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-x L , 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.

Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties

“…Although APRIL is mainly released in a soluble form (15), it can bind to proteoglycans and thus create niches for antibody-secreting cells (16,17). Heteromers of BAFF and APRIL are produced in autoimmune diseases and are sometimes also detected in healthy subjects (18,19).…”

Pathogenic Long-Lived Plasma Cells and Their Survival Niches in Autoimmunity, Malignancy, and Allergy

“…Whereas the large majority of MPCs are localized in the bone marrow (5,12), LLPCs are also found in lymphatic organs such as spleen (13), lymph nodes (14), mucosa-associated lymphatic tissues (15), as well as in chronically inflamed tissues such as the synovium in rheumatoid arthritis (16), the CNS in induced multiples sclerosis (17), the kidneys in systemic lupus erythematosus (SLE) (18), the salivary glands in Sjögren's syndrome (19), or the lung during chronic airway inflammation in allergy/asthma (20,21). In secondary lymphatic tissues, PCs reside in extrafollicular areas such as the lamina propria of mucosa and the red pulp of spleen, and LLPCs are associated with APRIL, BAFF, and IL-6 sources in the vicinity (14,15,22,23). Whereas APRIL is produced by several cell types in the bone marrow (24), only few cells in specific areas (e.g., the subepithelium zone in tonsillar crypts or intestinal villi in the mucosa) secrete this survival factor in other organs (15).…”

“…In secondary lymphatic tissues, PCs reside in extrafollicular areas such as the lamina propria of mucosa and the red pulp of spleen, and LLPCs are associated with APRIL, BAFF, and IL-6 sources in the vicinity (14,15,22,23). Whereas APRIL is produced by several cell types in the bone marrow (24), only few cells in specific areas (e.g., the subepithelium zone in tonsillar crypts or intestinal villi in the mucosa) secrete this survival factor in other organs (15). Moreover, certain organs have different potential to support PC survival, and induction of angiogenesis seems crucial to maintain PCs in inflamed tissues (25).…”

Molecular pathogenesis of lymphomas of mucosa-associated lymphoid tissue—from (auto)antigen driven selection to the activation of NF-κB signaling

“…In addition to the contact stimulation of BCRs and CD4 + T cells mediated by CD40/CD40L and Th2 cytokines induced by certain pathogens or autoantigens, another important component of the "acquired lymphoid tissue" are the neutrophils [33]. Certain pathogens, such as Hp, recruits neutrophils and promotes reactive oxygen species (ROS) [34].…”