APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa
Bertrand Huard, … , Pascal Schneider, Eddy Roosnek
Bertrand Huard, … , Pascal Schneider, Eddy Roosnek
Published July 10, 2008
Citation Information: J Clin Invest. 2008;118(8):2887-2895. https://doi.org/10.1172/JCI33760.
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Research Article Immunology

APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa

Abstract

The bone marrow constitutes a favorable environment for long-lived antibody-secreting plasma cells, providing blood-circulating antibody. Plasma cells are also present in mucosa-associated lymphoid tissue (MALT) to mediate local frontline immunity, but how plasma cell survival there is regulated is not known. Here we report that a proliferation-inducing ligand (APRIL) promoted survival of human upper and lower MALT plasma cells by upregulating expression of the antiapoptotic proteins bcl-2, bcl-xL, and mcl-1. The in situ localization of APRIL was consistent with such a prosurvival role in MALT. In upper MALT, tonsillar epithelium produced APRIL. Upon infection, APRIL production increased considerably when APRIL-secreting neutrophils recruited from the blood infiltrated the crypt epithelium. Heparan sulfate proteoglycans (HSPGs) retained secreted APRIL in the subepithelium of the infected zone to create APRIL-rich niches, wherein IgG-producing plasma cells accumulated. In lower MALT, neutrophils were the unique source of APRIL, giving rise to similar niches for IgA-producing plasmocytes in villi of lamina propria. Furthermore, we found that mucosal humoral immunity in APRIL-deficient mice is less persistent than in WT mice. Hence, production of APRIL by inflammation-recruited neutrophils may create plasma cell niches in MALT to sustain a local antibody production.

Authors

Bertrand Huard, Thomas McKee, Carine Bosshard, Stéphane Durual, Thomas Matthes, Samir Myit, Olivier Donze, Christophe Frossard, Carlo Chizzolini, Christiane Favre, Rudolf Zubler, Jean Philippe Guyot, Pascal Schneider, Eddy Roosnek

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Figure 6

Inflammation regulates APRIL production in tonsils.

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Inflammation regulates APRIL production in tonsils. (A) A representative...
(A) A representative example of Stalk-1 staining for crypt epithelium from control and acutely infected tonsils (left and middle panels). Quantification of the staining obtained in 5 control, 5 chronically, and 5 acutely infected tonsils is shown in the right panel. (B) APRIL transcription was analyzed by 40 cycles of RT-PCR in the indicated cells. Actin was used as housekeeping gene (left panel). Quantitative RT-PCR for APRIL mRNA was performed on epithelial HEK cells treated for 48 hours with PGN (10 μg/ml), LPS (100 ng/ml), Loxoribine (250 μg/ml), or CpG (10 μg/ml) (right panel). (C–E) A representative example of Stalk-1 (C), Aprily-2 (D), and anti-Ig (E) stainings is shown as in A (left and middle panels). Quantification of the number of Stalk-1–stained neutrophils infiltrating the crypt epithelium (C), of the Aprily-2 staining (D), and of the number of plasma cells (PCs) in the subepithelial crypt area is also shown in right panels. Original magnification, ×40.