Autoimmune Disease in Lyn-Deficient Mice Is Dependent on an Inflammatory Environment Established by IL-6

Tsantikos, Evelyn; Oracki, Sarah A.; Quilici, Cathy; Anderson, Gary P.; Tarlinton, David M.; Hibbs, Margaret L.

doi:10.4049/jimmunol.0901878

Cited by 75 publications

(130 citation statements)

References 69 publications

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“…With age, lyn −/− mice develop an inflammatory and autoimmune disease that is characterized by increased production of proinflammatory cytokines such as BAFF, IFN-γ, and IL-6 (14,36). Serum levels of the anti-inflammatory cytokine IL-10 were also elevated in lyn −/− mice at 2 mo of age and progressively increased, reaching a plateau at approximately 4-6 mo of age (Fig.…”

Section: Il-10 Deficiency Dramatically Increases Splenomegaly and Lymmentioning

confidence: 92%

“…IL-10 is a well known suppressor of proinflammatory cytokine production by several cell types, including myeloid cells (17,18). Deregulation of cytokine production plays an important role in the inflammatory/autoimmune disease developed by lyn −/− mice (14,36). We therefore investigated whether IL-10 deficiency caused increased proinflammatory cytokine production in lyn reported (*P < 0.05; **P < 0.01; ***P < 0.001).…”

Section: Il-10mentioning

confidence: 99%

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B cell-derived IL-10 suppresses inflammatory disease in Lyn-deficient mice

Scapini

Lamagna²,

Hu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Lyn kinase deficient mice represent a well established genetic model of autoimmune/autoinflammatory disease that resembles systemic lupus erythematosus. We report that IL-10 plays a crucial immunosuppressive role in this model, modulating the inflammatory component of the disease caused by myeloid and T-cell activation. Double-mutant lyn −/− IL-10 −/− mice manifested severe splenomegaly and lymphadenopathy, dramatically increased proinflammatory cytokine production, and severe tissue inflammation. Single-mutant lyn −/− mice showed expansion of IL-10–producing B cells. Interestingly, WT B cells adoptively transferred into lyn −/− mice showed increased differentiation into IL-10–producing B cells that assumed a similar phenotype to endogenous lyn −/− IL-10–producing B cells, suggesting that the inflammatory environment present in lyn −/− mice induces IL-10–producing B-cell differentiation. B cells, but not T or myeloid cells, were the critical source of IL-10 able to reduce inflammation and autoimmunity in double mutant lyn −/− IL-10 −/− mice. IL-10 secretion by B cells was also crucial to sustain transcription factor Forkhead Box P3 (Foxp3) expression in regulatory T cells during disease development. These data reveal a dominant immunosuppressive function of B-cell–derived IL-10 in the Lyn-deficient model of autoimmunity, extending our current understanding of the role of IL-10 and IL-10–producing B cells in systemic lupus erythematosus.

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Section: Il-10 Deficiency Dramatically Increases Splenomegaly and Lymmentioning

confidence: 92%

Section: Il-10mentioning

confidence: 99%

B cell-derived IL-10 suppresses inflammatory disease in Lyn-deficient mice

Scapini

Lamagna²,

Hu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…We think this experiment differs substantially from our study because the T cell-deficient BAFF-Tg mice displayed IgG antinuclear antibodies, yet this aspect of the disease does not dominate our colony. It is possible that these seemingly disparate observations may reflect on an important yet ill-defined interplay between IgG and IgA immune responses, as discussed above, potentially as exemplified by the Lyn -/-mice (48).…”

Section: Discussionmentioning

confidence: 99%

Mice overexpressing BAFF develop a commensal flora–dependent, IgA-associated nephropathy

McCarthy¹,

Kujawa²,

Wilson³

et al. 2011

J. Clin. Invest.

215

165

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B cell activation factor of the TNF family (BAFF) is a potent B cell survival factor. BAFF overexpressing transgenic mice (BAFF-Tg mice) exhibit features of autoimmune disease, including B cell hyperplasia and hypergammaglobulinemia, and develop fatal nephritis with age. However, basal serum IgA levels are also elevated, suggesting that the pathology in these mice may be more complex than initially appreciated. Consistent with this, we demonstrate here that BAFF-Tg mice have mesangial deposits of IgA along with high circulating levels of polymeric IgA that is aberrantly glycosylated. Renal disease in BAFF-Tg mice was associated with IgA, because serum IgA was highly elevated in nephritic mice and BAFF-Tg mice with genetic deletion of IgA exhibited less renal pathology. The presence of commensal flora was essential for the elevated serum IgA phenotype, and, unexpectedly, commensal bacteria-reactive IgA antibodies were found in the blood. These data illustrate how excess B cell survival signaling perturbs the normal balance with the microbiota, leading to a breach in the normal mucosal-peripheral compartmentalization. Such breaches may predispose the nonmucosal system to certain immune diseases. Indeed, we found that a subset of patients with IgA nephropathy had elevated serum levels of a proliferation inducing ligand (APRIL), a cytokine related to BAFF. These parallels between BAFF-Tg mice and human IgA nephropathy may provide a new framework to explore connections between mucosal environments and renal pathology.

