Open forum infectious diseases · 2026
Antibody-Dependent Immune Complex Signaling and Inflammatory Cytokine Responses in Acute Febrile Illness: A Mechanistic Study in Arboviral and Leptospiral Infection.
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Asaga Peter Mac, Kadukkatti Vijeesh, Airiohuodion Philomena, Mathew Brijil, Omilabu Sunday
Аннотация
BACKGROUND: Arboviral infections are characterized by heterogeneity in inflammatory responses and clinical outcomes. While antibodies are essential for protection, antibody-antigen immune complexes may modulate innate immune signaling through Fc receptor engagement. The extent to which immune complex signaling contributes to coordinated cytokine responses in human arboviral infection remains incompletely defined.
METHODS: We conducted a mechanistic immunology study nested within a prospective cohort of patients with acute arboviral infection in southern India. Using paired ex vivo stimulation assays, we compared cytokine responses following antigen-only and antibody-antigen immune complex stimulation. Fc dependence was interrogated using Fcγ receptor blockade and immunoglobulin G (IgG) subclass depletion. Cytokines were quantified using the LEGENDplex Human Inflammation Panel (BioLegend). Principal component analysis was applied to identify coordinated cytokine response patterns, and multivariable regression models were used to assess associations with humoral immune state.
RESULTS: Among 80 participants, immune complex stimulation was associated with higher concentrations of pro-inflammatory cytokines compared with antigen alone. This difference was attenuated by Fcγ receptor blockade and was influenced by antibody subclass composition. Principal component analysis revealed a coordinated cytokine pattern characterized by positive contributions from interleukin-6 (IL-6), tumor necrosis factor, IL-1β, and CXCL10, with an inverse contribution from IL-10. In multivariable analysis, individuals with lower neutralization capacity or altered IgG subclass profiles exhibited higher inflammatory cytokine program scores (β = +1.80 standard deviation; 95% confidence interval 1.54-2.06; P = 7.18 × 10-22).
CONCLUSIONS: These findings suggest that antibody-dependent immune complex signaling may contribute to inflammatory cytokine responses during acute arboviral and leptospiral infection.
METHODS: We conducted a mechanistic immunology study nested within a prospective cohort of patients with acute arboviral infection in southern India. Using paired ex vivo stimulation assays, we compared cytokine responses following antigen-only and antibody-antigen immune complex stimulation. Fc dependence was interrogated using Fcγ receptor blockade and immunoglobulin G (IgG) subclass depletion. Cytokines were quantified using the LEGENDplex Human Inflammation Panel (BioLegend). Principal component analysis was applied to identify coordinated cytokine response patterns, and multivariable regression models were used to assess associations with humoral immune state.
RESULTS: Among 80 participants, immune complex stimulation was associated with higher concentrations of pro-inflammatory cytokines compared with antigen alone. This difference was attenuated by Fcγ receptor blockade and was influenced by antibody subclass composition. Principal component analysis revealed a coordinated cytokine pattern characterized by positive contributions from interleukin-6 (IL-6), tumor necrosis factor, IL-1β, and CXCL10, with an inverse contribution from IL-10. In multivariable analysis, individuals with lower neutralization capacity or altered IgG subclass profiles exhibited higher inflammatory cytokine program scores (β = +1.80 standard deviation; 95% confidence interval 1.54-2.06; P = 7.18 × 10-22).
CONCLUSIONS: These findings suggest that antibody-dependent immune complex signaling may contribute to inflammatory cytokine responses during acute arboviral and leptospiral infection.