Synovial tissues concentrate secreted APRIL
© Gabay et al.; licensee BioMed Central Ltd. 2009
Received: 8 July 2009
Accepted: 29 September 2009
Published: 29 September 2009
A proliferation-inducing ligand (APRIL) from the TNF family, owing to its role in the generation and survival of plasma cells (PCs), is currently targeted for rheumatoid arthritis (RA) treatment. However, little is known about APRIL expression in RA lesions, hampering our understanding of the way APRIL may modulate this autoimmune disease.
We performed immunological staining of human normal, non-RA and RA synovial tissues with a pair of antibodies specifically recognizing APRIL-producing cells and secreted APRIL.
We detected significant amounts of secreted APRIL in normal synovium mostly concentrated around blood vessels and at the lining layer, but no cells producing APRIL. Meanwhile, we observed that blood neutrophils constitutively secrete APRIL, indicating that blood APRIL may diffuse into the synovium via its fenestrated vessels. Synovium from non-RA and RA patients retained similarly secreted APRIL, but in this case APRIL-producing cells, including neutrophils and macrophages, were present in the tissue. Notably, PCs - when present in RA synovium - accumulated in areas of APRIL retention, spreading from blood vessels towards the lining layer.
PCs accumulate in synovial zones rich in secreted APRIL, consistent with a pro-survival role of APRIL for PCs in RA. The concentration of APRIL by normal synovium indicates that this tissue may constitute a proper environment for PCs even before RA onset.
A proliferation-inducing ligand (APRIL, TNFSF13) is one of the latest members cloned from the TNF superfamily . APRIL modulates late steps of humoral immune responses by inducing immunoglobulin switch [2–5], and by transmitting a survival signal into plasmablast/plasma cells (PCs) [6–8]. In cancer patients, APRIL promotes selectively the development of chronic lymphocytic leukemia  and diffuse large B-cell lymphoma . This selectivity is consistent with the restricted expression of APRIL signaling receptors - the transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI, TNFSFR13), and the B-cell maturation antigen (BCMA, TNFSFR17) - to specific B-cell differentiation stages . In addition to TACI and BCMA, heparan sulfate proteoglycans (HSPG) bind APRIL [12, 13] and TACI .
APRIL is also implicated in autoimmune pathologies, particularly rheumatic diseases . Use of a soluble form of TACI that antagonizes both APRIL and the closely related B-cell activation factor from the TNF family (BAFF, TNFSF13B)  ameliorated rheumatoid arthritis (RA) in mouse models [17–19]. A subsequent phase I clinical trial with soluble TACI in RA patients showed a decrease in levels of rheumatoid factor and antibodies against citrullinated proteins in treated patients [20, 21], indicating promising perspectives for such a therapeutic approach. Expression of BAFF in RA lesions is well characterized, with a wide expression in B cells, T cells, fibroblast-like synoviocytes  and monocyte/macrophages . In contrast, APRIL expression appears much more restricted, since only CD83+ dendritic cells  and fibroblast-like synoviocytes  have been reported to produce APRIL in RA lesions.
Ectopic germinal centers (GCs) with PC generation are present in more than 10% of RA patients . Knowing the role of APRIL in humoral immunity, we studied APRIL expression in RA lesions, with particular attention to lesions with GCs, and compared this expression with normal and non-RA synovium samples. We performed the present study with a pair of well-characterized antibodies selectively recognizing APRIL-producing cells and secreted APRIL in tissues . The pattern of expression for APRIL observed here is consistent with a pro-survival role of APRIL for synovial PCs.
Materials and methods
Synovial biopsies were obtained from the Geneva School of Medicine and from the Charité Universitätsmedizin in agreement with local ethics committees and patients' informed consent upon knee arthroscopy of patients with active disease. Clinical diagnosis was performed for psoriatic arthritis according to Moll and Wright , and for RA according to the classification criteria and of the American College of Rheumatology . The presence of rheumatoid factor of IgM serotype or IgA isotype defined seropositivity. We defined GCs by a characteristic histomorphology and the presence of CD23+ follicular dendritic cells .
