Antibody-Dependent Immune Complex Signaling and Inflammatory Cytokine Responses in Acute Febrile Illness: A Mechanistic Study in Arboviral and Leptospiral Infection

Open Forum Infectious Diseases, vol. 13, pp. ofag300

Abstract

Abstract 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.

Authors 5

1. Peter Mac Asaga corresponding

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Institute for Infection Prevention and Control, Medical Center, University of Freiburg , Breisacher str 115b, 79106 Freiburg ,

2. Vijeesh Kadukkatti Aachen Institute of Occupational Health

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   RWTH Uniklinik, Aachen, Institute of Occupational Health , Social and Enviromental Medicine, Pauwelsstr 30, 52074 Aachen ,

3. Philomena Ehi Airiohuodion

   World Health Organization · Special Programme for Research and Training in Tropical Diseases

   Affiliation as printed

   Special Programme for Research and Training in Tropical Diseases, World Health Organization , Geneva ,

4. Brijil Mathew
   Affiliation as printed

   Aster MIMS Hospital , Kannur 670621, Kerala ,

5. Sunday Omilabu

   University of Lagos

   Affiliation as printed

   CHAHZY Central Research Laboratory, College of Medicine, University of Lagos , Lagos ,