The Effect of BAFF Inhibition on Autoreactive B-Cell Selection in Murine Systemic Lupus Erythematosus

Boneparth, Alexis; Woods, Megan; Huang, Weiqing; Akerman, Meredith; Lesser, Martin; Davidson, Anne

doi:10.2119/molmed.2016.00022

Cited by 17 publications

(11 citation statements)

References 42 publications

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“…There is a similar lack of effect of BAFF over-or underexpression on regulation of the autoreactive HKIR transgene, which is also regulated by central tolerance (56). BAFF inhibition has a modest effect on germinal center entry and proliferation of 3H9-positive autoreactive B cells and on selection of the plasma cell repertoire; these effects vary between lupus strains (16). The effect of BAFF inhibition on selection of the human B cell repertoire has not been previously reported.…”

Section: Dn B Cells In Chronic Belimumab-treated Patients Compared Wimentioning

confidence: 88%

“…Nevertheless, the light chain repertoire and clonal diversity of those D42 cells that escape deletion following BAFF inhibition is not substantially altered, and high-affinity autoreactive D42 B cells are still positively selected into the germinal center where they mature to autoreactive plasma cells (55). By contrast, B cells expressing the 3H9 autoreactive V region gene are deleted at the pre-B cell stage in the bone marrow with no additive effect of BAFF inhibition on the stringency of selection of naive 3H9 B cells that escape central deletion (16). There is a similar lack of effect of BAFF over-or underexpression on regulation of the autoreactive HKIR transgene, which is also regulated by central tolerance (56).…”

Section: Dn B Cells In Chronic Belimumab-treated Patients Compared Wimentioning

confidence: 99%

“…Finally, BAFF regulates inflammation through its effects on cytokine release by antigen-presenting cells (12). Conversely, BAFF deficiency delays the onset of lupus through mechanisms that may include altered B cell selection, B cell depletion, and decreased target organ inflammation (13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

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Belimumab promotes negative selection of activated autoreactive B cells in systemic lupus erythematosus patients

Huang¹,

Quách²,

Dascalu³

et al. 2018

JCI Insight

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Belimumab has therapeutic benefit in active systemic lupus erythematosus (SLE), especially in patients with high-titer anti-dsDNA antibodies. We asked whether the profound B cell loss in belimumab-treated SLE patients is accompanied by shifts in the immunoglobulin repertoire. We enrolled 15 patients who had been continuously treated with belimumab for more than 7 years, 17 matched controls, and 5 patients who were studied before and after drug initiation. VH genes of sort-purified mature B cells and plasmablasts were subjected to next-generation sequencing. We found that B cell-activating factor (BAFF) regulates the transitional B cell checkpoint, with conservation of transitional 1 (T1) cells and approximately 90% loss of T3 and naive B cells after chronic belimumab treatment. Class-switched memory B cells, B1 B cells, and plasmablasts were also substantially depleted. Next-generation sequencing revealed no redistribution of VH, DH, or JH family usage and no effect of belimumab on representation of the autoreactive VH4-34 gene or CDR3 composition in unmutated IgM sequences, suggesting a minimal effect on selection of the naive B cell repertoire. Interestingly, a significantly greater loss of VH4-34 was observed among mutated IgM and plasmablast sequences in chronic belimumab-treated subjects than in controls, suggesting that belimumab promotes negative selection of activated autoreactive B cells.

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Section: Dn B Cells In Chronic Belimumab-treated Patients Compared Wimentioning

confidence: 88%

Section: Dn B Cells In Chronic Belimumab-treated Patients Compared Wimentioning

confidence: 99%

See 1 more Smart Citation

Belimumab promotes negative selection of activated autoreactive B cells in systemic lupus erythematosus patients

Huang¹,

Quách²,

Dascalu³

et al. 2018

JCI Insight

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“…Autoantibodies in these mice are predominantly directed toward RNA-associated and phospholipidautoantigens [111][112][113][114][115][116]. Importantly, the various therapeutic approaches resulted in distinct impacts on each model tested, highlighting the complexity of lupus pathogenesis and predicting similar heterogeneity of clinical response in human studies.…”

mentioning

confidence: 99%

“…Finally, NZW/BXSB male mice express an additional copy of TLR7 via the Yaa translocation, produce both GC and EF derived autoantibodies, and develop severe glomerulonephritis and interstitial renal disease. Autoantibodies in these mice are predominantly directed toward RNA-associated and phospholipidautoantigens [111][112][113][114][115][116].…”

mentioning

confidence: 99%

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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