Cutting Edge: BAFF Overexpression Reduces Atherosclerosis via TACI-Dependent B Cell Activation

Jackson, Shaun W.; Scharping, Nicole E.; Jacobs, Holly M.; Wang, Shari; Chait, Alan; Rawlings, David J.

doi:10.4049/jimmunol.1601198

Cited by 39 publications

(26 citation statements)

References 46 publications

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“…Furthermore, there may be additional mechanisms through increased plasma BAFF levels, as a result of B cell deficiency. BAFF, a critical survival factor for B cells, has anti-inflammatory effects as BAFF overexpression or neutralization reduced atherosclerosis (47,48). In addition to BAFF Receptor (BAFFR), BAFF also interacts with B cell maturation antigen (BCMA), and TNFR homolog transmembrane activator and Ca 2+ modulator and CAML interactor (TACI).…”

Section: Discussionmentioning

confidence: 99%

B Cell and CD4 T Cell Interactions Promote Development of Atherosclerosis

et al. 2020

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Interaction between B and CD4 T cells is crucial for their optimal responses in adaptive immunity. Immune responses augmented by their partnership promote chronic inflammation. Here we report that interaction between B and CD4 T cells augments their atherogenicity to promote lipid-induced atherosclerosis. Genetic deletion of the gene encoding immunoglobulin mu (µ) heavy chain (µMT) in ApoE −/− mice resulted in global loss of B cells including those in atherosclerotic plaques, undetectable immunoglobulins and impaired germinal center formation. Despite unaffected numbers in the circulation and peripheral lymph nodes, CD4 T cells were also reduced in spleens as were activated and memory CD4 T cells. In hyperlipidemic µMT −/− ApoE −/− mice, B cell deficiency decreased atherosclerotic lesions, accompanied by absence of immunoglobulins and reduced CD4 T cell accumulation in lesions. Adoptive transfer of B cells deficient in either MHCII or co-stimulatory molecule CD40, molecules required for B and CD4 T cell interaction, into B cell-deficient µMT −/− ApoE −/− mice failed to increase atherosclerosis. In contrast, wildtype B cells transferred into µMT −/− ApoE −/− mice increased atherosclerosis and increased CD4 T cells in lesions including activated and memory CD4 T cells. Transferred B cells also increased their expression of atherogenic cytokines IL-1β, TGF-β, MCP-1, M-CSF, and MIF, with partial restoration of germinal centers and plasma immunoglobulins. Our study demonstrates that interaction between B and CD4 T cells utilizing MHCII and CD40 is essential to augment their function to increase atherosclerosis in hyperlipidemic mice. These findings suggest that targeting B cell and CD4 T cell interaction may be a therapeutic strategy to limit atherosclerosis progression.

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Section: Discussionmentioning

confidence: 99%

B Cell and CD4 T Cell Interactions Promote Development of Atherosclerosis

et al. 2020

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“…Interaction of BAFF with BAFF-R on immature B cells promotes their differentiation into the transitional stage, and immature B cells with minimal BAFF-R levels have been associated with an autoreactive phenotype (48). In accord, decreased Baff-R expression as observed in Mifdeficient B cells may favor BAFF signaling over its lower affinity receptor TACI, which has been shown to increase autoantibody titers against modified LDL in atherosclerosis (49). Moreover, pan B cells in Mif 2/2 Apoe 2/2 BM showed an increased expression of Bcl-2, which has been associated with delayed elimination of self-reactive B cells (33).…”