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“…Besides, IL-6 is elevated in the cerebrospinal fluid (CSF) or peripheral blood of NMO patients compared with that of CMS patients and HS (27,28). In a rodent autoimmunity model, IL-6 deficiency caused impaired autoantibody secretion by B cells (29). Given the potential role of IL-6 in NMO, we performed flow cytometry analysis for the expression of IL-6R.…”

Section: Expanded Cells Resemble Early Plasma Cells In Gene Expressiomentioning

confidence: 99%

Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica

Chihara

Aranami

Sato

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

380

297

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Neuromyelitis optica (NMO) is an inflammatory disease affecting the optic nerve and spinal cord, in which autoantibodies against aquaporin 4 (AQP4) water channel protein probably play a pathogenic role. Here we show that a B-cell subpopulation, exhibiting the CD19 int CD27 high CD38 high CD180 − phenotype, is selectively increased in the peripheral blood of NMO patients and that anti-AQP4 antibodies (AQP4-Abs) are mainly produced by these cells in the blood of these patients. These B cells showed the morphological as well as the phenotypical characteristics of plasmablasts (PB) and were further expanded during NMO relapse. We also demonstrate that interleukin 6 (IL-6), shown to be increased in NMO, enhanced the survival of PB as well as their AQP4-Ab secretion, whereas the blockade of IL-6 receptor (IL-6R) signaling by anti-IL-6R antibody reduced the survival of PB in vitro. These results indicate that the IL-6-dependent B-cell subpopulation is involved in the pathogenesis of NMO, thereby providing a therapeutic strategy for targeting IL-6R signaling.neuroinflamatory disease | autoimmunity | multiple sclerosis | central nervous system | IL-6 receptor blockade N euromyelitis optica (NMO) is an inflammatory demyelinating disorder characterized by recurrent attacks of severe optic neuritis and myelitis. Unlike the conventional form of multiple sclerosis (CMS), the lesions of NMO tend to spare the cerebral white matter, especially during the early stage (1), and even a single episode of attack can cause serious neurological deficits such as total blindness and paraplegia. Accordingly, accumulation of irreversible damage to the central nervous system (CNS) along with rapid progression of disability is more frequently found in NMO compared with CMS (2).NMO can be distinguished from CMS by clinical, neuroimaging, and serological criteria (3). It is now known that serum anti-aquaporin 4 (AQP4) autoantibodies can be used as a disease marker of NMO (1, 2). AQP4 is the most abundantly expressed water channel protein in the CNS and is highly expressed in the perimicrovessel astrocyte foot processes, glia limitans, and ependyma (4). Emerging clinical and pathological observations suggest that anti-AQP4 antibodies (AQP4-Abs) play a key role in the pathogenesis of NMO. Prior studies have documented a significant correlation of serum AQP4-Ab levels with the therapeutic efficacy of plasma exchange during clinical exacerbations of NMO (2, 5). In the CNS lesions of NMO, reduced expression of AQP4 on astrocytes is evident even during the early stage (6), which is followed by the occurrence of vasculocentric destruction of astrocytes associated with perivascular deposition of complement and IgG (7).On the other hand, recent studies have suggested that AQP4-Abs alone are incapable of causing the clinical and pathological features of NMO. In fact, Hinson et al. emphasized the role of cellular immunity in combination with AQP4-Abs by showing that the attack severity of NMO was not correlated with serum AQP4-Ab levels (8). It was also d...

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Autoimmune Disease in Lyn-Deficient Mice Is Dependent on an Inflammatory Environment Established by IL-6

Cited by 75 publications

References 69 publications

B cell-derived IL-10 suppresses inflammatory disease in Lyn-deficient mice

B cell-derived IL-10 suppresses inflammatory disease in Lyn-deficient mice

Mice overexpressing BAFF develop a commensal flora–dependent, IgA-associated nephropathy

Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica

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