Myeloid cells, BAFF, and IFN-γ establish an inflammatory loop that exacerbates autoimmunity in Lyn-deficient mice

Abstract

Autoimmunity is traditionally attributed to altered lymphoid cell selection and/or tolerance, whereas the contribution of innate immune cells is less well understood. Autoimmunity is also associated with increased levels of B cell–activating factor of the TNF family (BAFF; also known as B lymphocyte stimulator), a cytokine that promotes survival of self-reactive B cell clones. We describe an important role for myeloid cells in autoimmune disease progression. Using Lyn-deficient mice, we show that overproduction of BAFF by hyperactive myeloid cells contributes to inflammation and autoimmunity in part by acting directly on T cells to induce the release of IFN-γ. Genetic deletion of IFN-γ or reduction of BAFF activity, achieved by either reducing myeloid cell hyperproduction or by treating with an anti-BAFF monoclonal antibody, reduced disease development in lyn−/− mice. The increased production of IFN-γ in lyn−/− mice feeds back on the myeloid cells to further stimulate BAFF release. Expression of BAFF receptor on T cells was required for their full activation and IFN-γ release. Overall, our data suggest that the reciprocal production of BAFF and IFN-γ establishes an inflammatory loop between myeloid cells and T cells that exacerbates autoimmunity in this model. Our findings uncover an important pathological role of BAFF in autoimmune disorders.

Hck Tyrosine Kinase Regulates TLR4-Induced TNF and IL-6 Production via AP-1

“…Different SFKs have also been shown to recognize different substrates (43), and this combined with the sequential regulation of Hck and Src may explain why different SFK family members play distinct roles within a single cell type. A recent publication by Keck et al (44) demonstrated that the ablation of Lyn in murine macrophages actually resulted in increased TNF, IL-6, and IFNa/b, and there is exacerbated autoimmunity in these mice (45). Thus, the lack of effect in the triple SFK knockouts may be because of not only functional redundancy, but may also be attributed to the kinases having both positive and negative effects on cytokine production.…”

Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation

“…Lungs, liver, skin, and kidneys were processed and stained with H&E by the UCSF Pathology core. Kidneys were snap-frozen in optimal cutting temperature compound and 5-μm sections were stained for C3 as previously described (2). For detection of ANA, sera were diluted 1:40 and used for detection of ANAs on fixed Hep-2 ANA slides (Bio-Rad Laboratories) and revealed with FITC-conjugated goat anti-mouse IgG (Jackson ImmunoResearch Laboratories, Inc.).…”

“…Recent findings from our laboratory demonstrate that (i) in vitro, lyn −/− DCs secrete high levels of cytokines associated with autoimmunity; (ii) in vivo, the increase in serum levels of some of these cytokines precedes the generation of autoantibodies; and (iii) deletion of Lyn in myeloid cells in lyn −/− rag-1 −/− doublemutant mice causes myeloid expansion, suggesting that the myeloproliferative phenotype observed in lyn −/− mice is only partly dependent on B-cell-mediated autoimmunity (2). Hence, we hypothesized that the autoimmunity in lyn −/− mice is not only due to defects in B cells, but also to the hyperactivation of cells from myeloid and dendritic cell lineages.…”

“…Given that autoantibody production is a hallmark of SLE, most studies have focused on alterations of B-cell tolerance as the main initiator of disease. However, T and myeloid cells are also key players in the pathogenesis of SLE (1,2). Myeloid expansion is also often observed in SLE, and myeloid-derived cytokines have been found to be major contributors to disease progression in animal models.…”

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

“…TFH, in turn, produces BAFF, and this may enhance the survival and selection of high-affinity B cells (18). Furthermore, activated T cells are also responsive to BAFF, releasing interferon-γ that amplifies autoimmune effector responses (19). The ability of BAFF inhibition to regulate plasma cells that arise either from naive autoreactive B cells or from the GC has not been fully explored in spontaneous models of SLE.…”