BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma

Abstract

We report that B cell–activating factor of the tumor necrosis factor (TNF) family (BAFF) is expressed in the normal human brain at ∼10% of that in lymphatic tissues (tonsils and adenoids) and is produced by astrocytes. BAFF was regularly detected by enzyme-linked immunosorbent assay in brain tissue lysates and in normal spinal fluid, and in astrocytes by double fluorescence microscopy. Cultured human astrocytes secreted functionally active BAFF after stimulation with interferon-γ and TNF-α via a furin-like protease-dependent pathway. BAFF secretion per cell was manifold higher in activated astrocytes than in monocytes and macrophages. We studied brain lesions with B cell components, and found that in multiple sclerosis plaques, BAFF expression was strongly up-regulated to levels observed in lymphatic tissues. BAFF was localized in astrocytes close to BAFF-R–expressing immune cells. BAFF receptors were strongly expressed in situ in primary central nervous system (CNS) lymphomas. This paper identifies astrocytes as a nonimmune source of BAFF. CNS-produced BAFF may support B cell survival in inflammatory diseases and primary B cell lymphoma.

BAFF synthesis by rheumatoid synoviocytes is positively controlled by α5β1 integrin stimulation and is negatively regulated by tumor necrosis factor α and toll‐like receptor ligands

“…For example, Ittah et al (32) demonstrated that BAFF is not expressed by TNF␣-stimulated salivary gland epithelial cells from patients with primary Sjögren's syndrome. In another study, BAFF expression and production by astrocytes were not up-regulated by TNF␣ (10). The fact that in our model, TNF␣ is unlikely to function as an inducer of BAFF synthesis by FLS, could not be due to impaired activity of TNF␣ insofar as FLS release high concentrations of IL-6 in response to TNF␣.…”

“…This cytokine, which is present at low levels in normal human brain tissue as compared with lymphoid tissue, is constitutively produced by astrocytes (10). Its production is increased in sclerotic cerebral lesions and in cerebral primary lymphomas.…”

Neuroinflammation: Ways in Which the Immune System Affects the Brain

“…Meningeal inflammation in MS may include Bcell-rich collections of immune cells [97], and secretory products of MS B cells have been shown to be cytotoxic to oligodendrocytes [98]. Astrocytes have been implicated in support of B-cell survival in inflamed MS CNS, through expression of the B-cell-activating factor of the TNF family [99]. Ongoing research is directed at elucidating effects of glial cells on B-cell subsets and, in turn, effects of B-cell regulatory and effector (Breg and Beff, respectively) products on CNS cells.…”

CSF TACI and BAFF levels in patients with primary CNS lymphoma as novel diagnostic biomarkers

“…BAFF and APRIL play crucial roles in B cell‐development, survival, and production of immunoglobulin by binding with receptors 1. Three BAFF receptors have been identified: BCMA, TACI, and BAFF‐R 2.…”

“…However, MRI characteristics are not specific for PCNSL, and in most cases diagnosis requires a neuropathological examination 6. Krumbholz et al established astrocytes as BAFF producers and suggested that CNS‐derived BAFF may promote B cell survival in PCNSL 1. Thaler et al reported that CSF and serum TACI and BCMA levels were higher in patients with PCNSL than in control patients 7…”