Interferon‐α accelerates murine systemic lupus erythematosus in a T cell–dependent manner

Liu, Zheng; Bethunaickan, Ramalingam; Huang, Weiqing; Lodhi, Umairullah; Solano, Ingrid; Madaio, Michael P.; Davidson, Anne

doi:10.1002/art.30087

Cited by 124 publications

(121 citation statements)

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“…Commentary of TLR7 on B cells, T-cell-independent expansion of marginal zone B cells and high serum levels of BAFF and IL-6, autoantibody production, and clinical disease in this murine model of SLE is absolutely T-cell dependent [9]. Considering the large number of germinal centers that form, it is surprising that the multitude of plasma cells that arise 2-3 wk following IFN-a induction and persist throughout the disease are short-lived and that they fail to migrate to the BM or the inflamed kidney or survive for long periods in the spleen [8,9].…”

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confidence: 90%

“…Considering the large number of germinal centers that form, it is surprising that the multitude of plasma cells that arise 2-3 wk following IFN-a induction and persist throughout the disease are short-lived and that they fail to migrate to the BM or the inflamed kidney or survive for long periods in the spleen [8,9].…”

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confidence: 99%

“…Liu et al [9] showed a defect in BM expression of CXCL12 and VCAM-1 in IFN-a-induced NZB/W mice. Suppression of CXCL12 in the BM by TNFa, a cytokine that is upregulated in the IFN-a-induced model, is a feature of acute inflammation that promotes lymphoid cell mobilization from the BM [22].…”

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confidence: 99%

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Plasma cells in systemic lupus erythematosus: The long and short of it all

2011

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Plasma cells can be classified as long-or short-lived. The lifespan of a plasma cell largely depends on whether it arises from a germinal center or an extrafollicular locus and most importantly whether it can find a survival niche in the spleen or BM. In systemic lupus erythematosus (SLE) patients, long-lived plasma cells are believed to be responsible for the production of anti-RNA and anti-cardiolipin antibodies, whereas short-lived plasma cells, which are more susceptible to anti-proliferation therapies, are the main producers of anti-DNA antibodies. A previous study showed that transient overexpression of interferon-a (IFN-a), a cytokine that plays a pathogenic role in SLE, accelerates disease onset in lupusprone NZB/W mice. In this issue of the European Journal of Immunology, the same group report that IFN-a induces large numbers of short-lived plasma cells, accompanied by high titers of anti-dsDNA antibodies in NZB/W, but not BALB/c, mice. Our commentary discusses this interesting observation in the context of the previous data regarding plasma cell differentiation and conveys our view about the clinical implications with respect to therapies that target plasma cells in SLE patients.Keywords: Interferon-a . Plasma cells . Systemic lupus erythematosus See accompanying article by Mathian et al.Type I IFNs are believed to play a significant role in systemic lupus erythematosus (SLE) pathogenesis. IFN-a facilitates the maturation of myeloid DC that contribute to T-cell activation and follicular T-helper cell differentiation [1], and that produce the B-cell survival factor B-cell activating factor (BAFF) [2]. IFN-a also directly stimulates CD4 T cells to enhance antigen-specific B-cell activation, increases TLR7 expression in B cells, and promotes T-independent B-cell proliferation and differentiation into early plasmablasts [3]. In several lupus-prone mouse strains, type I IFNs accelerate the break in B-cell tolerance to nucleic acids that occurs spontaneously in these mice with age [4][5][6]. Nucleic acid-containing immune complexes, in turn, can activate intracellular TLRs, resulting in further release of type I IFNs and pro-inflammatory cytokines [7].Consistent with the known biologic functions of IFN-a, Mathian et al. [8] show in this issue of the European Journal of Immunology that NZB/W mice treated with a small dose of IFN-aexpressing adenovirus develop increased serum levels of BAFF, IL-6, and TNFa, and high titers of anti-dsDNA antibodies. In contrast, nonautoimmune BALB/c mice maintain tolerance to self-antigens despite IFN-a-induced upregulation of inflammatory mediators. This indicates that a genetic predisposition is required for IFN-a to initiate autoimmunity and may explain the reason why only few patients develop SLE during type I IFN therapy [3].The findings reported by Mathian et al. [8] complement the recent studies by our group, showing that IgG2a autoantibodies in IFN-a-induced NZB/W mice were derived from germinal centers, whereas IgG3 autoantibodies were derived predominantly from extra...

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Plasma cells in systemic lupus erythematosus: The long and short of it all

2011

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“…We hypothesized that this feature might be regulated by type I IFN. IFN acts subsequent to high-affinity somatic mutations that occur within the GC reactions via the downregulation of chemotactic molecules involved in the migration of newly formed PCs to the bone marrow (72)(73)(74)(75). Our study demonstrated that B6.Sle1 lupusprone animals have an upregulated IFN signature early in life, before expansion of ASCs can be detected.…”

Section: Cd8mentioning

confidence: 64%

Loss of Immune Tolerance Is Controlled by ICOS in Sle1 Mice

Mittereder¹,

Kuta²,

Bhat³

et al. 2016

The Journal of Immunology

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ICOS, a member of the CD28 family, represents a key molecule that regulates adaptive responses to foreign Ags. ICOS is prominently expressed on T follicular helper (TFH) cells, a specialized CD4+ T cell subset that orchestrates B cell differentiation within the germinal centers and humoral response. However, the contribution of ICOS and TFH cells to autoantibody profiles under pathological conditions has not been thoroughly investigated. We used the Sle1 lupus-prone mouse model to examine the role of ICOS in the expansion and function of pathogenic TFH cells. Genetic deletion of ICOS impacted the expansion of TFH cells in B6.Sle1 mice and inhibited the differentiation of B lymphocytes into plasma cells. The phenotypic changes observed in B6.Sle1-ICOS–knockout mice were also associated with a significant reduction in class-switched IgG, and anti-nucleosomal IgG-secreting B cells compared with B6.Sle1 animals. The level of vascular cell adhesion protein 1, a molecule that was shown to be elevated in patients with SLE and in lupus models, was also increased in an ICOS-dependent manner in Sle1 mice and correlated with autoantibody levels. The elimination of ICOS-expressing CD4+ T cells in B6.Sle1 mice, using a glyco-engineered anti-ICOS–depleting Ab, resulted in a significant reduction in anti-nucleosomal autoantibodies. Our results indicate that ICOS regulates the ontogeny and homeostasis of B6.Sle1 TFH cells and influences the function of TFH cells during aberrant germinal center B cell responses. Therapies targeting the ICOS signaling pathway may offer new opportunities for the treatment of lupus and other autoimmune diseases.

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“…Spleen and bone marrow B cells were analyzed as previously described (21,26,27 (20). Somatic mutation rates were calculated by using a program available on the IMGT website.…”

Section: Flow Cytometry and Sortingmentioning

confidence: 99%