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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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 1

In vitro prosurvival role for APRIL in tonsillar plasma cells.

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In vitro prosurvival role for APRIL in tonsillar plasma cells. (A) APRIL...
(A) APRIL-receptor expression on tonsillar plasma cells. The histograms show the expression of the indicated receptors on cells from the CD19+CD38highcytosplasmic-Ig+ (Cyt-Ig+) subset in the top left dot plot (rectangle). Similar results were obtained with tonsil cell suspensions from 8 patients. (B) CD19+CD38+ and CD19+CD38low/– tonsillar B cells (top panel, rectangles) were purified and incubated in medium containing ACRP-APRIL or control ACRP, both at 3 μg/ml. The number of viable cells was counted by trypan-blue exclusion every day for 4 days (bottom panel). Data are presented as mean ± SD. (C) Intracellular expression of bcl-2, bcl-xL, and mcl-1 was analyzed by flow cytometry on purified CD19+CD38+ at the initiation of the culture and after 4 days of culture with ACRP-APRIL or control ACRP. Dotted lines correspond to isotype control staining. (D) Binding of APRILA88 and APRILH98 to plastic-coated HSPG (1 μg/ml) was revealed with the Aprily-5 mAb (1 μg/ml) (top panel). CD19+CD38+ tonsillar plasma cells were incubated in plastic wells coated with HSPG- or HSPG-binding APRILA88 for 4 days. Intracellular bcl-2 expression was analyzed as in C (bottom panel). Data are representative of 2 independent experiments performed with 2 different donors. Sn, supernatant.