COPD selectively remodels microbe-B cell receptor interactions within compartmentalized airway immune niches

The human airway hosts distinct immune-microbial ecosystems, yet how COPD and HIV modifies B cell receptor (BCR) repertoires across airway compartments remains poorly understood. Here, we integrated bulk RNA seq-derived BCR reconstruction with airway microbiome profiling to map clonotype-level microbe-BCR interactions across induced sputum, bronchoalveolar lavage (BAL), and peripheral blood in individuals with HIV infection and/or chronic obstructive pulmonary disease (COPD). Across compartments, anatomical location was the dominant determinant of BCR repertoire structure, with limited clonotype sharing between sputum, BAL, and blood. In contrast, disease effects emerged primarily at the level of microbe-clonotype coupling, rather than global repertoire architecture. Using outer membrane vesicle (OMV)-adjusted interaction modeling, we identified extensive, clonotype-resolved interaction remodeling in sputum for both HIV and COPD, attenuated and COPD-restricted effects in BAL, and selective COPD-associated interactions in blood, with complete absence of HIV-associated systemic effects. These patterns reveal a hierarchical, compartment-specific architecture in which disease selectively retunes microbe-BCR interactions without disrupting underlying repertoire organization. Together, our findings define a model of fine-scale ecological tuning of airway B cell immunity driven by disease and anatomical context.