Neonatal Fc Receptor Regulation of Lung Immunoglobulin and CD103+ Dendritic Cells Confers Transient Susceptibility to Tuberculosis.

Anca Dorhoi,Laura Lozza,Ulrike Zedler,Alexis Vogelzang,Karin Hahnke,Stefan H E Kaufmann,Stephen T Reece,S Ehrt,Dagmar Oberbeck-Mueller,Carolina Perdomo

doi:10.1128/iai.00533-16

Anca Dorhoi, Laura Lozza + Show 8 more

Open Access

https://doi.org/10.1128/iai.00533-16

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Abstract

The neonatal Fc receptor (FcRn) extends the systemic half-life of IgG antibodies by chaperoning bound Fc away from lysosomal degradation inside stromal and hematopoietic cells. FcRn also transports IgG across mucosal barriers into the lumen, and yet little is known about how FcRn modulates immunity in the lung during homeostasis or infection. We infected wild-type (WT) and FcRn-deficient (fcgrt−/−) mice with Pseudomonas aeruginosa or Mycobacterium tuberculosis to investigate whether recycling and transport of IgG via FcRn influences innate and adaptive immunity in the lung in response to bacterial infection. We found that FcRn expression maintains homeostatic IgG levels in lung and leads to preferential secretion of low-affinity IgG ligands into the lumen. Fcgrt−/− animals exhibited no evidence of developmental impairment of innate immunity in the lung and were able to efficiently recruit neutrophils in a model of acute bacterial pneumonia. Although local humoral immunity in lung increased independently of the presence of FcRn during tuberculosis, there was nonetheless a strong impact of FcRn deficiency on local adaptive immunity. We show that the quantity and quality of IgG in airways, as well as the abundance of dendritic cells in the lung, are maintained by FcRn. FcRn ablation transiently enhanced local T cell immunity and neutrophil recruitment during tuberculosis, leading to a lower bacterial burden in lung. This novel understanding of tissue-specific modulation of mucosal IgG isotypes in the lung by FcRn sheds light on the role of mucosal IgG in immune responses in the lung during homeostasis and bacterial disease.

Highlights

Secretory immunoglobulin A (IgA) and IgM are exported by a dedicated receptor to the mucosa, where they coat pathogens and nurture beneficial microbiota [1]
We measured the relative abundances of antibody isotypes in serum, homogenized lung tissue, and bronchoalveolar lavage fluid (BALF) of wild-type (WT) and fcgrtϪ/Ϫ mice to determine how ablation of IgG recycling or transport across lung epithelia influences homeostatic immunity in the lung
Our analysis of antibody in BALF of WT and fcrgtϪ/Ϫ mice revealed that, unlike IgM and IgA, luminal IgG strongly depended on FcRn expression, as fcgrtϪ/Ϫ mice had 10- to 100-fold lower concentrations of locally dominant IgG isotypes

Summary

Introduction

Secretory immunoglobulin A (IgA) and IgM are exported by a dedicated receptor to the mucosa, where they coat pathogens and nurture beneficial microbiota [1]. Despite FcRn being the primary means by which IgG is transported across epithelial barriers, conflicting reports in a variety of infection models have questioned whether FcRn is required for the protective action of mucosal IgG, implying immune roles at the mucosal interface beyond neutralization of pathogenic determinants [8–10]. Knowledge of the role of FcRn in the lung remains limited, expression has been identified in parenchyma and recruited immune cells [11, 12]. Antibodies are thought to play a limited protective role in natural M. tuberculosis infection despite strong local recruitment of B cells to granulomas [17, 18]. FcRn Impairs Adaptive Immunity during Tuberculosis characterize specific immune roles for IgG at the lung interface with the external environment

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