Increased anti-nucleocapsid secretory IgA and consumption of complement component 3 in post-COVID syndrome patients.

Introduction: Post-COVID syndrome represents a major global health challenge which is characterized by immune dysregulation, although many aspects of the immune response remain incompletely understood, particularly the antibody response and the role of the complement system. We previously studied a post-COVID syndrome cohort in comparison to a COVID-recovered control cohort from Comunidad de Madrid (Spain) and found that post-COVID syndrome patients exhibited readily detectable serum anti-Nucleocapsid antibodies while showing deficient antibody production against the full-length Spike, despite maintaining a well-preserved anti-receptor binding domain (RBD) response. Methods: In the present study, we quantified anti-Nucleocapsid secretory immunoglobulin A (sIgA) in saliva and analyzed selected key components of the complement system, including C3, C4, factor B (FB), factor H (FH), and total hemolytic activity (CH50). Additionally, we quantified circulating immune complexes. We conducted general, stratified, correlation, and regression analyses. Results: Anti-Nucleocapsid sIgA was increased in post-COVID syndrome samples compared with COVID-recovered controls. Although CH50 levels were similar, we detected a reduced concentration of C3. The levels of C4 were decreased but not significantly. Interestingly, in recently reinfected fully vaccinated patients, serum anti-Nucleocapsid IgG showed a negative correlation with FH and CH50. No differences were found for the concentration of circulating immune complexes. Regression analysis indicated that C3 levels can discriminate patients from controls efficiently, and combining anti- Nucleocapsid sIgA and C3 levels yielded improved discriminatory power. Discussion: The elevated anti-Nucleocapsid sIgA levels found did not correlate with increased anti-Nucleocapsid IgG in serum, as expected from their different temporal dynamics. The reduced C3 levels may reflect ongoing complement activation and subsequent consumption, which might be potentiated by increments in serum of anti-Nucleocapsid antibodies produced after reinfections. In conclusion, our findings suggest that salivary anti-Nucleocapsid IgA and C3 consumption, which seems to be more subtle parameter than CH50, may serve as candidate biomarkers of post-COVID syndrome, requiring validation in independent cohorts. Furthermore, these results implicate the complement system as a key dysregulated component of the immune response contributing to the pathophysiology of post-COVID syndrome, thus potentially amenable to targeted therapies.