The BAFFling persistence of memory B cells

Brooks, Jeremy F.; Zikherman, Julie

doi:10.1084/jem.20202057

Cited by 3 publications

(2 citation statements)

References 18 publications

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“…Studies have shown that RelB deficiency in humans results in impairment of B cell development, with an absence of CD27+ MBCs leading to severe B cell immunodeficiency and shortage in the secretion of antibodies ( 169 ). Overall, BAFF is required for GC-independent MBC generation, and MBC survival depends on the synergy of BCR- and BAFF-mediated activation of the NFκB pathway ( 170 ).…”

Section: The Nfκb Signaling System In Memory B Cellsmentioning

confidence: 99%

The NFκB signaling system in the generation of B-cell subsets: from germinal center B cells to memory B cells and plasma cells

Roy,

Chakraborty,

Kumar

et al. 2023

Front. Immunol.

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Memory B cells and antibody-secreting cells are the two prime effector B cell populations that drive infection- and vaccine-induced long-term antibody-mediated immunity. The antibody-mediated immunity mostly relies on the formation of specialized structures within secondary lymphoid organs, called germinal centers (GCs), that facilitate the interactions between B cells, T cells, and antigen-presenting cells. Antigen-activated B cells may proliferate and differentiate into GC-independent plasmablasts and memory B cells or differentiate into GC B cells. The GC B cells undergo proliferation coupled to somatic hypermutation of their immunoglobulin genes for antibody affinity maturation. Subsequently, affinity mature GC B cells differentiate into GC-dependent plasma cells and memory B cells. Here, we review how the NFκB signaling system controls B cell proliferation and the generation of GC B cells, plasmablasts/plasma cells, and memory B cells. We also identify and discuss some important unanswered questions in this connection.

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Section: The Nfκb Signaling System In Memory B Cellsmentioning

confidence: 99%

The NFκB signaling system in the generation of B-cell subsets: from germinal center B cells to memory B cells and plasma cells

Roy,

Chakraborty,

Kumar

et al. 2023

Front. Immunol.

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“…Antibodies targeting B cell surface molecules CD20 and CD19 can successfully deplete B cells but do not protect against IgA nephropathy 8 . Because BAFF is considered to drive B cell function and development, 9 this molecule is a potential target of new therapies for autoimmune disease. Several strategies have been developed to block BAFF and APRIL in vivo and have been successful in clinical trials including for SLE 10 …”

mentioning

confidence: 99%

Interleukin-33 Exacerbates IgA Glomerulonephritis in Transgenic Mice Overexpressing B Cell Activating Factor

Wang

Shaw

Zhang

et al. 2022

JASN

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BackgroundThe cytokine IL-33 is an activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation. B cell activating factor (BAFF) plays a central role in B cell proliferation and differentiation, and high levels of this protein cause excess antibody production, including IgA. BAFF-transgenic mice overexpress BAFF and spontaneously develop glomerulonephritis that resembles human IgA nephropathy.MethodsWe administered IL-33 or PBS to wild-type and BAFF-transgenic mice. After treating Rag1-deficient mice with IL-33, with or without anti-CD90.2 to preferentially deplete ILC2s, we isolated splenocytes, which were adoptively transferred into BAFF-transgenic mice.ResultsBAFF-transgenic mice treated with IL-33 developed more severe kidney dysfunction and proteinuria, glomerular sclerosis, tubulointerstitial damage, and glomerular deposition of IgA and C3. Compared with wild-type mice, BAFF-transgenic mice exhibited increases of CD19+ B cells in spleen and kidney and ILC2s in kidney and intestine, which were further increased by administration of IL-33. Administering IL-33 to wild-type mice had no effect on kidney function or histology, nor did it alter the number of ILC2s in spleen, kidney, or intestine. To understand the role of ILC2s, splenocytes were transferred from IL-33–treated Rag1-deficient mice into BAFF-transgenic mice. Glomerulonephritis and IgA deposition were exacerbated by transfer of IL-33–stimulated Rag1-deficient splenocytes, but not by ILC2 (anti-CD90.2)–depleted splenocytes. Wild-type mice infused with IL-33–treated Rag1-deficient splenocytes showed no change in kidney function or ILC2 numbers or distribution.ConclusionsIL-33–expanded ILC2s exacerbated IgA glomerulonephritis in a mouse model. These findings indicate that IL-33 and ILC2s warrant evaluation as possible mediators of human IgA nephropathy.

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Belimumab treatment of adult idiopathic inflammatory myopathy

et al. 2023

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Objective To evaluate belimumab addition to standard of care (SoC) in patents with refractory Idiopathic Inflammatory Myopathy (IIM). Methods We conducted a 40-week multicentre randomized, double-blind, placebo-controlled trial with 1:1 IV belimumab 10 mg/kg or placebo randomization and a 24-week open-label extension. Clinical responses were measured by the Definition of Improvement (DOI) and Total Improvement Score (TIS). Flow cytometry analyses were performed on available samples before randomization, at 24 and 60–64wk. Descriptive statistics, t test, Fisher’s exact test and ANOVA tests were used. Results 17 patients were randomized, 15 received ≥ 5 doses of belimumab or placebo and were included in the intention -to-treat analysis. More belimumab patients vs placebo attained TIS ≥ 40 (55.5% vs 33.3%; p=NS) and achieved DOI (33.3% vs 16.7%; p = NS) at Wk40 and Wk64; mean TIS was similar among groups. Two patients achieved major responses (TIS= 72.5) after Wk40 in the belimumab arm, none in the placebo arm. No improvement in placebo arm after switching to the open label phase was observed. There was no steroid-sparing effect. No new safety signals were detected. Although total B-cells were not reduced, belimumab induced naïve B-cells depletion while enhancing memory B cells number and frequency. Conclusion The study did not meet the primary end point and no statistically significant differences were observed in clinical responses between arms. More patients achieved sustained TIS ≥ 40 and reached DOI. Most patients who received belimumab longer than 40 weeks had clinical improvement. Phenotypic changes in B cell populations were not associated with clinical responses. Clinical trial registration number Clinicaltrials.gov, https://clinicaltrials.gov/, NCT02347891

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The BAFFling persistence of memory B cells

Cited by 3 publications

References 18 publications

The NFκB signaling system in the generation of B-cell subsets: from germinal center B cells to memory B cells and plasma cells

The NFκB signaling system in the generation of B-cell subsets: from germinal center B cells to memory B cells and plasma cells

Interleukin-33 Exacerbates IgA Glomerulonephritis in Transgenic Mice Overexpressing B Cell Activating Factor

Belimumab treatment of adult idiopathic inflammatory myopathy

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