(424) Systems Serology in Cystic Fibrosis: Anti-Pseudomonas IgG1 Responses and Reduced Lung Function

Background: Cystic fibrosis (CF) is an inherited lethal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approximately 60% of patients carry the homozygous F508del mutation which exhibits a variable phenotype in terms of their lung function and age of first Pseudomonas aeruginosa (PA) infection. Gene modifier studies has identified that major compatibility complex (MHC) class II alleles are associated with those two pulmonary phenotypes, strongly implicating the involvement of strong but adaptive immunity.

Methods: We performed systems serology assays using mucoid PA and sera from age-matched F508del CF patients with reduced lung function versus normal lung function. We also immunized different mouse models using combinations of Pseudomonas-specific antigens and different adjuvants to mimic CF lung pathology.

Results: The reduced lung function cohort showed greater PA outer membrane protein IgG antibody responses compared to the normal function cohort. Further, we identified outer membrane protein I (OprI) as an important B cell antigen. Patients with reduced lung function had significant higher anti-OprI IgG/IgG1 titers and a greater degree of antibody-mediated complement deposition. Mice immunized with either recombinant OprI or inactivated whole PA subcutaneously developed high anti-OprI IgG titers in serum and increased lung pathology when challenged with mucoid PA, compared to unimmunized controls. This pathology was abrogated in immunized Rag2^-/- mice. Moreover, enhanced lung pathology could be transferred into unimmunized mice using sera from immunized mice with a dominant anti-OprI IgG2c response.

Conclusions: These data suggest that complement fixing antibodies to specific PA antigens influence lung function in CF patients with homozygous F508del mutation.

Acknowledgements: The authors would like to thank Dr. Jennifer Bomberger (University of Pittsburgh) to provide the Pseudomonas clinical isolate and Meihua Bo for technical supports. This work was supported by NIH R35HL 139930 and CF Foundation Award (KOLLS21I0).

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