APRIL in B-cell Malignancies and Autoimmunity

Abstract

A Proliferation Inducing Ligand (APRIL) was first identified as a cytokine expressed predominantly by tumour tissues and was not found in most normal tissues. The activity of this new cytokine, in terms of its ability to stimulate tumour cell proliferation in vivo, determined the catchy acronym of yet another TNF family cytokine: APRIL. Reports showing an association between APRIL and cancer have since been prolific, in particular, those showing a link with B cell malignancies. Evidence is accumulating that APRIL is also a player in several autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and Sjoegren's syndrome. However, we now know that APRIL also plays an important role in the immune system and in lymphocyte biology. In this chapter we outline the physiological role of APRIL in immunity and describe what is known regarding the role of APRIL in B cell malignancies and autoimmune disease.

Intrarenal production of B-cell survival factors in human lupus nephritis

“…However, our results of mesangial cells expressing APRIL are in line with the well-documented expression of APRIL by cells other than those of the hematopoietic lineage, e.g., non-hematopoietic, non-immune cells in solid tumors, 32,33 and in other cells such as osteoclasts. 5 In the tubulointerstitium, APRIL could be localized to infiltrating inflammatory cells, in line with the report by Chu et al 31 Also, BLyS could be localized by us to inflammatory infiltrates in the tubulointerstitium in selected cases. Although we detected by immunohistochemistry a more pronounced signal for APRIL than BLyS, we found strong positive correlations between mRNA levels of APRIL and BLyS.…”

“…As expected, APRIL was also positive in inflammatory cells of glomeruli and the tubulointerstitium in lupus nephritis (Figure 3d). 5 An accumulation of CD68-positive monocytes/macrophages was present in glomeruli with prominent expression of APRIL (Figure 3e and f).…”

“…APRIL and BLyS are expressed by monocytes, macrophages, dendritic cells, T cells, B cells, but also non-hematopoietic cells, eg, cancer cells. 4,5 The three known receptors of the mentioned ligands are TNFRSF13C/BAFF-R (tumor necrosis factor receptor superfamily, member 13C/B-cell activating factor receptor), TNFRSF17/BCMA (member 17/B-cell maturation antigen), and TNFRSF13B/TACI (member 13B/transmembrane activator and CAML interactor). BAFF-R has a strong selectivity for BLyS, whereas BCMA has a higher affinity for APRIL, and TACI binds both ligands equally.…”

“…6,7 The receptors for BAFF and APRIL are mainly expressed on B cells. 4 In addition to the well established role in B-cell survival, these factors exert functions on different subsets of cells, eg, T cells 4,5 and monocytes. 8,9 In systemic lupus erythematosus, APRIL and BLyS have been shown to be involved in the B-cellmediated pathology.…”

The Design and Characterization of Receptor-selective APRIL Variants

“…APRIL has also been identified as a prosurvival factor for several B cell malignancies, possibly via the activation of transcription factor NF-B (reviewed in Ref. 5). APRIL is also thought to promote tumor formation in a number of solid malignancies, either indirectly via infiltrating cells or directly via autocrine stimulation of the tumor itself (1,6,7).…”