8 males 3 females
43 (30 to 78)
Disease duration (years)
3.8 (1 to 7)
With germinal center
Nonsteroidal anti-inflammatory drug
Methothrexate + prednisolone
Lefluonimide + prednisone
2 males 3 females
53 (45 to 80)
Disease duration (years)
10.3 (5 to 12)
Disease duration (years)
Nonsteroidal anti-inflammatory drug
Disease duration (years)
Nonsteroidal anti-inflammatory drug
Immunohistochemistry analyses were performed on formalin-fixed paraffin-embedded tissues. Polymorphonuclear cells and peripheral blood mononuclear cells, obtained as previously described , were injected into a fragment of a murine intestine. The intestine fragment was then processed as a tissue for immunohistochemistry. Stalk-1, Aprily-2 (and its competition with soluble APRIL), Aprily-8, anti-CD138, anti-human immunoglobulin, anti-elastase and the corresponding secondary antibodies have all been previously described . The anti-CD68 (clone PG-M1, IgG3; Santa Cruz, CA, USA) was used at 3 μg/ml with anti-IgG3 conjugated to biotin and streptavidin conjugated to Alexa 488 (Becton Dickinson Biosciences, San Jose, CA, USA). The anti-heparan sulfate 10e4 (Seikagaku Corporation, Tokyo, Japan) was used at 1 μg/ml.
Images were visualized under light or fluorescent microscopy with Axiophot 1 (Carl Zeiss AG, Berlin, Deutschland), captured with an axiocam (Carl Zeiss AG) color CCD camera, and treated on a Pentium III computer with axioVision™ software (Carl Zeiss AG). The original magnification was 20× unless stated. In some experiments, 4',6'-diamidino-2-phénylindole staining was included in the merged images. Confocal analyses were performed with a LSM 510 microscope (Carl Zeiss AG). For quantification of the Aprily-2 signal, images of the lining layers and blood vessels for RA lesions and for normal synovium, respectively, were acquired with the 40× objective. An area of identical size in a zone exhibiting the strongest staining was selected for each lesion, and was processed using MetaMorph Image Analysis software (Molecular Devices, Union City, CA, USA). Color thresholds were selected in the Hue, Saturation, Intensity space. Saturation values obtained in the threshold field were added, logged to a spreadsheet, and expressed in arbitrary units. Stalk-1 stained cells were numerated in the corresponding area from a serial cut, after image acquisition with the 40× objective and counting the entire field, corresponding to a tissue area of 30 mm2.
Human umbilical vein endothelial cells (HUVECs) were cultured as described by Bradfield and colleagues . The cells were harvested from culture dishes with PBS 3 mM ethylenediamine tetraacetic acid at 37°C and were washed twice with PBS. Binding of ACRP30-APRIL in the presence or absence of heparin was performed as previously described . Binding was assessed by flow cytometry on a FACSCAN and Cellquest (Becton Dickinson Biosciences).
Presence of secreted APRIL in normal synovium
The presence of secreted APRIL on synovial blood vessels correlated well with their expression of the APRIL-binding partner, HSPG (Figure 1b). We did not observe such accumulation of secreted APRIL in blood vessels irrigating a secondary lymphoid organ, such as tonsils, despite the fact that tonsil vessels expressed comparable amounts of HSPG. In an in vitro staining assay, we confirmed binding of secreted APRIL at the surface of endothelial cells (Figure 1c). In this experiment, APRIL bound to HSPG since it was inhibited by heparin, a potent antagonist of APRIL/HSPG interactions .
Taken together, these findings indicate that the normal synovial tissue concentrates specifically secreted APRIL.
Blood neutrophils secrete constitutively APRIL
Most proteins in the synovium originate from the blood . This process is due to the fenestration of blood vessels irrigating this tissue . APRIL concentrated by the synovial tissue may therefore originate from blood. To test this hypothesis, we studied APRIL expression in blood.
APRIL production and retention in inflamed RA synovium
Aprily-2 also stained Stalk-1- cells, indicating that nonproducing cells also retained secreted APRIL. Stalk-1+ cells were also present in the lining layer from a minority (3/9 patients) of RA patients. The lining layer contains fibroblast-like synoviocytes, reported by others to produce APRIL when cultured . The Stalk-1 stained cells in the lining layer, however, were not fibroblast-like synoviocytes based on morphological criteria. T cells can also produce APRIL , but the T cells infiltrating RA lesions were not stained by Stalk-1 (data not shown).
Taken together, inflammatory reactions within synovial tissues recruit neutrophils and macrophages, insuring high levels of APRIL production, both in non-RA lesions and RA lesions. Retention of secreted APRIL per zone was only slightly increased compared with normal synovium.
