IgG-Immune Complexes Promote B Cell Memory by Inducing BAFF

Kang, Sun Ah; Keener, Amanda B.; Jones, Shannon; Benschop, Robert J.; Caro‐Maldonado, Alfredo; Rathmell, Jeffrey C.; Clarke, Stephen H.; Matsushima, Glenn K.; Whitmire, Jason K.; Vilen, Barbara J.

doi:10.4049/jimmunol.1402527

Cited by 19 publications

(22 citation statements)

References 88 publications

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“…Consistent with a higher metabolism, KBN CD4 + T cells and B cells also showed a higher mTORC1 activation as measured by pS6, pE4-BP and CD98 expression, as compared to KRN (Figure 1D ). Overall, these results show that consistent with their autoantibody production for B cells ( 20 ) and their enhance effector functions for CD4 + T cells ( 1 ), KBN lymphocytes are more metabolically active than KRN controls.…”

Section: Resultssupporting

confidence: 57%

Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis

et al. 2018

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The K/BxN mouse is a spontaneous model of arthritis driven by T cell receptor transgenic CD4+ T cells from the KRN strain that are activated by glucose-6-phosphate isomerase (GPI) peptides presented by the H-2g7 allele from the NOD strain. It is a model of autoimmune seropositive arthritis because the production of anti-GPI IgG is necessary and sufficient for joint pathology. The production of high levels of anti-GPI IgG requires on the expansion of CD4+ follicular helper T (Tfh) cells. The metabolic requirements of this expansion have never been characterized. Based on the therapeutic effects of the combination of metformin and 2-deoxyglucose (2DG) in lupus models that normalized the expansion of effector CD4+ T cells. We showed that the CD4+ T cells and to a lesser extent, the B cells from K/BxN mice are more metabolically active than the KRN controls. Accordingly, preventive inhibition of glycolysis with 2DG significantly reduced joint inflammation and the activation of both adaptive and innate immune cells, as well as the production of pathogenic autoantibodies. However, contrary to the lupus-prone mice, the addition of metformin had little beneficial effect, suggesting that glycolysis is the major driver of immune activation in this model. We propose that K/BxN mice are another model in which autoreactive Tfh cells are highly glycolytic and that their function can be limited by inhibiting glucose metabolism.

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Section: Resultssupporting

confidence: 57%

Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis

et al. 2018

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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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“…On the basis of previous work suggesting that MLL1 influences immune cell function, we investigated the role of MLL1 in directing macrophage-mediated inflammation during both normal and pathological wound healing (17,19,20,25). Specifically, by using a myeloid-specific MLL1 knockout ( Mll1 f/f Lyz2 Cre+ ), we demonstrate that MLL1 is necessary for an adequate early inflammatory response in normal wound healing and that the absence of MLL1 delays wound healing.…”

Section: Introductionmentioning

confidence: 99%

The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes

et al. 2017

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Macrophages are critical for the initiation and resolution of the inflammatory phase of wound repair. In diabetes, macrophages display a prolonged inflammatory phenotype in late wound healing. Mixed-lineage leukemia-1 (MLL1) has been shown to direct gene expression by regulating nuclear factor-κB (NF-κB)–mediated inflammatory gene transcription. Thus, we hypothesized that MLL1 influences macrophage-mediated inflammation in wound repair. We used a myeloid-specific Mll1 knockout (Mll1f/fLyz2Cre+) to determine the function of MLL1 in wound healing. Mll1f/fLyz2Cre+ mice display delayed wound healing and decreased wound macrophage inflammatory cytokine production compared with control animals. Furthermore, wound macrophages from Mll1f/fLyz2Cre+ mice demonstrated decreased histone H3 lysine 4 trimethylation (H3K4me3) (activation mark) at NF-κB binding sites on inflammatory gene promoters. Of note, early wound macrophages from prediabetic mice displayed similarly decreased MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines compared with controls. Late wound macrophages from prediabetic mice demonstrated an increase in MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines. Prediabetic macrophages treated with an MLL1 inhibitor demonstrated reduced inflammation. Finally, monocytes from patients with type 2 diabetes had increased Mll1 compared with control subjects without diabetes. These results define an important role for MLL1 in regulating macrophage-mediated inflammation in wound repair and identify a potential target for the treatment of chronic inflammation in diabetic wounds.

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IgG-Immune Complexes Promote B Cell Memory by Inducing BAFF

Cited by 19 publications

References 88 publications

Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis

Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis

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

The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes

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