BAFF Regulates Follicular Helper T Cells and Affects Their Accumulation and Interferon‐γ Production in Autoimmunity

Coquery, Christine M.; Loo, William; Wade, Nekeithia S.; Bederman, Annelise G.; Tung, Kenneth S. K.; Lewis, Jacqueline S.; Hess, Henry; Erickson, Loren D.

doi:10.1002/art.38950

Cited by 55 publications

(46 citation statements)

References 52 publications

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“…Sle1.Yaa mice. IL-21 + Tfh cells that coproduce IFN-γ with pathogenic drive have also been reported in other murine lupus models (22, 39, 40), and in our hands, in circulating Tfh-like cells in patients with SLE (our unpublished data). Tfh cells with a similar phenotype are found following viral challenge in mice (41, 42) and humans (43), albeit they are short-lived.…”

Section: Discussionsupporting

confidence: 86%

Disruption of Pathogenic Cellular Networks by IL-21 Blockade Leads to Disease Amelioration in Murine Lupus

Choi

Seth

Kashgarian

et al. 2017

The Journal of Immunology

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Systemic lupus erythematosus (SLE, lupus) is characterized by autoantibody-mediated organ injury. Follicular helper T cells (Tfh) orchestrate physiological germinal center (GC) B cell responses, while in lupus they promote aberrant GC responses with autoreactive memory B cell development and plasma cell-derived autoantibody production. IL-21, a Tfh cell-derived cytokine, provides instructional cues for GC B cell maturation, with disruption of IL-21 signaling representing a potential therapeutic strategy for autoantibody-driven diseases such as SLE. We used blockade of IL-21 to dissect the mechanisms by which this cytokine promotes autoimmunity in murine lupus. Treatment of lupus-prone B6.Sle1.Yaa mice with an anti-IL-21 blocking antibody reduced titers of autoantibodies, delayed progression of glomerulonephritis and diminished renal infiltrating Tfh and T helper 1 (Th1) cells, and improved overall survival. Therapy inhibited excessive accumulation of Tfh cells co-expressing IL-21 and IFN-γ, and suppressed their production of the latter cytokine, albeit while not affecting their frequency. Anti-IL-21 treatment also led to a reduction in GC B cells, CD138hi plasmablasts, IFN-γ-dependent IgG2c production, and autoantibodies, indicating that Tfh-cell derived IL-21 is critical for pathological B cell cues in lupus. Normalization of GC responses were, in part, due to uncoupling of Tfh-B cell interactions, as evidenced by reduced expression of CD40L on Tfh cells and reduced B cell proliferation in treated mice. Our work provides mechanistic insight into the contribution of IL-21 to the pathogenesis of murine lupus, while revealing the importance of T-B cellular cross-talk in mediating autoimmunity, demonstrating that its interruption impacts both cell types leading to disease amelioration.

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Section: Discussionsupporting

confidence: 86%

Disruption of Pathogenic Cellular Networks by IL-21 Blockade Leads to Disease Amelioration in Murine Lupus

Choi

Seth

Kashgarian

et al. 2017

The Journal of Immunology

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“…Splenic T FH and GC B cells were increased in DC- Abca1/g1 deficient mice compared to their controls (Figure S7G–J), and we also observed an increase in short-lived plasma cells that are present in GCs (Figure 7K–L). Further supporting B-cell proliferation and differentiation, and contributing to T FH accumulation (Coquery et al, 2015), plasma levels of B-cell activating factor (BAFF) were increased in DC- Abca1/g1 deficient mice compared to their controls (Figure S7M). In sum, these findings show that deficiency of cholesterol efflux pathways in DCs promotes inflammasome activation and inflammatory cytokine secretion that leads to a dramatic expansion of T h 17 cells, and increases in T h 1 T-cells, T FH cells, GC B-cells, plasma cells, and in BAFF plasma levels, changes which have previously been linked to the development of SLE (Kim et al, 2011; Kyttaris et al, 2010; Pisitkun et al, 2012).…”

Section: Resultsmentioning

confidence: 94%

Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity

et al. 2017

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Summary Autoimmune diseases such as systemic lupus erythematosus (SLE) are associated with increased cardiovascular disease and reduced plasma high-density lipoproteins (HDL) levels. HDL mediates cholesterol efflux from immune cells via the ATP Binding Cassette Transporters A1 and G1 (ABCA1/G1). The significance of impaired cholesterol efflux pathways in autoimmunity is unknown. We observed that Abca1/g1 deficient mice develop enlarged lymph nodes (LNs) and glomerulonephritis suggestive of SLE. This lupus-like phenotype was recapitulated in mice with knockouts of Abca1/g1 in dendritic cells (DCs) but not in macrophages or T-cells. DC-Abca1/g1 deficiency increased LN and splenic CD11b+ DCs, which displayed cholesterol accumulation and inflammasome activation, increased cell surface levels of the GM-CSF receptor, and enhanced inflammatory cytokine secretion. Consequently, DC-Abca1/g1 deficiency enhanced T-cell activation, Th1 and Th17-cell polarization. NLRP3 inflammasome deficiency diminished the enlarged LNs and enhanced Th1-cell polarization. These findings identify an essential role of DC cholesterol efflux pathways in maintaining immune tolerance.

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“…Further, in patients with lupus nephritis, only cognate interactions between Tfh cells and B cells induce high levels of Bcl-6 and IL21 in the renal tubulointerstitium (49). This might occur as a consequence of BAFF promoting the expression of ICOSL on activated B cells (50), and inducing the formation of Tfh cells (51, 52). Thus, renal TLSs may form in lupus nephritis as a consequence of hematopoietic cell infiltration into the kidney, but require high BAFF levels to form or maintain properly compartmentalized TLSs.…”

Section: Discussionmentioning

confidence: 99%

BAFF Induces Tertiary Lymphoid Structures and Positions T Cells within the Glomeruli during Lupus Nephritis

Kang

Fedoriw

Brenneman

et al. 2017

The Journal of Immunology

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Tissue-specific immune responses play an important role in the pathology of autoimmune diseases. In systemic lupus erythematosus (SLE), deposits of IgG-immune complexes and the activation of complement in the kidney have long been thought to promote inflammation and lupus nephritis. However, the events that localize cells in non-lymphoid tertiary organs and sustain tissue-specific immune responses remain undefined. In this manuscript, we show that B cell activating factor of the TNF family (BAFF) promotes events leading to lupus nephritis. Using an inducible model of SLE, we found that passive transfer of anti-nucleosome IgG into AID−/−MRL/lpr mice elevated autoantibody levels and promoted lupus nephritis by inducing BAFF production in the kidneys, and the formation of renal tertiary lymphoid structures (TLSs). Reducing BAFF in vivo prevented the formation of TLSs and lupus nephritis; however, it did not reduce immune cell infiltrates, or the deposits of IgG and complement in the kidney. Mechanistically, lowering BAFF levels also diminished the number of T cells positioned inside the glomeruli and reduced inflammation. Thus, BAFF plays a previously unappreciated role in lupus nephritis by inducing renal TLSs and regulating the position of T cells within the glomeruli.

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BAFF Regulates Follicular Helper T Cells and Affects Their Accumulation and Interferon‐γ Production in Autoimmunity

Cited by 55 publications

References 52 publications

Disruption of Pathogenic Cellular Networks by IL-21 Blockade Leads to Disease Amelioration in Murine Lupus

Disruption of Pathogenic Cellular Networks by IL-21 Blockade Leads to Disease Amelioration in Murine Lupus

Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity

BAFF Induces Tertiary Lymphoid Structures and Positions T Cells within the Glomeruli during Lupus Nephritis

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