Plasma cells in RA lesions accumulate in APRIL-rich niches
In the present study we report a significant expression of APRIL in the synovium of normal donors, non-RA and RA patients. Concentration of secreted APRIL per defined area was only slightly upregulated in non-RA and RA patients compared with normal donors. In contrast, the density of APRIL-producing cells greatly increased in inflamed synovium. Recruitment of APRIL-producing cells is therefore not specific to RA, but the presence of such cells in non-RA lesions is consistent with the detection of secreted APRIL in the synovial fluid from non-RA patients reported by others [35, 36]. Since neutrophils are the major source of APRIL in these latter lesions, our study indicates that presence of APRIL is a consequence of the ongoing inflammation in these diseases. In non-RA lesions, APRIL may be a bystander inflammatory product with no specific role in the pathological process, owing to the current knowledge in APRIL physiology.
Since APRIL plays a major role in the immunoglobulin switch process and PC survival, one may expect that APRIL promotes autoimmune reactions associated with production of autoantibodies, such as RA. In the present study we report the presence of cells producing and secreting APRIL, including neutrophils and macrophages within RA lesions. Neutrophils constitute a major source of APRIL in tissues, while macrophages generally do not produce this molecule . Synovial macrophages are therefore different from macrophages in other tissues. In addition, synovial macrophages are also different from neutrophils in their mode of APRIL production. They produce less APRIL, and process efficiently the full-length product - but instead of secreting all of the produced APRIL, they retain some of it and/or bind secreted APRIL present in the extracellular medium. In contrast, retention and binding of secreted APRIL by neutrophils has never been observed. This is probably due to the lack of HSPG expression by neutrophils , compared with macrophages .
We frequently noticed a discrepancy between the concentration of the secreted APRIL product within the tissues and the density of APRIL-producing cells. This difference was best observed in normal synovium. Indeed, in samples from subjects without arthritis, we detected significant levels of secreted APRIL, covering the lining layer and endothelial cells, despite the paucity of APRIL-producing cells. This finding indicates that the normal synovial tissue is able to retain substantial amounts of secreted APRIL. Blood vessels irrigating the synovium are fenestrated, allowing the diffusion of blood proteins, and it is probable that APRIL produced constitutively by circulating neutrophils diffuses from the blood to accumulate into the synovial tissue. We previously showed that HSPG retain APRIL in various tissues [8, 10, 39, 40]. In a healthy synovium, syndecan-3/glypican-4 and syndecan-2/syndecan-3/glypican-4 - expressed by the lining layer and endothelial cells, respectively  - are likely to be the proteic carriers of heparan sulfate chains mediating APRIL retention. The accumulation of APRIL by the synovial vessels is specific to this tissue, since tonsil vessels do not retain secreted APRIL, consistent with the absence of fenestration for blood vessels in tonsils.
The study of lesions with ectopic GCs and generation of PCs led to some valuable observations regarding the role of APRIL in RA. Indeed, we noticed that PCs migrate from GCs towards endothelial cells. PC localization around blood vessels in RA lesions was reported a long time ago . The recent detection of the PC chemoattractant CXCL-12 on synovial vessels explained this homing . In the present study, we further provide evidence that PCs receive a survival signal from these endothelial cells, given in a trans fashion, similarly to tonsillar epithelial cells . When PCs accumulate extensively, they were also in contact with cells from the lining layer and synovial macrophages, both rich in secreted APRIL. The accumulation of APRIL in several synovial cells may therefore explain the persistence of PCs within the inflamed synovial tissue, as already proposed .
The present study demonstrates that normal synovium and pathologic synovium both for non-RA and RA patients retain soluble APRIL, constituting APRIL-rich niches. These niches are similar to those recently observed in mucosa-associated lymphoid tissues, wherein plasma cells survive to secrete locally antibodies against infectious agents. In non-RA lesions, these niches may not be functional. These APRIL-rich niches may provide an adequate environment for synovial PCs in RA lesions, therefore contributing to the generation of pathogenic autoantibodies. The specific retention of soluble APRIL in a normal synovium indicates that this organ offers a favorable environment for PCs, even before disease onset.
A proliferation-inducing ligand
B-cell activation factor
B-cell maturation antigen
heparan sulfate proteoglycans
transmembrane activator, calcium modulator and cyclophilin ligand interactor
tumor necrosis factor.
The present work was supported by the Henri Dubois Ferrière/Dinu Lipatti Foundation, the Swiss National Science Foundation (320000-119728 to CG, 31003A-12491 to CC, and 3100A0-116576 to BH), the Leenaards Foundation, and the Jacques und Gloria Gossweiler Stiftung.
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