BAFF and BAFF-Receptor in B Cell Selection and Survival

Smulski, Cristian R.; Eibel, Hermann

doi:10.3389/fimmu.2018.02285

Cited by 252 publications

(202 citation statements)

References 122 publications

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“…Each receptor exhibits a unique expression pattern on distinct B cell subsets, in part accounting for differential functional roles during an immune response. 28 29). 25 All three of the BAFF/APRIL receptors can be shed from the cell surface by the activity of γ-secretase (BCMA) or ADAM proteases (BAFF-R and TACI).…”

Section: Baff Family Receptorsmentioning

confidence: 99%

“…28 Importantly, constitutive cleavage of BCMA and TACI generates functional decoy receptors, whereas BAFF-R shedding does not appear to generate a decoy but rather regulates B cell survival via modulation of surface BAFF-R expression. 29…”

Section: Baff Family Receptorsmentioning

confidence: 99%

“…32,35,36 BAFF-R ligation also activates the phosphoinositide-3-kinase-dependent signaling cascade to enhance protein synthesis and mediate metabolic reprogramming in order to facilitate cell survival (reviewed in Ref. 29). Importantly, since immature and anergic B cells exhibit lower surface BCR expression, these cells exhibit an increased requirement for BAFF-R-mediated survival signals.…”

Section: Baff-rmentioning

confidence: 99%

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BAFF inhibition in SLE—Is tolerance restored?

Jackson

Davidson

2019

Immunological Reviews

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The B cell activating factor (BAFF) inhibitor, belimumab, is the first biologic drug approved for the treatment of SLE, and exhibits modest, but durable, efficacy in decreasing disease flares and organ damage. BAFF and its homolog APRIL are TNF‐like cytokines that support the survival and differentiation of B cells at distinct developmental stages. BAFF is a crucial survival factor for transitional and mature B cells that acts as rheostat for the maturation of low‐affinity autoreactive cells. In addition, BAFF augments innate B cell responses via complex interactions with the B cell receptor (BCR) and Toll like receptor (TLR) pathways. In this manner, BAFF impacts autoreactive B cell activation via extrafollicular pathways and fine tunes affinity selection within germinal centers (GC). Finally, BAFF and APRIL support plasma cell survival, with differential impacts on IgM‐ and IgG‐producing populations. Therapeutically, BAFF and combined BAFF/APRIL inhibition delays disease onset in diverse murine lupus strains, although responsiveness to BAFF inhibition is model dependent, in keeping with heterogeneity in clinical responses to belimumab treatment in humans. In this review, we discuss the mechanisms whereby BAFF/APRIL signals promote autoreactive B cell activation, discuss whether altered selection accounts for therapeutic benefits of BAFF inhibition, and address whether new insights into BAFF/APRIL family complexity can be exploited to improve human lupus treatments.

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Section: Baff Family Receptorsmentioning

confidence: 99%

Section: Baff Family Receptorsmentioning

confidence: 99%

Section: Baff-rmentioning

confidence: 99%

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BAFF inhibition in SLE—Is tolerance restored?

Jackson

Davidson

2019

Immunological Reviews

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“…BAFF via BAFF-R plays a role in B cell selection and B cell survival [17,24,25]. CD8+ Tregs had no significant effect on BAFF-R expression on B cells, suggesting that CD8+ Tregs may not influence B cell survival.…”

Section: Discussionmentioning

confidence: 99%

In vitro Effects of CD8+ Regulatory T Cells on Human B Cell Subpopulations

Gupta

Agrawal

2020

Int Arch Allergy Immunol

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Background: CD8+ regulatory T cells (CD8+ Tregs) are relatively recently described T cell subsets that have been shown to regulate various T cell responses and appear to play a role in autoimmunity. However, their effects on B cells have not been explored. Objectives: In this investigation we examine the effect of CD8+ Tregs on various subsets of peripheral B cells include naïve B cells, transitional B cells, marginal zone B cells, IgM memory B cells, class switched memory B cells, and plasmablasts, and on the expression of B cell-activating factor receptor (BAFF-R). Methods: CD8+ T cells were first purified and then activated with anti-CD3/CD28 beads to generate CD8+ Tregs. Purified CD19+ B cells were cultured alone or with sorted CD8+ Tregs (CD8+CD183+CCR7+CD45RA-) and activated with anti-CD40 monoclonal antibody and CpG. B cell subsets and the expression of BAFF-R on naïve and memory B cells were analyzed using various monoclonal an-tibodies and corresponding control isotypes. Ten thousand cells were acquired and analyzed by FACSCalibur using the FlowJo software. Results: CD8+ Tregs selectively and significantly suppressed plasmablasts without any significant effect on other B cell subsets or on the expression of BAFF-R. Conclusion: CD8+ Tregs may play a role in autoimmunity by regulating antibody production via suppression of plasmablasts.

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“…( 48 ) Belimumab, a monoclonal antibody to BAFF that blocks BAFF–BAFFR signaling, has been shown to be effective for systemic lupus erythematosus and approved by the U.S. Food and Drug Administration and European Medicines Agency for human use. ( 49 ) VAY736, a monoclonal antibody to BAFFR, has been shown to be effective for primary Sjogren’s syndrome and is now under clinical trial (Table 6). Blockade of APRIL–BCMA signaling by a monoclonal antibody to APRIL was shown to be effective in murine model of systemic lupus erythematosus and immunoglobulin A nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

et al. 2020

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Genome-wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease-susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single-nucleotide polymorphisms (P < 0.00001), and data set 2 for mRNA microarray analysis of liver biopsy specimens (36 patients with PBC and 5 normal controls), which included 1,574 genes with fold change >2 versus controls (P < 0.05). Hierarchical cluster analysis and categorization of cell type-specific genes were performed for data set 2. There were 27 genes, 10 pathways, and 149 upstream regulators that overlapped between data sets 1 and 2. All 10 pathways were immune-related. The most significant common upstream regulators associated with PBC disease susceptibility identified were interferon-gamma (IFNG) and CD40 ligand (CD40L). Hierarchical cluster analysis of data set 2 revealed two distinct groups of patients with PBC by disease activity. The most significant upstream regulators associated with disease activity were IFNG and CD40L. Several molecules expressed in B cells, T cells, Kupffer cells, and natural killer-like cells were identified as potential therapeutic targets in PBC with reference to a recently reported list of cell type-specific gene expression in the liver. Conclusion: Our integrated analysis using GWAS and mRNA microarray data sets predicted that IFNG and CD40L are the central upstream regulators in both disease susceptibility and activity of PBC and identified potential downstream therapeutic targets. (Hepatology Communications 2020;4:724-738). P rimary biliary cholangitis (PBC) is a rare chronic autoimmune cholestatic liver disease that predominantly affects middle-aged females. PBC is characterized by lymphocytic cholangitis and gradual destruction of the small intrahepatic bile ducts, which leads to fibrosis, cirrhosis, and

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BAFF and BAFF-Receptor in B Cell Selection and Survival

Cited by 252 publications

References 122 publications

BAFF inhibition in SLE—Is tolerance restored?

BAFF inhibition in SLE—Is tolerance restored?

In vitro Effects of CD8+ Regulatory T Cells on Human B Cell Subpopulations

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

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