Section: Discussionmentioning

confidence: 99%

Mif ‐deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis

et al. 2018

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The inflammatory cytokine macrophage migration-inhibitory factor (MIF) promotes atherosclerosis via lesional monocyte and T-cell recruitment. B cells have emerged as important components in atherogenesis, but the interaction between MIF and B cells in atherogenesis is unknown. Here, we investigated the atherosclerotic phenotype of Mif-gene deletion in Apoe mice. Apoe Mif mice fed a Western diet exhibited strongly reduced atherosclerotic lesions in brachiocephalic artery (BC) and abdominal aorta compared with controls. This phenotype was accompanied by reduced circulating B cells. Flow cytometry revealed a B-cell developmental defect with increased premature and immature B-cell counts in bone marrow (BM) of Apoe Mif mice and diminished B-cell numbers in spleen. This finding was linked with a decreased expression of Baff-R and differentiation-driving transcription factors at the immature B-cell stage, whereas peritoneal B cells exhibited unchanged CD80 and CD86 expression but vastly decreased CD9 and elevated CD23 levels, indicating that the developmental block favors the generation of immature, egressing, and reactive B cells. Mif deficiency did not affect absolute B-cell numbers in the vessel wall but favored a relative increase of B cells in the atheroprone BC region and the appearance of periadventitial B-cell-rich clusters. Of note, Mif mice exhibited a significant increase in oxidized low-density lipoprotein (oxLDL)-specific antibodies after the injection of oxLDL, indicating that Mif deficiency is associated with higher sensitivity of B cells against natural-occurring antigens such as oxLDL. Importantly, Apoe mice adoptively transplanted with ApoeMif BM showed reduced peripheral B cells compared with Apoe BM transplantation but no atheroprotection in the BC; also, whereas there was a selective increase in atheroprotective IgM-anti-oxLDL-antibodies in global Mif deficiency, BM-specific Mif deficiency also led to elevated proatherogenic anti-oxLDL-IgG. Together, these findings reveal a novel link between MIF and B cells in atherogenesis. Protection from atherosclerosis by Mif deficiency is associated with enhanced B-cell hypersensitivity, which in global but not BM-restricted Mif deficiency favors an atheroprotective autoantibody profile in atherosclerotic mice. Targeting MIF may induce protective B-cell responses in atherosclerosis.-Schmitz, C., Noels, H., El Bounkari, O., Straussfeld, E., Megens, R. T. A., Sternkopf, M., Alampour-Rajabi, S., Krammer, C., Tilstam, P. V., Gerdes, N., Bürger, C., Kapurniotu, A., Bucala, R., Jankowski, J., Weber, C., Bernhagen, J. Mif-deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis.

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“…135,136 In murine arthritis, BAFF-silenced synovial dendritic cells remained immature and were unable to support T-helper type 17 (Th17) differentiation. 141,142 Mechanistically, BAFF-dependent TACI signals in atheroma M1 macrophages decreased the production of the pro-atherogenic chemokine CXCL10, resulting in accelerated atherosclerosis after global and myeloid-specific TACI deletion. For example, an intriguing new study showed that TACI-dependent production of the regulatory cytokine IL-10 by IgA + plasma cells protected against experimental autoimmune encephalomyelitis (EAE) in BAFF-Tg mice.…”

Section: Other Effec Ts Of Baff Inhib Iti On On Infl Ammationmentioning

confidence: 99%

“…Similarly, whereas global and B cellspecific BAFF-R deletion protected against atherosclerosis, BAFF neutralization increased and BAFF overexpression limited atheroma formation in mouse models. 141,142 Mechanistically, BAFF-dependent TACI signals in atheroma M1 macrophages decreased the production of the pro-atherogenic chemokine CXCL10, resulting in accelerated atherosclerosis after global and myeloid-specific TACI deletion. 141 Since elevated serum BAFF levels are associated with increased atherosclerosis risk in human SLE, 143 the clinical relevance of these animal models to human lupus is unclear.…”

Section: Other Effec Ts Of Baff Inhib Iti On On Infl Ammationmentioning

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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Cutting Edge: BAFF Overexpression Reduces Atherosclerosis via TACI-Dependent B Cell Activation

Cited by 39 publications

References 46 publications

B Cell and CD4 T Cell Interactions Promote Development of Atherosclerosis

B Cell and CD4 T Cell Interactions Promote Development of Atherosclerosis

Mif ‐deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis

BAFF inhibition in SLE—Is tolerance restored?

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