sex similarity in the most highly frequent symptom types, males demonstrated a broader AAB response with a greater number of distinct AAB clusters identified across particularly the milder levels of symptom burden. The sex specificity of triggered AABs reactivity in association with either distinct symptoms, or symptom clusters, may be related not only to sex differences in acute illness but also in post-acute and chronic clinical syndromes experienced by a substantial number of individuals recovering from COVID-19 [27].

While apparently paradoxical at the outset, our sex-specific findings are congruent with ongoing emerging data regarding potential mechanisms underlying sex differences in the susceptibility and response to SARS-CoV-2. Early studies reported that while men and women have similar prevalence, men with COVID-19 are at greater risk for worse outcomes and death independent of age [28, 29]. Consistent with these findings, conventional inflammatory markers are founded to be more substantially elevated in men compared to women who are hospitalized for COVID-19 [30]. Accordingly, males in our study had greater AAB reactivity after adjusting for age. For classic autoimmune disease, clinical prevalence and incidence of autoimmune diseases tend to exhibit sex-specific patterns based on pathobiology. Male-predominant autoimmune diseases usually manifest clinically (i.e., show signs and symptoms of clinical disease) prior to age 50 and are characterized by acute inflammation and a Th1-type response, whereas autoimmune diseases with a greater incidence in females that occur early in life have a clearer antibody-mediated pathology. Autoimmune diseases that have a greater incidence in females and also appear clinically later in life tend to present with evidence of chronic pathology, fibrosis, and increased numbers of autoantibodies are present [31].

The conventional sex bias seen for classic autoimmune diseases has been attributed in part to women who have a generally stronger cellular and humoral immunity, higher levels of circulating antibodies, more numerous circulating CD4+ T cells, and more robust cytokine production in response to immune stressors such as infection [32, 33]. By contrast, males are now recognized as more vulnerable to the immune-modulated effects of active SARS-CoV-2 infection likely due to multiple mechanisms (e.g. lower immune cell expression of TLR7, lower observed antibody response, and lower interleukin mediated tissue resilience and tissue repair activity) [33].

Our findings revealed a broad anti-viral immune response detected in previously COVID-19 infected individuals that included reactivity to proteins with molecular homology with SARS-CoV-2 including: MOV10, a protein interaction partner of SARS-CoV-2; adenylate kinase 4 (AK4), a Y14-protein homologue of SARS-CoV-2); and, La ribonucleoprotein domain family member 1 (LARP1), a N protein interaction partner of SARS-CoV-2. Importantly, the autoantibody responses seen across all seropositive individuals were not significantly correlated with concurrent elevations in anti-N IgG index, thus indicating orthogonal immune activation. Notably, only AK4 has been described as SARS-CoV-2 homolog that correlates with anti-N IgG index. However, of the total 12 homologs or interaction partners of SARS-CoV-2 detected by the array, a significantly elevated response to the MOV10 antigen was detected in males and in correlation with the symptom of fever. By contrast, a more prominent AAB response to LARP1 was elevated in females.

These findings demonstrate that SARS-CoV-2 directly triggers the development of AABs not limited to structural proteins similar to SARS-CoV-2. Importantly, our study also demonstrates for the first time an autoimmune activation in females compared to males following asymptomatic infection. As context, the stability of AABs in classic autoimmune diseases is known to vary substantially, with some autoantibodies fluctuating with flares of disease, while others remain stable.

We can speculate that the preponderance of AABs positivity in females—in the absence of symptomatic or recognized infection—represents initiation or proliferation and then persistence of self-reactive immunity with implications for post-acute chronic immune-driven disease states. These findings may be particularly relevant to rapidly accumulating evidence of the post-acute SARS-CoV-2 syndromes (e.g. “long-haul COVID”) that can emerge even weeks to months following resolution of mild or asymptomatic infection and with clinical manifestations that appear to differ in women compared to men [27].

The existence of autoantibodies within normal healthy individuals has been already shown by other investigators [34]. The fact that across the breadth of AABs assayed in our healthy control sample, titers were also male predominant suggesting that larger population-based screening studies are needed to clarify our understanding of sex differences in basal AAB variation in the absence of clinical disease. Importantly, variations in the AAB titers found in the HCWs were different than those seen in healthy control subjects. In the latter group, the most dominant AAB was for granulocyte–macrophage colony-stimulating factor, also known as colony-stimulating factor 2 (CSF2), well-known to be a regulator of monocyte/macrophage differentiation. By contrast, AAB against CSF2 in the HCWs was barely reactive in the male population and were seen to be upregulated in female in asymptomatic group.

Several limitations of our study merit consideration. Our cohort includes HCWs from a single center who volunteered and responded to surveys, potentially limiting generalizability. Given this study’s focus on the milder spectrum of COVID-19 disease presentation and its sequelae, gradation of illness severity was determined based on self-reported symptom burden and very few of our cases (1.7%) required hospitalization and none were treated with immune-modulating therapies for their COVID-19 illness. Thus, further studies are needed to evaluate generalizability of our findings to populations that experienced more severe COVID-19 illness requiring targeted treatments. We were unable to verify exact dates of prior COVID-19 infection due to lack of universal PCR testing available during the initial phases of the pandemic and, thus, associations between timing of infection, symptoms, and AAB response could not be precisely analyzed. We have a relatively small number of male subjects (n = 63) that may have limited the ability to detect potential additional predicators of post-COVID autoimmunity; thus, further investigations of larger sized samples are needed. Our sampling included a 1:3 ratio of controls to cases, and a further balanced ratio of controls to cases in future larger sized studies could offer even greater statistical power for detecting additional potential associations of interest and importance. Although this was a prospective study, the survey method involved requesting participants to self-report symptoms occurring up to 6 months prior to the blood draw, contributing to potential recall bias. Whether examined subjectively or objectively, symptomatology can vary not only between but also within individuals over time. Similarly, the status of AAB reactivity may change over time and in relation to the timing of initial or repeated exposures. Thus, future longitudinal studies are warranted to understand temporal trends in similarly measured exposure and outcomes.

In summary, this comprehensive study of AABs to a wide array of antigens found that male sex carries the risk of diverse autoimmune activation following symptomatic COVID-19 illness, whereas female sex carries risk for a distinct profile of autoimmune activation following asymptomatic SARS-CoV-2 exposure. Importantly, both sets of sex-specific AAB reactivity patterns were found to persist up to 6 months following associated symptomatology. Further understanding of the nature of triggered and persistent AAB activation among individuals who are exposed to SARS-CoV-2—and vulnerable to its potentially morbid clinical sequelae—will be essential for developing effective interventions and therapeutics.

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